Cancer Research and Treatment

Silence of Transmembrane Channel-Like 5 Inhibits Cell Proliferation, Migration, and Invasion While Promoting Apoptosis Via Deactivating the AKT Pathway in Breast Cancer: Jinnan Wan, Yang Li, Zhimin Liu; Received July 30, 2025 Accepted December 7, 2025 Published online December 9, 2025; DOI: https://doi.org/10.4143/crt.2025.805 [Accepted]

Abstract PDF: Purpose
Transmembrane channel-like 5 (TMC5) plays a tumor-promoting role in the progression of various tumors. However, its effect on regulating breast cancer cell function remains scarce. The current study aimed to evaluate the effect of TMC5 silence on the proliferation, apoptosis, migration, and invasion of breast cancer cell lines.
Materials and Methods
TMC5-specific small interfering RNA (siTMC5) and siNC were transfected into MDA-MB-231 and MCF-7 cell lines; subsequently, the 740Y-P was co-cultured. Then, the proliferation, apoptosis, migration, invasion, and p-AKT expression were determined.
Results
In MDA-MB-231 and MCF-7 cell lines, silence of TMC5 could reduce the proliferation rate at 48 hours (h) and 72 h, migration rate, and invasion rate, while elevate the apoptosis rate. Besides, silence of TMC5 could decrease the p-AKT/AKT expression. The combination of 740Y-P with the silence of TMC5 could reversely increase the proliferation rate at 48h and 72h, migration rate, and invasion rate compared with the silence of TMC5 only. The apoptosis rate showed the opposite trend.
Conclusion
The silence of TMC5 could inhibit the proliferation, migration, and invasion while promoting the apoptosis of breast cancer, while more in vivo validation is needed to explore its potential to be a treatment target for patients with breast cancer.

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Zolbetuximab Plus Chemotherapy as First-Line Treatment in Patients with Claudin 18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma: Korean Population Subgroup—Combined Efficacy and Safety Analysis from SPOTLIGHT and GLOW: Keun-Wook Lee, Sang Cheul Oh, Jong Gwang Kim, Sun Jin Sym, Byoung Yong Shim, Seok Yun Kang, In-Ho Kim, Jwa Hoon Kim, Hong Jae Chon, Sang-Hee Cho, Eun-Kee Song, Do-Youn Oh, Jin-Soo Kim, Young Iee Park, Won Ki Kang, Hyung-Don Kim, Janise Lee, Miri Yi, Min-Hee Ryu; Received August 28, 2025 Accepted December 4, 2025 Published online December 5, 2025; DOI: https://doi.org/10.4143/crt.2025.935 [Accepted]

Abstract PDF: Purpose
The phase 3 SPOTLIGHT and GLOW trials, in patients with claudin 18 isoform 2–positive, human epidermal growth factor receptor 2–negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) with first-line zolbetuximab plus chemotherapy versus placebo plus chemotherapy. This analysis evaluated efficacy and safety in the Korean subgroup from SPOTLIGHT and GLOW.
Materials and Methods
Patients were randomized 1:1 to receive zolbetuximab plus chemotherapy or placebo plus chemotherapy (mFOLFOX6 [modified folinic acid, 5-fluorouracil, and oxaliplatin] or CAPOX [capecitabine and oxaliplatin]). Primary endpoint was PFS, assessed per RECIST v1.1 by independent review committee. Other efficacy and safety parameters were assessed.
Results
The Korean subgroup consisted of 49 patients in the zolbetuximab group and 47 in the placebo group. Median PFS (95% confidence interval [CI]) was 12.3 months (7.3-15.3), and median OS was 30.5 months (16.1-45.5) with zolbetuximab versus 8.1 months (4.2-10.4) and 15.8 months (11.8-19.7) with placebo, respectively. Most common TEAEs in patients who received zolbetuximab versus placebo were nausea (79.6% vs. 53.2%), vomiting (55.1% vs. 21.3%), and decreased appetite (53.1% vs. 23.4%). Treatment-related TEAEs led to discontinuation of zolbetuximab and placebo in 4.1% and 2.1% of patients, respectively.
Conclusion
Zolbetuximab plus chemotherapy demonstrated favorable PFS and OS versus placebo plus chemotherapy in the Korean subgroup, with numerically greater efficacy compared with the overall pooled population. This may be potentially attributable to low rates of zolbetuximab discontinuation and toxicity management.

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Association between FGFR2b Positivity and Survival Outcomes of Patients with Gastric Cancer Treated with First-Line Nivolumab Plus Chemotherapy: Hyung-Don Kim, Heonwoo Lee, Hyungeun Lee, Meesun Moon, Jaewon Hyung, Jungeun Ma, Young Soo Park, Min-Hee Ryu; Received June 6, 2025 Accepted November 22, 2025 Published online November 24, 2025; DOI: https://doi.org/10.4143/crt.2025.598 [Accepted]

Abstract PDF: Purpose
Fibroblast growth factor receptor 2b (FGFR2b) is a promising therapeutic target in gastric cancer; however, its clinical relevance in immune checkpoint inhibitor (ICI)-based chemotherapy remains unclear. Therefore, this study aims to evaluate the expression pattern and predictive value of FGFR2b in patients undergoing first-line nivolumab plus chemotherapy.
Materials and Methods
This single-center study included 503 patients diagnosed with gastric cancer. Among them, 296 underwent nivolumab-chemotherapy, while 207 underwent chemotherapy alone. FGFR2b expression was assessed via immunohistochemistry using samples collected after mid-2022. FGFR2b positivity was defined as membranous staining intensity of 2+/3+ in ≥ 1% of tumor cells, with ≥ 10% as overexpression, and 1–9% as low expression.
Results
FGFR2b overexpression and positivity were identified in 9.3% and 18.7% of cases, respectively. Discordance between paired biopsy and surgical samples was observed (20.0% and 40.0% for overexpression and positivity, respectively), indicating marked intratumoral heterogeneity. Among patients who underwent nivolumab-chemotherapy, FGFR2b overexpression and low expression were associated with favorable survival trends compared to those of FGFR2b-negative cases. These associations were not observed in patients treated with chemotherapy alone. Compared to chemotherapy alone, nivolumab-chemotherapy was associated with a greater survival benefit in patients with FGFR2b positivity. Multivariate interaction analyses revealed a significant interaction between FGFR2b expression and nivolumab-based chemotherapy.
Conclusion
FGFR2b expression exhibits substantial intratumoral heterogeneity in gastric cancer and may be linked to favorable outcomes in patients undergoing first-line ICI plus chemotherapy. Therefore, future studies should validate this finding, along with mechanistic investigations.

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Kidney Failure–Related Mortality in Patients with Cancer: Insights from the Cancer Public Library Database in South Korea: Chang Seong Kim, Sang Heon Suh, Hong Sang Choi, Eun Hui Bae, Seong Kwon Ma, Jin Hyung Jung, Bongseong Kim, Kyung-Do Han, Soo Wan Kim; Received April 29, 2025 Accepted November 22, 2025 Published online November 24, 2025; DOI: https://doi.org/10.4143/crt.2025.466 [Accepted]

Abstract PDF Supplementary Material: Purpose
Kidney failure is associated with an increased risk of death. However, since the impact of kidney failure on overall and cancer-related mortality among individuals with cancer remains unclear, we investigated kidney failure–related mortality in patients with cancer, stratified by various cancer types.
Materials and Methods
A total of 1,307,680 participants newly diagnosed with cancer were identified from the Cancer Public Library Database. We analyzed data from patients with preexisting kidney failure before cancer diagnosis and compared their mortality risk with patients without kidney failure using multivariable Cox proportional hazard models.
Results
All-cause and cancer-related mortality was significantly higher in the kidney failure group. Preexisting kidney failure was associated with an increased risk of mortality in all cancer types after adjusting for comorbidities and treatment modalities (adjusted hazard ratio [aHR] of all-cause death 1.75, 95% CI 1.70–1.81; aHR of cancer-related death 1.27, 95% CI 1.22–1.32). Among specific cancer types, thyroid and breast cancers showed the highest mortality risks of kidney failure, with thyroid cancer presenting the greatest risk. However, the risk of death was attenuated in liver, gallbladder, and lung cancers. Furthermore, aHRs were lower for mortality in metastatic cancer compared to localized and regional stages.
Conclusion
Preexisting kidney failure significantly increases the risk of all-cause and cancer-related death among cancer patients, particularly in localized cancer and specific cancer types.

