Cancer Research and Treatment

Original Articles

Gynecologic cancer

Identification of Patients with Recurrent Epithelial Ovarian Cancer Who Will Benefit from More Than Three Lines of Chemotherapy: Aeran Seol, Ga Won Yim, Joo Yeon Chung, Se Ik Kim, Maria Lee, Hee Seung Kim, Hyun Hoon Chung, Jae-Weon Kim, Noh Hyun Park, Yong Sang Song; Cancer Res Treat. 2022;54(4):1219-1229. Published online November 17, 2021; DOI: https://doi.org/10.4143/crt.2021.1010

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Purpose
This study aimed to identify patients who would benefit from third and subsequent lines of chemotherapy in recurrent epithelial ovarian cancer (EOC).
Materials and Methods
Recurrent EOC patients who received third, fourth, or fifth-line palliative chemotherapy were retrospectively analyzed. Patients’ survival outcomes were assessed according to chemotherapy lines. Based on the best objective response, patients were divided into good-response (stable disease or better) and poor response (progressive disease or those who died before response assessment) groups. Survival outcomes were compared between the two groups, and factors associated with chemotherapy responses were investigated.
Results
A total of 189 patients were evaluated. Ninety-four and 95 patients were identified as good and poor response group respectively, during the study period of 2008 to 2021. The poor response group showed significantly worse progression-free survival (median, 2.1 months vs. 9.7 months; p < 0.001) and overall survival (median, 5.0 months vs. 22.9 months; p < 0.001) compared with the good response group. In multivariate analysis adjusting for clinicopathologic factors, short treatment-free interval (TFI) (hazard ratio [HR], 5.557; 95% confidence interval [CI], 2.403 to 12.850), platinum-resistant EOC (HR, 2.367; 95% CI, 1.017 to 5.510), and non-serous/endometrioid histologic type (HR, 5.045; 95% CI, 1.152 to 22.088) were identified as independent risk factors for poor response. There was no difference in serious adverse events between good and poor response groups (p=0.167).
Conclusion
Third and subsequent lines of chemotherapy could be carefully considered for palliative purposes in recurrent EOC patients with serous or endometrioid histology, initial platinum sensitivity, and long TFIs from the previous chemotherapy regimen.

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CircSETDB1 contributes to paclitaxel resistance of ovarian cancer cells by sponging miR-508-3p and regulating ABCC1 expression
Chunyan Huang, Li Qin, Sailan Chen, Qin Huang
Anti-Cancer Drugs.2022;[Epub] CrossRef

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Long Non-coding RNA HOXA11 Antisense Promotes Cell Proliferation and Invasion and Predicts Patient Prognosis in Serous Ovarian Cancer: Ga Won Yim, Hee Jung Kim, Lee Kyung Kim, Sang Wun Kim, Sunghoon Kim, Eun Ji Nam, Young Tae Kim; Cancer Res Treat. 2017;49(3):656-668. Published online October 11, 2016; DOI: https://doi.org/10.4143/crt.2016.263

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Purpose
The biological function of long non-coding RNAs (lncRNAs) is only partially understood; therefore, in this study, we investigated the expression of the novel HOXA11 antisense (HOXA11as) lncRNA and its oncogenic role in serous ovarian cancer (SOC).
Materials and Methods
HOXA11as expression was examined in 129 SOC tissue samples by real time reverse transcription polymerase chain reaction. Clinicopathological factors and patient survival were compared between the high (n=27) and low HOXA11as expression group (n=102). To investigate the role of HOXA11as in cell proliferation, invasion, and migration, HOXA11as expression in ovarian cancer cells was knocked down using RNA interference.
Results
HOXA11as expression in cancer tissue was 77-fold higher than that of noncancerous tissue (p < 0.05). Higher HOXA11as expression was significantly correlated with histological grade (p=0.017) and preoperative cancer antigen 125 (p=0.048). HOXA11as overexpression in SOC cells led to increased cell proliferation, invasion, and migration. Moreover, HOXA11as was associated with the expression of genes involved in cell invasion, migration, and epithelial-mesenchymal transition (EMT), including vascular endothelial growth factor, matrix metalloproteinase 9 (MMP-9), B-catenin, E-cadherin, Snail, Twist, and vimentin. Multivariate analysis revealed that HOXA11as was a prognostic factor of progressive disease and mortality (hazard ratio [HR], 1.730; p=0.043 and HR, 2.170; p=0.033, respectively). Progression-free and overall survival were significantly shorter in patients with high HOXA11as expression.
Conclusion
These findings highlight the clinical significance of HOXA11as to predicting the prognosis of SOC patients and suggest its potential in promoting tumor aggressiveness via regulation of vascular endothelial growth factor (VEGF), MMP-9, and EMT-related mechanisms.