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Skeletal Muscle Index to Red Cell Distribution Width Ratio: A Novel Prognostic Indicator for Patients with Stage I-III Colorectal Cancer: Jiahn Choi, Jeonghyun Kang; Received August 15, 2025 Accepted November 12, 2025 Published online November 17, 2025; DOI: https://doi.org/10.4143/crt.2025.884 [Accepted]

Abstract PDF: Purpose
Herein, a novel prognostic marker based on the skeletal muscle index (SMI) and red cell distribution width (RDW) for patients with colorectal cancer (CRC) was developed.
Materials and Methods
585 Patients with stage I–III CRC who underwent surgery between January 2004 and April 2011 were included. The ratio of SMI to RDW (SRR) was calculated, and patients were grouped into sex-specific quartiles (G1 to G4) based on SRR. The Kaplan-Meier method was employed to estimate survival differences, and the Cox proportional hazards model was applied to evaluate the association between SRR and overall survival (OS). The Concordance Index (C-index) was calculated to assess the individual and combined effects of SMI and RDW on survival.
Results
There was a significant difference in OS across SRR quartiles (G1: 65.0%, G2: 82.9%, G3: 84.1%, G4: 89.8%, p<0.001). G1 had worse OS compared to the other groups, and SRR was confirmed as an independent prognostic factor for OS (G1 vs. G2, HR=0.531, 95% CI=0.320-0.882, p=0.014; G1 vs. G3, HR=0.534, 95% CI=0.302-0.942, p=0.030; G1 vs. G4, HR=0.419, 95% CI=0.212-0.827, p=0.012). SRR demonstrated greater prognostic power for OS than SMI or RDW alone.
Conclusion
SRR is a novel and significant predictor of overall survival in patients with stages I–III CRC demonstrating greater prognostic power than either SMI or RDW alone.

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Dual-Functional PTX@Fe₃O₄ Nanobubbles: A Novel Theranostic Platform for Enhanced Ultrasound Imaging and Controlled Drug Delivery in Breast Cancer: Weiyang Lv, Xiaomei Ning, Chunxin Huang, Xing Li, Lianjie Bai, Xiaotong Wang, Zihan Wang, Yunna Song, Huilin Liu; Received September 26, 2025 Accepted November 16, 2025 Published online November 17, 2025; DOI: https://doi.org/10.4143/crt.2025.1055 [Accepted]

Abstract PDF: Purpose
This study aimed to develop a novel theranostic nanoplatform that integrates ultrasound imaging and controlled drug delivery for the treatment of breast cancer.
Methods
PTX@Fe₃O₄ nanobubbles (NBs) were synthesised via microfluidics. Characterisation included transmission electron microscopy, dynamic light scattering, drug release kinetics, phantom imaging and biocompatibility assays in vitro and in mice.
Results
The NBs exhibited uniform size (178 ± 12 nm), high drug loading (8.3%) and pH/ultrasound-responsive release (68.2% at pH 5.5+US). Ultrasound signal enhancement correlated linearly with concentration (R² = 0.988), with imaging duration three times longer than SonoVue. The system exhibited minimal haemolysis (<2%) and low cytotoxicity and induced S-phase arrest (68.2%) in MCF-7 cells. No significant toxicity was observed in mice at 10 mg Fe/kg.
Conclusion
PTX@Fe₃O₄ NBs represent a promising, biocompatible theranostic platform for image-guided breast cancer therapy.

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Changes in Uptake, Participant Disparities, and Screening Outcomes of the Korean National Lung Cancer Screening Program: A Five-Year Experience: Chang Kyun Choi, Na-Young Lee, Mina Suh, Kui Son Choi, Yeol Kim; Received January 15, 2025 Accepted November 6, 2025 Published online November 10, 2025; DOI: https://doi.org/10.4143/crt.2025.067 [Accepted]

Abstract PDF: Purpose
Low-dose computed tomography (LDCT) is effective in reducing lung cancer mortality among high-risk smokers. The Korean National Lung Cancer Screening Program (KNLCS), the world’s first nationwide lung cancer screening initiative using LDCT, was launched in 2019. This study aimed to evaluate the KNLCS uptake rates in relation to participants’ economic status and changes in positive screening rates across screening rounds.
Materials and Methods
Data from the National Health Insurance Service (NHIS) and National Cancer Screening Information System for 2019–2023 were analyzed. Eligible participants in the KNLCS were current smokers aged 54–74 years with a smoking history of at least 30 pack-years. The KNLCS provides counseling by physicians on screening results and smoking cessation. Screening uptake rates, counseling rates, and Lung CT Screening Reporting and Data System (Lung-RADS) distributions were assessed.
Results
Screening uptake rates increased from 24.7% in 2019 to 51.2% in 2023 (p < 0.001). Economic disparities were observed, with higher-income groups showing consistently higher uptake rates than lower-income group. Screening positive rates has been decreased from 9.1% in 2019 to 7.0% in 2023 according to increasing the proportion of subsequent screening participants. The inter-institutional variance in Lung-RADS category 4 decreased significantly over the years (p < 0.001).
Conclusion
The KNLCS rapidly increased screening uptake rates by systematically inviting eligible participants. Positive screening rates decreased primarily due to a reduction in Lung-RADS category 3 findings in subsequent rounds.

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The Impact of Post Mastectomy Radiotherapy on T1-2N0-1 Male Breast Cancer and establishment of an artificial neural network predicting model: Population-Based Study: Kaiyan Huang, Yushuai Yu, Xiaofen Li, Yushan Liu, Kailong Huang, Xin Wang, Jie Zhang; Received May 14, 2025 Accepted November 4, 2025 Published online November 5, 2025; DOI: https://doi.org/10.4143/crt.2025.518 [Accepted]

Abstract PDF: Purpose
The objective of this study was to analyze the impact of post-mastectomy radiotherapy (PMRT) in male breast cancer (MBC) patients and develop an artificial neural network (ANN) model to identify a potential PMRT benefit population.
Materials and Methods
Data from a total of 2,247 MBC patients with T1-2N0-1M0 who underwent total mastectomy between 1998 and 2016 were enrolled from the SEER database. Propensity score matching was used to reduce covariate imbalances. Cox regression analysis was conducted to compare overall survival (OS) between the PMRT and no-PMRT groups. The hypothesis was that patients who had undergone PMRT and lived longer than the median OS of the no-PMRT group could benefit from PMRT. An ANN model was then developed to predict PMRT benefit population.
Results
Multivariate Cox regression analysis demonstrated better OS in the PMRT group compared to the no-PMRT group of matched patients. This survival benefit was particularly significant in patients with grade III or T2N0 and T2N1 disease, while no significant difference was observed in patients with grade I/II or T1N0 and T1N1 disease. An ANN model was established to predict PMRT benefit population based on patients with T2N0/T2N1. The optimal cut-off value for the model predicted probability was 0.51. Survival curves indicated that a score of 0.51 could accurately distinguish potential PMRT benefit population.
Conclusion
For MBC patients with T2N0, T2N1, and grade III, PMRT would improve survival. The ANN model would be used to identify patients who are likely to benefit from PMRT and aid in clinical decision-making.

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Longitudinal Circulating Tumor DNA Profiling as a Biomarker for Response and Resistance in Platinum-Refractory Head and Neck Squamous Cell Carcinoma: Wonyoung Choi, Jong-Ho Lee, Junsun Ryu, Sung Weon Choi, Yuh-Seog Jung, Joo-Yong Park, Chang Hwan Ryu, Sung Yong Choi, Weon Seo Park, Sun-Young Kong, Tak Yun; Received October 5, 2025 Accepted November 3, 2025 Published online November 4, 2025; DOI: https://doi.org/10.4143/crt.2025.1089 [Accepted]

Abstract PDF: Purpose
Immune checkpoint inhibitors (ICIs) are the standard treatment for platinum-refractory head and neck squamous cell carcinoma (HNSCC). This study aimed to characterize genomic alterations, monitor dynamic changes in circulating tumor DNA (ctDNA) associated with treatment response, and identify novel alterations linked to resistance through serial ctDNA profiling.
Materials and Methods
Patients with platinum-refractory HNSCC receiving nivolumab were enrolled. ctDNA was analyzed using FoundationOne Liquid CDx at baseline, 6 weeks after treatment, and at disease progression.
Results
A total of 36 patients were enrolled, and 33 were evaluable for ctDNA. The most frequent baseline alterations were TP53 (75.8%), followed by TERT (27.3%), NOTCH1 (24.2%), CDKN2A (12.1%), and CCND1 (12.1%). Of 27 patients with measurable lesions, 5 achieved a partial response with a response rate of 18.5%. Dynamic ctDNA profiling revealed all responders had marked reductions in both the sum of variant allele frequencies (sumVAF) and the maximum variant allele frequencies (maxVAF) across detected mutations. A decrease in sumVAF or maxVAF correlated with longer treatment durations, and patients with a >50% decrease in either sumVAF or maxVAF showed significantly longer progression-free survival. Additionally, serial profiling identified de novo mutations in 17 patients, detected during stable disease or progression.
Conclusion
Serial ctDNA analysis provides a noninvasive tool for monitoring treatment response and detecting emerging resistance in HNSCC treated with ICIs. A significant reduction in ctDNA at 6 weeks was associated with improved clinical outcomes and warrants validation in larger, prospective studies to define its role as a predictive biomarker in HNSCC.

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PHF10 is a Novel Substrate of Keap1 to Protect Non-Small-Cell Lung Cancer (NSCLC) Cells Against Oxidative Stress and Confer Ferroptosis Resistance: Xuan Lu, Ningning Kang, Yajun Chen, Xinru Zhao, Donglin Zhu, Jun Yang, Yong Yang, Hongya Xie; Received June 18, 2025 Accepted October 31, 2025 Published online November 3, 2025; DOI: https://doi.org/10.4143/crt.2025.635 [Accepted]

Abstract PDF: Purpose
Keap1 mutations mainly caused NRF2-dependent anti-oxidative stress responses, yet whether there are other downstream substrates and pathways remains unknown. This study aimed to uncover the role of Keap1 mutations in regulating PHF10-NRF2 axis in NSCLC and ferroptosis evasion.
Materials and Methods
Tandem affinity purification with mass spectrometry was used to screen peptides. Co-IP and ubiquitination assays were used to confirm the Keap1-PHF10 axis. A series of analyses in cell lines, patient samples, and xenograft models were conducted to uncover the functional dependency between Keap1 and NRF2. Transmission electron microscope was used to detect mitochondrion swelling under ferroptosis.
Results
Here, we reported that Keap1 binds and promotes polyubiquitination and degradation of PHF10, a subunit of the PBAF complex. NSCLC-associated Keap1 mutations are incapable of degrading PHF10, and thus induces PHF10 proteins stability. PHF10 ablation shows synthetic lethality in Keap1-deficient NSCLC cells. Mechanistically, PHF10 interacts with NRF2 to activate its downstream targets and enhance the NRF2-dependent anti-oxidative stress capacity in NSCLC. PHF10 recruits SMARCA2, one core cBAF subunit, to increase chromatin accessibility in NRF2-binding transcriptional regions. Cancer-associated Keap1 mutants confer resistance to ROS-induced cell death via accumulating PHF10-SMARCA2 complex. Increased PHF10 further induced ferroptosis resistance in Keap1-deficient NSCLC. Lastly, we utilized one small molecule inhibitor, SMARCA2-IN-8, to inhibit progression of Keap1-deficient NSCLC murine models.
Conclusion
Together, our study highlight the synthetic lethal relationship between Keap1 and PHF10, and provide targeting PHF10-SMARCA2 complex as an effective option to hit Keap1-deficient NSCLC.

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Chemoradiotherapy Increases the Incidence Rate of Cachexia in Head and Neck Cancer: A Cohort Study: Nan-Chin Lin, Kuo-Ting Sun, Yu-Hsin Tseng, Tzong-Ming Shieh, Yin-Hwa Shih; Received May 6, 2025 Accepted October 15, 2025 Published online October 30, 2025; DOI: https://doi.org/10.4143/crt.2025.482 [Accepted]

Abstract PDF: Purpose
In Taiwan, head and neck cancer (HNC) ranks among the five most prevalent cancers in men. HNC tumours can impair the patient's ability to ingest food following treatment, which may lead to cachexia. Currently, in Taiwan, no study has investigated the association between the risk of cachexia and the patients’ clinical characteristics.
Materials and Methods
This retrospective cohort study analysed data from the cancer registry database of Show-Chwan Memorial Hospital between 2021-2022. We evaluated 115 patients who underwent initial treatment and assessed the presence of cachexia 6 months after treatment. Clinical data were collected and compared between patients with cachexia and those without cachexia to explore the associated risk factors in the HNC population.
Results
In the database, oral cancer constituted the primary diagnosis for 70% of cases. According to pathological assessments, most patients presented with locally advanced disease and moderate tumour differentiation. No correlation was observed between patient-reported complications, risk behaviours, and the incidence of cachexia. Notably, patients who underwent concurrent chemoradiotherapy exhibited a 3.8-fold higher risk of developing cachexia.
Conclusion
Concurrent chemotherapy is the leading risk factor of treatment-induced cachexia. The results of this study could help clinicians manage this issue adequately and devise solutions to limit its incidence.

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Predictive Role of Baseline Peripheral Lung SUVmax on PET/CT for Immune-Related Pneumonitis and Adverse Events in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Kun Ho Kim, Seong Min Kim, Jeong Eun Lee, Song Soo Kim, Da Hyun Kang, Chaeuk Chung; Received May 22, 2025 Accepted October 22, 2025 Published online October 28, 2025; DOI: https://doi.org/10.4143/crt.2025.548 [Accepted]

Abstract PDF: Purpose
Immune checkpoint inhibitors (ICIs) offer durable responses in lung cancer patients lacking actionable mutations or with resistance to prior therapies. However, predicting their efficacy and associated immune-related adverse events (irAEs), such as severe pneumonitis, remains a clinical challenge. This study investigated the predictive value of positron emission tomography/computed tomography (PET/CT)-derived metabolic parameters for pneumonitis and other irAEs in lung cancer patients treated with ICIs.
Materials and Methods
We retrospectively analyzed 151 patients with advanced non-small cell lung cancer (NSCLC) who received ICIs as first-line treatment, either as monotherapy or in combination. Pre-treatment PET/CT was used to measure SUVmax at the primary tumor, tumor-uninvolved peripheral lung, and metastatic sites. Pneumonitis and irAEs were assessed using clinical and radiological findings.
Results
Pneumonitis, severe pneumonitis (grade ≥3), and irAEs occurred in 26.5%, 19.9%, and 37.1% of patients, respectively. A peripheral SUVmax cutoff of >1.1 significantly predicted pneumonitis (area under the curve [AUC] = 0.720, p <0.001). High peripheral SUVmax was associated with higher rates of pneumonitis (42.9% vs. 12.3%, p <0.001), severe pneumonitis (31.4% vs. 9.9%, p=0.001), and irAEs (46.4% vs. 29.5%, p=0.038). In multivariate analysis, high peripheral SUVmax independently predicted pneumonitis (odds ratio [OR]: 4.621; 95% confidence interval [CI]: 1.868–11.431; p=0.001), severe pneumonitis (OR: 2.848; 95% CI: 1.043–7.779; p=0.041), and irAEs (OR: 2.509; 95% CI: 1.114–5.504; p=0.022).
Conclusion
Baseline peripheral SUVmax on PET/CT may serve as a noninvasive biomarker for predicting immune-related pneumonitis and other irAEs in NSCLC patients receiving ICIs, supporting early risk identification.