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The Role of EMT-Related lncRNAs in Ovarian Cancer
Dimitra Ioanna Lampropoulou, Marios Papadimitriou, Christos Papadimitriou, Dimitrios Filippou, Georgia Kourlaba, Gerasimos Aravantinos, Maria Gazouli
International Journal of Molecular Sciences.2023; 24(12): 10079. CrossRef
LncRNAs and the Angiogenic Switch in Cancer: Clinical Significance and Therapeutic Opportunities
Peace Mabeta, Rodney Hull, Zodwa Dlamini
Genes.2022; 13(1): 152. CrossRef
Long non-coding RNA HOXA11-AS knockout inhibits proliferation and overcomes drug resistance in ovarian cancer
Yuwei Chen, Zhaolei Cui, Qiaoling Wu, Huihui Wang, Hongmei Xia, Yang Sun
Bioengineered.2022; 13(5): 13893. CrossRef
The role of altered long noncoding RNAs in overall survival of ovarian cancer: A systematic review and meta-analysis
Elahe Seyed Hosseini, Marziyeh Alizadeh Zarei, Hamed Haddad Kashani, Alireza Milajerdi, Zahra Zare Dehghanani, Hassan Hassani Bafrani, Hossein Nikzad
Pathology - Research and Practice.2021; 219: 153363. CrossRef
Non-Coding RNAs as Biomarkers of Tumor Progression and Metastatic Spread in Epithelial Ovarian Cancer
Karolina Seborova, Radka Vaclavikova, Lukas Rob, Pavel Soucek, Pavel Vodicka
Cancers.2021; 13(8): 1839. CrossRef
Long non-coding RNAs: A view to kill ovarian cancer
Alexey V. Zamaraev, Pavel I. Volik, Gennady T. Sukhikh, Gelina S. Kopeina, Boris Zhivotovsky
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.2021; 1876(1): 188584. CrossRef
Long non-coding RNA CASC15 favors tumorigenesis and development of ovarian cancer via sponging miR-542-3p
Qiang LI, Wenjing LIU, Sumei LI, Su ZHANG
Panminerva Medica.2021;[Epub] CrossRef
Long non-coding RNAs in ovarian cancer: expression profile and functional spectrum
Selin Oncul, Paola Amero, Cristian Rodriguez-Aguayo, George A. Calin, Anil K. Sood, Gabriel Lopez-Berestein
RNA Biology.2020; 17(11): 1523. CrossRef
A comprehensive review of the role of long non-coding RNAs in organs with an endocrine function
Soudeh Ghafouri-Fard, Mohammadhosein Esmaeili, Hamed Shoorei, Mohammad Taheri
Biomedicine & Pharmacotherapy.2020; 125: 110027. CrossRef
Cyclooxygenase-2 promotes ovarian cancer cell migration and cisplatin resistance via regulating epithelial mesenchymal transition
Lin Deng, Ding-qing Feng, Bin Ling
Journal of Zhejiang University-SCIENCE B.2020; 21(4): 315. CrossRef
Long Noncoding RNA E2F4as Promotes Progression and Predicts Patient Prognosis in Human Ovarian Cancer
Sun-Ae Park, Lee Kyung Kim, Young Tae Kim, Tae-Hwe Heo, Hee Jung Kim
Cancers.2020; 12(12): 3626. CrossRef
lncRNA HOXA11-AS Promotes Proliferation and Migration via Sponging miR-155 in Hypopharyngeal Squamous Cell Carcinoma
Jianing Xu, Qiyu Bo, Xiang Zhang, Dapeng Lei, Jue Wang, Xinliang Pan
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics.2020; 28(3): 311. CrossRef