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WNT3A Upregulates the RIP1/HIF-1α/GDF-15 Pathway to Induce EMT and Thereby Increase Colorectal Cancer Cell Migration and Invasion: A-Ram Kang, Tae-Jun Kim, Jung-Yoon Yoo, Sang-Gu Hwang, Jie-Young Song, Jong Kuk Park; Received June 15, 2025 Accepted October 17, 2025 Published online October 20, 2025; DOI: https://doi.org/10.4143/crt.2025.620 [Accepted]

Abstract PDF: Purpose
We previously demonstrated that WNT signaling, a key regulator of epithelial-mesenchymal transition (EMT), promotes malignancy via RIP1 in colorectal cancer (CRC). In this study, we aimed to reveal the novel signaling pathway through which WNT3A induces EMT in CRC.
Materials and Methods
CRC cells (DLD-1, HCT116) and mouse embryonic fibroblasts (MEFs; wtMEF and RIP1−/− MEF) were used in this study. Expression levels of GDF-15 and GFRAL were assessed by RT-qPCR, immunoblotting, and ELISA. RIP1 and HIF-1α were silenced using siRNA or shRNA. Cytokine profiling and ELISA were performed to quantify GDF-15 secretion. Migration and invasion assays were conducted in GDF-15-treated cells. Expression of HIF-1α within the pathway was analyzed with RT-qPCR and immunoblotting. In vivo expressions of GDF-15 and GFRAL were detected in human blood and CRC tissue specimens.
Results
WNT3A treatment significantly upregulated both mRNA and protein levels of GDF-15 and GFRAL in CRC cells. Silencing of RIP1 with siRIP1 or shRIP1 decreased the expression and secretion of GDF-15 and GFRAL. Cytokine profiling and ELISA confirmed that RIP1 facilitates GDF-15 secretion. Treatment with GDF-15 led to enhanced cell migration, invasion, and increased EMT marker expression. We also detected increases of GDF-15 in blood specimens and metastatic tissues of CRC patients. Furthermore, HIF-1α was identified as a key transcription factor downstream of RIP1 that regulates GDF-15 expression.
Conclusion
Our findings demonstrate that the novel WNT3A/RIP1/HIF-1α/GDF-15 signaling axis induces EMT, migration, and invasion in CRC. This pathway might represent a potential therapeutic target for limiting metastatic progression in CRC.

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Disease Burden and Treatment Pattern of Advanced or Recurrent Endometrial Cancer in Korea: A Nationwide Database (DIRECTION) Study: Hyun-Woong Cho, Se Ik Kim, Min-Ji Bae, Kyoung-Eun Kwon, ChoungWon Jung, YoungEun Lee, JiYoon Ahn, Kidong Kim; Received January 15, 2025 Accepted October 16, 2025 Published online October 20, 2025; DOI: https://doi.org/10.4143/crt.2025.065 [Accepted]

Abstract PDF: Purpose
Advanced/recurrent endometrial cancer (EC) patients has a poor prognosis, with higher recurrence and mortality than early-stage. However, as the real-world disease burden in these patients remains unclear, we aimed to investigate systemic anticancer therapy (SACT) patterns, healthcare resource utilization (HCRU), and costs in advanced/recurrent EC patients.
Materials and Methods
This nationwide population-based study used Korean claims data from 2008 to 2022. Adult patients with advanced/recurrent EC who received first-line SACT were included. For advanced EC, first-line SACT was defined as the initial therapy following EC diagnosis, while for recurrent EC it was defined as the initial therapy after recurrence following completion of primary therapy. We analyzed SACT patterns, prognosis, all cause- and EC-related HCRU, and costs.
Results
A total of 2,704 EC patients were included. The most commonly used SACT was platinum-based regimen. From the first to third line, median values of SACT-free interval (18.40, 5.03, and 3.22 months) and time to next treatment (TTNT, 25.43, 9.27 and 6.44 months) showed decreasing trends. All-cause/EC-related HCRU and costs were increased with SACT progression; all-cause inpatient visits and total costs increased from 0.58 to 1.04 times per-patient-per-month (PPPM) and from $1,197.96 to $2,354.37 USD PPPM.
Conclusion
This study demonstrated significant variability in SACT regimen sequence, highlighting the lack of consensus on standard treatment after disease relapse. Shorter TTNT and SACT-free intervals and higher HCRU and costs in later lines indicate worsening prognosis and increasing disease burden. These findings suggest the urgent need for more effective treatments, including new therapeutic agents, to address the unmet clinical needs of advanced/recurrent EC patients.

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Excess Cholesterol Biosynthesis by Up-Regulated HMGCS1 in Colorectal Cancer Cells Induced M2-Like Tumor-Associated Macrophage Polarization Via Extracellular Vesicles: Liu Yang, Bo Wu, Tingyi Sun, Haimei Sun, Jian Ma, Xiaohui Liu, Deshan Zhou, Shu Yang; Received May 22, 2025 Accepted October 11, 2025 Published online October 13, 2025; DOI: https://doi.org/10.4143/crt.2025.550 [Accepted]

Abstract PDF

Purpose
The aetiology of colorectal cancer (CRC) is attributed to the intrinsic malignant cell transformation and the extrinsic tumor microenvironment (TME). Within the TME, M2-like tumor-associated macrophages (TAMs) play a pivotal role in promoting CRC malignancy. Although the interaction between tumor cells and TAMs has been studied, the mechanism underlying the polarization of M2-like TAMs directed by CRC cells remains unclear.
Materials and Methods
Macrophage polarization was analyzed by flow cytometry. Cytokine production was quantified by qPCR. EVs were identified by transmission electron microscopy and western blotting. CRC cell apoptosis and viability were measured by flow cytometry and CCK8 assay, respectively.
Results
The results showed that CRC cells have high expression of HMGCS1, the enzyme responsible for catalyzing the synthesis of HMG-CoA during cholesterol biosynthesis. The increased expression of HMGCS1 resulted in an excess of cholesterol in CRC patients. The excess cholesterol derived from CRC cells was released via extracellular vesicles (EVs) and taken up by surrounding macrophages via the CD36 receptor. Macrophages that took up CRC cell-derived cholesterol showed a preferential polarization towards M2-like TAMs, which produced large amounts of pro-tumor cytokines. The production of these cytokines further accelerated the progression of the surrounding CRC.
Conclusion
Our findings revealed a mutual stimulatory effect between CRC cells and M2-like TAMs. CRC cells with hyper-expressed HMGCS1 facilitated M2-like TAM polarization by releasing cholesterol-rich EVs, and M2-like TAMs in turn promoted CRC malignancy. These findings suggest that inhibiting excessive cholesterol production may be a promising strategy for the treatment of advanced CRC.

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Parallel Alterations in Gut and Tumor Microbiota in Pediatric Oncology: Potential Impacts on Disease Progression and Treatment Response
Patrik József Szabó, Viktória Sági, Levente Károly Kassai, Renáta Mária Kiss-Miki, Nóra Makra, Dóra Szabó, Miklós Garami
Cancers.2025; 17(21): 3426. CrossRef

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Effects of Exercise Interventions on Breast Cancer Patients During Adjuvant Therapy: A Systematic Review and Meta-Analysis: Zhiyuan Sun, Tengteng Han, Lianshi Feng, Dewei Mao, Can Zhao, Jie Han, Qinghui Shang; Received July 22, 2025 Accepted September 28, 2025 Published online October 2, 2025; DOI: https://doi.org/10.4143/crt.2025.762 [Accepted]

Abstract PDF: Purpose
Exercise can enhance the therapeutic effects of adjuvant medications, improve both physiological and psychological functions, and increase physical fitness among breast cancer patients receiving adjuvant therapy. This systematic review and meta-analysis examined the latest research on the effects of exercise interventions in this population. Furthermore, subgroup analyses were performed based on exercise type, intensity, frequency, duration and Types of adjuvant therapy.
Materials and Methods
The PubMed, Embase, CINAHL, and CENTRAL databases were systematically searched from inception to April 2024 to identify randomized controlled trials (RCTs) examining the use of exercise interventions among breast cancer patients receiving adjuvant therapy. The data extracted from the included studies were analyzed via RevMan 5.4.
Results
A total of 34 studies involving 2,696 participants were included, with 1,369 in the intervention group and 1,327 in the control group, and a mean age ranging from 40 to 60 years. Compared to the control group, exercise interventions improved fatigue, muscular strength, cardiorespiratory fitness, inflammation, and quality of life in breast cancer patients (fatigue: SMD=–0.29, 95% CI (–0.50, 0.09), p=0.005; upper limb strength: SMD=0.50, 95% CI (0.33, 0.68), p<0.00001, lower limb strength: SMD=0.37, 95% CI (0.22, 0.52), p<0.0001; cardiorespiratory fitness: SMD =0.51, 95% CI (0.26,0.75), p<0. 0001; inflammation: SMD =–0.36, 95% CI (–0.66, –0.06), p=0.02; quality of life: SMD=0.21, 95% CI (0.11, 0.31), p< 0.0001). Moderate effect sizes were observed for the alleviation of anxiety and depressive symptoms, although these results did not reach statistical significance (depression: SMD=–0.13, 95% CI (–0.28, 0.02), p=0.08; anxiety: SMD=–0.81, 95% CI (–1.65, 0.03), p=0.06). This meta-analysis was registered in Prospero, the international register of systematic reviews, with registration number: CRD42024553589.
Conclusion
Exercise during adjuvant therapy can reduce the side effects of adjuvant medications, improve both physiological and psychological functions, and enhance physical fitness among patients with breast cancer.

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Impact of Occupational Lead Exposure on Lung Cancer Risk in Korean Male Workers: A Retrospective Cohort Study: Kyung-Eun Lee, Sanggil Lee, Jin-Ha Yoon, Shinhee Ye; Received March 12, 2025 Accepted September 30, 2025 Published online October 2, 2025; DOI: https://doi.org/10.4143/crt.2025.282 [Accepted]

Abstract PDF: Purpose
In 2006, the IARC reported that inorganic lead is carcinogenic in animals but with limited evidence in humans. In addition, some studies have reported that exposure to lead increases the risk of lung cancer, but this remains controversial. Therefore, we aimed to assess the risk of developing lung cancer according to blood lead levels in workers with occupational lead exposure.
Materials and Methods
A retrospective cohort study of male workers with 2009 blood lead (PbB) concentrations was conducted using nationwide special health examination data (SHED) from 2009 to 2021 and cancer registry data from 1999 to 2020 from the Republic of Korea. Standardized incidence ratios (SIRs) for lung cancer risk at each PbB level were calculated with a five-year wash-out period, adjusting for age, smoking status, duration of exposure, and the number of co-exposures to lung carcinogens.
Results
The study included 26,092 workers with an average follow-up period of 9.98 years. Compared with workers with PbB levels <3.130 µg/dL, the adjusted SIRs for lung cancer risk were 2.95 (95% confidence interval [CI]: 1.47–5.27) and 3.13 (95% CI: 1.82–5.00) for workers with PbB levels of 3.130–4.899 and ≥4.900 µg/dL, respectively, indicating a significant dose-response trend.
Conclusion
This study demonstrates a significant association between lead exposure and an increased risk of lung cancer, highlighting the need for stronger occupational health policies and ongoing monitoring of workers exposed to lead. The observed dose-response relationship underscores the importance of reassessing current occupational safety standards and strengthening measures to reduce lead exposure in the workplace.

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IFITM1 Influences Natural Killer Cell-Mediated Cytotoxicity by Modulation of HLA class I Expression in Triple-Negative Breast Cancer Cells: Heejin Lee, Chanyeon Park, Keunsoo Kang, Soon Auck Hong, Gyungmin Cho, Inyoung Cheon, Young-Ho Ahn, Jung-Sook Yoon, Yoon Ho Ko, Hye Sung Won; Received April 24, 2025 Accepted September 23, 2025 Published online September 25, 2025; DOI: https://doi.org/10.4143/crt.2025.444 [Accepted]

Abstract PDF: Purpose
Interferon-induced transmembrane protein 1 (IFITM1) is associated with a poor prognosis in triple-negative breast cancer (TNBC); however, the mechanisms by which IFITM1 contributes to oncogenesis in TNBC are unclear.
Materials and Methods
We established two stable cell lines: IFITM1-overexpressing cell line (MB-231-IFITM1-OE) and IFITM1 knockdown cell line (BT-20-IFITM1-KD). The transcriptional activity of β-catenin and the cytotoxic activity of natural killer (NK) cells were evaluated using the luciferase assay and the lactate dehydrogenase cytotoxicity assay. The expression of IFITM1, β-catenin, and HLA class I was assessed by immunohistochemistry in patients with TNBC.
Results
Knockdown of IFITM1 in BT-20 cells reduced cell proliferation and ectopically expressed IFITM1 in MB-231 cells increased cell proliferation. RNA sequencing analysis revealed that IFITM1 expression positively correlated with the Wnt/β-catenin signaling pathway and NK cell-mediated cytotoxicity. MB-231-IFITM1-OE cells showed increased β-catenin transcriptional activity and NK cell cytotoxic activity compared with controls, while transient knockdown of IFITM1 in MB-231-IFITM1-OE cells led to a decrease in β-catenin transcriptional activity and NK cell cytotoxic activity. MB-231-IFITM1-OE cells exhibited decreased HLA class I expression, which may have contributed to their increased susceptibility to NK cell-mediated lysis. β-catenin or JAK inhibitor reduced NK cell-mediated cytotoxicity via upregulation of HLA class I. Patients with IFITM1 overexpression showed a trend toward increased β-catenin positivity and HLA class I negativity.
Conclusion
IFITM1 overexpression was associated with Wnt/β-catenin signaling and NK cell-mediated cytotoxicity via downregulation of HLA class I in TNBC cells, suggesting that IFITM1 might have immunoregulatory effects on the tumor microenvironment.

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LRRC15 Promotes the Development of Breast Cancer by Regulating Autophagy through the PI3K/AKT/mTOR Signaling Pathway: Xinru Fan, Liu Gao, Zheng Zhang, Xu Jiang, Xiawei Wang, Jiayu Shi, Yu Ling, Rundong Yan, Jiani Shi, Li Yu; Received May 20, 2025 Accepted September 21, 2025 Published online September 24, 2025; DOI: https://doi.org/10.4143/crt.2025.543 [Accepted]

Abstract PDF: Purpose
Leucine-rich repeats (LRR) play important roles in tumorigenesis and may serve as novel biomarkers for cancer therapy. The expression of leucine-rich repeat-containing protein 15 (LRRC15) is increased in several cancers. However, it is still unknown whether LRRC15 is involved in breast cancer and autophagy.
Materials and Methods
This study conducted bioinformatic analysis on LRRC15 expression and prognosis in breast cancer. Clinical samples were collected and subjected to immunohistochemistry and qRT-PCR to analyze LRRC15 expression in tissues and serum. Clonal formation, MTT, wound healing, and Transwell assays were used to examined breast cancer cell proliferation, migration, and invasion. Western blotting detected autophagy-related and PI3K/AKT/mTOR signaling pathway proteins.
Results
Patients with breast cancer having elevated expression of LRRC15 have a markedly worse prognosis compared with those having lower levels. Furthermore, LRRC15 expression was strongly correlated with tumor aggressiveness and poor differentiation in breast cancer cell lines. Functionally, LRRC15 drives cancer cell proliferation, migration, and invasion. LRRC15 inhibited autophagy in breast cancer cells, thus modulating their proliferative capacity. Mechanistically, LRRC15 exerted these effects by activating the PI3K/AKT/mTOR signaling cascade.
Conclusion
LRRC15 regulates autophagy-induced proliferation and other biological activities of breast cancer cells through the PI3K/AKT/mTOR signaling pathway.

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LncRNA DGUOK-AS1 Promotes Bladder Cancer Progression by Enhancing EFTUD2 Stability: Wenwei Ying, Dingliang Li, Ninghan Feng, Wei Wei; Received April 30, 2025 Accepted September 17, 2025 Published online September 18, 2025; DOI: https://doi.org/10.4143/crt.2025.468 [Accepted]

Abstract PDF: Purpose
Long noncoding RNAs (lncRNAs) are increasingly being recognized to play important roles in cancer pathogenesis. However, the functional mechanisms of most lncRNAs remain poorly understood.
Materials and Methods
RNA sequencing was performed to identify differentially expressed lncRNAs between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). In vitro and in vivo assays were conducted to investigate the functional role of lncRNA deoxyguanosine kinase 1 antisense RNA 1 (DGUOK-AS1). Meanwhile, RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, Western blot, and reverse transcription quantitative polymerase chain reaction assays were performed to explore the potential regulatory mechanisms of DGUOK-AS1 on its target genes.
Results
Our analysis revealed a significant upregulation of lncRNA DGUOK-AS1 in MIBC compared with NMIBC. Functionally, DGUOK-AS1 was found to enhance the proliferation and invasion of bladder cancer (BC) cells by interacting with elongation factor Tu GTP binding domain containing 2 (EFTUD2), a 116-kDa U5 small nuclear ribonucleoprotein component. Mechanistically, DGUOK-AS1 directly binds to EFTUD2 and the deubiquitinating protein valosin-containing protein-interacting protein 1, thereby shielding EFTUD2 from ubiquitination and subsequent degradation. Furthermore, EFTUD2 orchestrates the exclusion of cassette exon 11 from macrophage-stimulating 1 receptor, leading to the production of the RON∆165 isoform. This isoform activates the Akt/PKB signaling pathway, which is crucial for cancer progression.
Conclusion
DGUOK-AS1 drives BC progression via the EFTUD2/MST1R/Akt axis, offering a promising therapeutic target for BC treatment.

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Synergistic Anticancer Effects of Lenvatinib and Celastrol via ROS-Mediated ER Stress and JNK Signaling in Colon Cancer Cells: Ying Yan, Chenyu Qiu, Wenying Fu, Chongchong Shu, Chenxin Xu, Yinghua Chen, Yiqun Xia, Jundixia Chen, Yunzhi Chen, Ri Cui, Peng Zou, Daoyong Ni; Received May 12, 2025 Accepted September 7, 2025 Published online September 9, 2025; DOI: https://doi.org/10.4143/crt.2025.508 [Accepted]

Abstract PDF: Purpose
Colon cancer, a predominant contributor to global cancer mortality, is characterized by uncontrolled cell growth in the colon or rectum. Therapeutic progress notwithstanding, including targeted therapies and chemotherapy, the survival rate remains unsatisfactory, especially for patients with advanced colon cancer, underscoring the need for novel strategies to enhance treatment efficacy.
Materials and Methods
In this study, we employed Western blot analysis to quantify target protein expression levels and immunofluorescence for protein detection and localization. To evaluate drug interactions, we calculated the Combination Index (CI). Intracellular ROS levels were measured using the DCFH-DA probe. Additionally, we generated target gene-knockdown cell lines via recombinant lentivirus transfection. For in vivo validation, we established a xenograft tumor model in nude mice to assess the therapeutic efficacy of the drug combination.
Results
In the study, we systematically evaluated the combinatorial potential of clinically approved lenvatinib and bioactive celastrol against colorectal cancer pathogenesis. Our results demonstrated that the combination treatment significantly inhibited cancer cell proliferation by enhancing reactive oxygen species (ROS) generation. This oxidative stress activated the ATF4-CHOP and JNK signaling pathways, ultimately inducing cell apoptosis as the main cause of death phenomenon.
Conclusion
Our research demonstrates that celastrol potentiates lenvatinib's anti-tumor effects in colon cancer by inducing ROS-dependent ER stress and triggering phosphorylation-dependent JNK pathway activation. These findings revealing a promising combinatorial strategy to enhance therapeutic efficacy in colorectal carcinoma.

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Analysis of T Cell Subsets Using Multiplex Immunohistochemistry and Clinical Outcomes of Immune Checkpoint Inhibitors in Advanced Gastric Cancer Patients: Tae-Yong Kim, Jeesun Yoon, Dae-Won Lee, Yoonjin Kwak, Hye Seung Lee, Do-Youn Oh; Received April 28, 2025 Accepted September 7, 2025 Published online September 9, 2025; DOI: https://doi.org/10.4143/crt.2025.458 [Accepted]

Abstract PDF: Purpose
As immunotherapy has become essential in the treatment of gastric cancer (GC), there has been growing interest in T-cells, which play a key role in immunotherapy. In this study, we evaluated the impact of T-cell subsets on immune responsiveness to immune checkpoint inhibitors (ICIs) in GC using multiplex immunohistochemistry (mIHC).
Materials and Methods
Eighty-four GC patients treated with ICIs were enrolled, and we repeated the staining-scanning-stripping procedure nine times to assess different kinds of T-cells or cell-surface immune checkpoints in a single tissue section.
Results
The proportions of patients with microsatellite instability-high (MSI-H), Epstein-Barr virus (EBV), and non-MSI/non-EBV were 8.3%, 3.6% and 88.1%. A high cytotoxic T-cell (T_cyto) density was related to longer overall survival (OS). GC with a high ratio of T_cyto/total T-cells (T_total) and a low ratio of regulatory T-cells (T_reg)/T_total showed better OS. A high density of PD-1- or TIM-3- expressing T_cyto were also associated with longer OS than a low density of those. Among memory T-cells (T_mem) subsets, GC with a high ratio of memory T_cyto/T_mem and a low ratio of memory T_reg/T_mem showed prolonged OS. Better tumor responses were observed in GC with a high ratio of T_cyto/T_total and memory T_cyto/T_mem.
Conclusion
T-cell subsets within the tumor microenvironment were associated with the clinical efficacy of ICIs in GC. PD-1- or TIM-3 expressing T-cells were also associated with response to ICIs, while memory T-cells subsets were associated with survival. mIHC is a feasible method for evaluating T-cell subsets in archival gastric tumor tissue.

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Noninvasive Assessment of Ki-67 Expression in Breast Cancer Using Ultrasound Radiomics: A Multi-Institutional Study: Sijie Mo, Zhibin Huang, Jing Zheng, Huaiyu Wu, Shuzhen Tang, Mengyun Wang, Jinfeng Xu, Hongtian Tian, Xiaoli Huang, Fajin Dong; Received May 30, 2025 Accepted September 2, 2025 Published online September 5, 2025; DOI: https://doi.org/10.4143/crt.2025.581 [Accepted]

Abstract PDF: Purpose
This study aimed to develop and rigorously evaluate machine learning models using ultrasound (US) breast cancer (BC) images to predict Ki-67 expression. Additionally, the study sought to identify independent factors influencing Ki-67 expression, with further test conducted through external datasets.
Materials and Methods
This study analyzed US images of BC from 347 patients (training set: n = 230; external test set: n=117) from Shenzhen People’s Hospital and Guangxi Academy of Medical Sciences. Radiomic features were extracted using manual region-of-interest (ROI) delineation and the Pyradiomics package. Feature selection was performed using LASSO and decision tree analysis, resulting in 16 features. Machine learning models-logistic regression (LR), support vector machine (SVM), and multilayer perceptron (MLP)-were developed, and their performance was assessed using the area under the receiver operating characteristic curve (ROC), accuracy, sensitivity, specificity, and decision curve analysis. Statistical analysis included univariate and multivariate logistic regression.
Results
Three machine learning models (LR, SVM, MLP) were developed to predict Ki-67 expression from US images. The LR model demonstrated the best diagnostic performance, with an AUC of 0.800 in external test set. Key predictors of Ki-67 expression included ill-defined mass maximum Maximum diameter and HER2 expression, along with other significant clinical variables.
Conclusion
This dual-center study demonstrates the potential of radiomics models based on US BC images to predict Ki-67 expression accurately. As a non-invasive diagnostic tool, this approach offers valuable support for clinical decision-making and personalized treatment planning in BC patients.

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Healthy Behaviors and All-cause Mortality among Korean Gastric Cancer Survivors: Donghyun Won, Jeeyoo Lee, Sooyoung Cho, Ji Yoon Baek, Hyuk-Joon Lee, Aesun Shin; Received February 14, 2025 Accepted September 1, 2025 Published online September 3, 2025; DOI: https://doi.org/10.4143/crt.2025.177 [Accepted]

Abstract PDF: Purpose
The incidence, prevalence and survival rates of gastric cancer are high, and the prognostic effects of healthy behaviors among survivors have not been well investigated. Therefore, We aimed to assess the effects of postdiagnosis healthy behaviors and behavior changes after gastric cancer diagnosis on all-cause mortality.
Materials and Methods
As a population-based retrospective cohort study, we used a cancer public library sample DB of gastric cancer patients between 2012 and 2019. Information from regular health check-up examinations were used to investigate their anthropometric measures, physical activities, alcohol consumption, and smoking status before and after cancer diagnosis. Hazard ratios (HRs) for all-cause deaths with 95% confidence intervals (CIs) were estimated via the Cox proportional hazards model.
Results
We analyzed 9,717 gastric cancer patients and 5,929 of those as a subgroup to assess the effects of behavior changes. Reduced mortality was shown among cancer patients who met the recommended criteria after the cancer diagnosis for physical activity (adjusted HR = 0.67 [95% CI=0.49-0.93], mean frequencies of moderate to vigorous physical activity per week: ≥5 days vs. 0 days) and smoking cessation (0.77 [0.61-0.97], smoking status: never-smokers vs. current smokers). Participants who reported enhancement in behaviors had significantly lower mortality than the others who reported no or limited changes in physical activity (0.73 [0.55–0.96]) and smoking status (0.56 [0.38–0.83]).
Conclusion
The current study highlights the advantages of physical activity and smoking cessation in reducing mortality, and these benefits are even greater when patients improve their behavior after cancer diagnosis.

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H3K18la Facilitates TRA2A-Mediated Alternative Splicing of STIL, Suppressing Ferroptosis and Cisplatin Treatment Sensitivity in Ovarian Cancer: Mingyang Gao, Shiming Wang, Zhiyuan Huang, Tianliang Wang, Yuexin Yu; Received July 18, 2025 Accepted August 28, 2025 Published online September 1, 2025; DOI: https://doi.org/10.4143/crt.2025.752 [Accepted]

Abstract PDF

Purpose
Ovarian cancer (OC) is a common and highly lethal malignant tumor in women. Due to its hidden early symptoms, most patients are diagnosed at an advanced stage, and the tumor often develops resistance to chemotherapy, making treatment challenging. Elucidating the mechanisms of OC development and identifying new therapeutic targets, are crucial for improving treatment outcomes.
Materials and Methods
We used bioinformatics analysis combined with qRT-PCR, WB, and IHC to study TRA2A expression and histone lactylation in OC samples. CCK8, clone formation, EdU, and Transwell experiments were used to assess OC cells proliferation. RT-PCR analyzed TRA2A-mediated alternative splicing. And the nude mouse xenograft model was constructed to validate TRA2A's molecular function in vivo.
Results
This study reveals a novel mechanism by which OC cells evade ferroptosis through the TRA2A-STIL signaling axis. Specifically, H3K18la is significantly enriched at the promoter region of the TRA2A gene, activating its transcription and upregulating expression. The upregulated TRA2A protein, functioning as a key splicing factor, specifically regulates alternative splicing (AS) of the STIL mRNA. This promotes expression of the STIL-L isoform, which inhibits ferroptosis in OC cells by modulating iron metabolism. Furthermore, targeted knockdown of TRA2A combined with cisplatin treatment significantly enhanced the therapeutic efficacy against OC. Consequently, targeting TRA2A-mediated AS represents a promising novel therapeutic target for OC.
Conclusion
This study uncovers for the first time a novel mechanism by which OC cells evade ferroptosis via an H3K18la-modified TRA2A-STIL signaling axis, thereby establishing a promising new therapeutic target for OC treatment.

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Targeting Lactylation for Cancer: Mechanisms, Effects, and Therapeutic Prospects
Dong Chang, Daolong Li, Yuxi Sun, Jiekang Shi, Shengping Zhang, Chuangui Wang
International Journal of Molecular Sciences.2025; 26(23): 11278. CrossRef

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1 Crossref

Long-Term Prognostic Value and Analytical Parameters of the Next-Generation Sequencing-Based Multigene Assay in Hormone Receptor-Positive, HER2-Negative Breast Cancer: Hyunji Kim, Jiwon Koh, Hyunwoo Lee, Gyungyub Gong, Sujin Oh, Jiyoung Lee, Ho Eun Chang, Yunhee Choi, Eunhye Kang, Jai Min Ryu, Dong Seung Shin, Sae Byul Lee, Hee Jin Lee, Hong-Kyu Kim, Hee-Chul Shin, Wonshik Han, Han-Byoel Lee, Kyoung Un Park; Received July 7, 2025 Accepted August 29, 2025 Published online September 1, 2025; DOI: https://doi.org/10.4143/crt.2025.701 [Accepted]

Abstract PDF: Purpose
In hormone receptor (HR)-positive, HER2-negative early breast cancer, gene expression testing facilitates treatment decisions. A next-generation sequencing (NGS)-based assay was developed to address test decentralization and underrepresentation of younger/premenopausal patients. We aimed to validate the long-term prognostic value of the NGS-based assay and analyze its quality control (QC) parameters.
Materials and Methods
We analyzed samples from 265 patients with breast cancer with at least 10 years of follow-up. We evaluated the long-term prognostic ability of the NGS-based assay according to the risk groups for distant recurrence, as determined by the Decision Index (DI), and the performance of the QC parameters used for the experimental process.
Results
Among 265 participants, 60.4% were ≤50 years old, and 39 (14.7%) experienced distant recurrence within 10 years. In the DI-stratified low- and high-risk groups (n=186; 70.2% and n=79; 29.8%), 10-year distant metastasis-free survival rates were 96.1% (95% CI 92.1-98.1) and 79.3% (95% CI 68.4-86.8), respectively. In patients aged ≤50 years, the high-risk group had a hazard ratio of 5.89 (95% CI 2.84-12.20). Analyses including 106 samples that failed the stringent QC criteria showed inferior prognostic value, wherein DV200 and cDNA concentrations were the most crucial parameters.
Conclusion
We validated the prognostic ability of an NGS-based assay to stratify HR-positive/HER2-negative breast cancers and predict the risk of distant recurrence, and confirmed the requirement for stringent QC criteria to ensure its prognostic ability.

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Concept of Depth of Invasion can Improve Staging Performance in Patients with Resected Distal Cholangiocarcinoma: Validation of the American Joint Committee on Cancer Staging System: Won-Gun Yun, Yoon Soo Chae, Youngmin Han, Young Jae Cho, Hye-Sol Jung, Wooil Kwon, Joon Seong Park, Haeryoung Kim, Kyoung Bun Lee, Jin-Young Jang; Received April 12, 2025 Accepted August 22, 2025 Published online August 25, 2025; DOI: https://doi.org/10.4143/crt.2025.406 [Accepted]

Abstract PDF: Purpose
The American Joint Committee on Cancer (AJCC) staging system for distal cholangiocarcinoma (dCC) has evolved significantly. However, the prognostic correlation of the newly proposed staging system remains unclear. Therefore, we aimed to compare the staging performance between AJCC 7th and 8th editions for dCC.
Materials and Methods
We reviewed pathological slides of consecutive patients who underwent resection for dCC between 2000 and 2022. According to the AJCC 8th edition, depth of invasion was defined as the distance from the basement membrane of adjacent normal or dysplastic epithelium to the deepest tumor invasion. We analyzed changes in the T category from the AJCC 7th to 8th edition and assessed overall survival and recurrence based on these staging systems.
Results
Among 428 patients, application of the 8th edition resulted in down-staging of 272 (63.6%) patients and up-staging of only 13 (3.0%). Lymph node metastases were identified in 150 (35.1%) patients, with 29 (6.8%) having ≥ 4 metastatic nodes. The C-indices for overall survival and recurrence are 0.557 and 0.569 for the T stage of the AJCC 7th edition, and 0.606 and 0.631 for that of the AJCC 8th edition (95% confidence interval for delta: 0.005–0.092 for survival, 0.023–0.100 for recurrence). Additionally, the T category of the 8th edition correlated more strongly with lymph node metastases than that of the 7th edition.
Conclusion
In dCC, the T category of the AJCC 8th edition demonstrates improved prognostic correlation and better alignment with lymph node metastases compared to that of the 7th edition.

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Genomic Insights into Innate Resistance in Early-Stage EGFR-Mutant Non-Small Cell Lung Cancer: A Comprehensive Analysis of Next-Generation Sequencing Data: Hayoung Seong, Soo Han Kim, Mi-Hyun Kim, Ahrong Kim, Ju Sun Song, Jung Seop Eom; Received January 28, 2025 Accepted August 19, 2025 Published online August 25, 2025; DOI: https://doi.org/10.4143/crt.2025.114 [Accepted]

Abstract PDF: Purpose
Comprehensive genomic profiling of early-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations remains limited. This study aimed to investigate genomic profiles of early- and advanced-stage EGFR-mutant NSCLC and identify potential innate resistance mechanisms to EGFR-tyrosine kinase inhibitors (TKIs) using targeted next-generation sequencing (NGS).
Materials and Methods
This retrospective observational study analyzed genomic profiles of patients with early-stage (IA–IIIA) and advanced-stage (IIIB–IV) EGFR-mutant NSCLC from the Lung Cancer NGS registry. Targeted NGS was performed to assess concurrent genetic alterations (GAs), tumor mutational burden (TMB), and variant allele frequency (VAF) of EGFR mutations.
Results
Overall, 160 patients (100 early-stage and 60 advanced-stage) were analyzed. The proportion of patients with concurrent GAs was not significantly different between stages (82.0% vs. 91.7%, p=0.092). Median TMB was 3.8 mutations/Mb in both stages, with no significant difference (p=0.206). However, the median VAF of EGFR mutations was significantly lower in early-stage compared to that in advanced-stage (19.3% vs. 29.6%, p=0.002). While TMB remained unchanged with disease progression (P = 0.192), VAF of EGFR mutations increased significantly (p<0.001). Moreover, the frequencies of concurrent single nucleotide variants and copy number variants were significantly lower in early-stage NSCLC.
Conclusion
Genomic heterogeneity in EGFR-mutant NSCLC arises early in tumorigenesis. The comparable TMB and lower VAF of EGFR mutations in early-stage disease suggest that innate resistance to EGFR-TKIs may be driven by concurrent GAs, supporting the consideration of combination therapies even in early-stage EGFR-mutant NSCLC.

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Nomograms Integrating Body Composition Metrics Predict Total Pathologic Complete Remission after Neoadjuvant Systemic Therapy for Breast Cancer: Jingjing Ding, Yichun Gong, Jue Wang, Yuanyuan Wang, Hao Yao, Xingye Sheng, Mingyu Wang, Danni Shen, Junhan Li, Xiaoming Zha, Lu Xu; Received April 28, 2025 Accepted August 17, 2025 Published online August 18, 2025; DOI: https://doi.org/10.4143/crt.2025.456 [Accepted]

Abstract PDF: Purpose
Neoadjuvant systemic therapy (NST) is a systemic treatment for locally advanced or initially unresectable breast cancer before surgery. Patients achieved total pathological complete response (tpCR) after NST exhibited significantly better overall prognosis than patients with non-pCR.
Materials and Methods
This study collected baseline indicators, body composition indicators and tpCR results of breast cancer patients at the First Affiliated Hospital of Nanjing Medical University. Patients were divided into training set and validation set in a ratio of 7:3. Univariate and multivariate logistic regression analyses were performed, and the probability of tpCR was predicted by constructing nomograms based on the results of the multivariate logistic regression analysis.
Results
The study included 500 patients between 2014 and 2022 with breast cancer who underwent NST. The training set and validation set consist of 350 and 150 patients respectively. Patients with progesterone receptor-negative status (p < 0.001), HER2 receptor-positive status (p < 0.001), large body surface area (p=0.091), low skeletal muscle index (p=0.008), and high skeletal muscle density (p < 0.004) were more likely to achieve tpCR. Patients with American Joint Committee on Cancer (AJCC) T-stage 4 (p=0.126), AJCC N-stage 1 (p=0.026) were less likely to achieve tpCR.
Conclusion
Existing tpCR prediction models mostly focus on tumor biological characteristics and ignore the effect of body compositions. This study constructed a nomogram to predict tpCR in patients with breast cancer undergoing NST based on baseline and body composition indicators. This nomogram can help assess efficacy and optimize treatment strategies, thus improving the overall prognosis of patients.

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Clinicopathological Factors Influencing PD-L1 Expression and The Effect of Immune Checkpoint Inhibitors on Survival Outcomes in Patients with Gastric Cancer Depending on Sex in a Tertiary Hospital in South Korea: Jeong hwan Lee, Nayoung Kim, Ji-Hyun Kim, Hyeon Jeong Oh, Yeejin Kim, Yonghoon Choi, Hyemin Jo, Ho-Kyoung Lee, Jinju Choi, Yu Kyung Jun, Hyuk Yoon, Cheol Min Shin, Young Soo Park, Dong Ho Lee, Hye Seung Lee, So Hyun Kang, Young Suk Park, Sang-Hoon Ahn, Yun-Suhk Suh, Do Joong Park, Hyung Ho Kim, Ji-Won Kim, Jin Won Kim, Keun-Wook Lee, Won Chang, Yoon Jin Lee, Kyoung Ho Lee, Young Hoon Kim, Soyeon Ahn; Received January 31, 2025 Accepted August 5, 2025 Published online August 13, 2025; DOI: https://doi.org/10.4143/crt.2025.126 [Accepted]

Abstract PDF: Purpose
Programmed cell death ligand-1 (PD-L1) negatively regulates T-cell activation, and exhibits sex-based differences in expression and immune responses. This study investigated sex-related differences in clinicopathological factors influencing PD-L1 expression and the effect of immune checkpoint inhibitors (ICIs) on survival in gastric cancer (GC) patients in South Korea.
Materials and Methods
We analyzed a prospective cohort of 468 GC patients who underwent PD-L1 immunohistochemistry. Age, tumor characteristics, molecular features, and survival outcomes were compared by sex. Multivariate analyses, including Cox proportional hazards modeling with an interaction term for sex, were performed.
Results
Among 468 patients, 280 (59.8%) were PD-L1 positive. In the overall cohort, PD-L1 positivity was significantly associated with Epstein-BarrVirus (EBV) infection (odd ratio [OR]=7.46, p<0.001), antral location of GC (OR=1.84, p=0.027), and macrosatellite instability-High (MSI-H) (OR=5.04, p=0.027). Diffuse-type histology was inversely associated (OR=0.22, p=0.041). In males, EBV (OR=36.27) and antral location (OR=2.38) were significant. In females, only MSI-H was significant (OR=11.63). ICI-containing therapy significantly improved survival in males (p=0.012) but not in females (p=0.415). Cox regression showed a survival benefit from ICIs (HR=0.70, p=0.080), with a borderline-significant interaction by sex (p=0.073).
Conclusion
PD-L1 expression and therapeutic efficacy of ICIs differ by sex in GC. EBV infection and antral tumor location were independent factors in males, while MSI-H status was significant in females. These findings highlights the importance of sex-based immunobiology in tailoring GC treatment strategies.

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