LncRNAs in ovarian cancer
Jin-yan Wang, Ai-qing Lu, Li-juan Chen
Clinica Chimica Acta.2019; 490: 17. CrossRef
Up-regulation of long intergenic noncoding RNA 01296 in ovarian cancer impacts invasion, apoptosis and cell cycle distribution via regulating EMT
Hui Xu, Jing-Fang Zheng, Cong-Zhe Hou, Yue Li, Pei-Shu Liu
Cellular Signalling.2019; 62: 109341. CrossRef
A novel risk score system for assessment of ovarian cancer based on co-expression network analysis and expression level of five lncRNAs
Qian Zhao, Conghong Fan
BMC Medical Genetics.2019;[Epub] CrossRef
Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils
Anquan Shang, Weiwei Wang, Chenzheng Gu, Chen Chen, Bingjie Zeng, Yibao Yang, Ping Ji, Junjun Sun, Junlu Wu, Wenying Lu, Zujun Sun, Dong Li
Journal of Experimental & Clinical Cancer Research.2019;[Epub] CrossRef
LINC01210 accelerates proliferation, invasion and migration in ovarian cancer through epigenetically downregulating KLF4
Chu Zhang, Jie Liu, Yang Zhang, Chengyan Luo, Tong Zhu, Rongrong Zhang, Ruiqin Yao
Biomedicine & Pharmacotherapy.2019; 119: 109431. CrossRef
Prognostic and clinicopathological significance of long noncoding RNA HOXA11-AS expression in human solid tumors: a meta-analysis
Shidai Mu, Lisha Ai, Fengjuan Fan, Chunyan Sun, Yu Hu
Cancer Cell International.2018;[Epub] CrossRef
Long non-coding RNAs in ovarian cancer
Lei Zhan, Jun Li, Bing Wei
Journal of Experimental & Clinical Cancer Research.2018;[Epub] CrossRef
HOXA11 antisense long noncoding RNA (HOXA11‐AS): A promising lncRNA in human cancers
Cheng‐Wei Lu, Dan‐Dan Zhou, Tian Xie, Ji‐Long Hao, Om Prakash Pant, Cheng‐Bo Lu, Xiu‐Fen Liu
Cancer Medicine.2018; 7(8): 3792. CrossRef
Long noncoding RNA LINC00152 promotes cell proliferation through competitively binding endogenous miR‐125b with MCL‐1 by regulating mitochondrial apoptosis pathways in ovarian cancer
Puxiang Chen, Xiaolin Fang, Bing Xia, Yan Zhao, Qiaoyan Li, Xiaoying Wu
Cancer Medicine.2018; 7(9): 4530. CrossRef
Altered long noncoding RNAs and survival outcomes in ovarian cancer
Li Ning, Ying-chao Hu, Shu Wang, Jing-he Lang
Medicine.2018; 97(32): e11481. CrossRef
Long non-coding RNAs as emerging regulators of epithelial to mesenchymal transition in gynecologic cancers
Xiaojing Lin, Junjun Qiu, Keqin Hua
BioScience Trends.2018; 12(4): 342. CrossRef
RETRACTED ARTICLE: Systematic analyses reveal long non-coding RNA (PTAF)-mediated promotion of EMT and invasion-metastasis in serous ovarian cancer
Haihai Liang, Xiaoguang Zhao, Chengyu Wang, Jian Sun, Yingzhun Chen, Guoyuan Wang, Lei Fang, Rui Yang, Mengxue Yu, Yunyan Gu, Hongli Shan
Molecular Cancer.2018;[Epub] CrossRef
LncRNAs KB‑1836B5, LINC00566 and FAM27L are associated with the survival time of patients with ovarian cancer
Huijian Li, Mi Gong, Min Zhao, Xinru Wang, Wenjun Cheng, Yankai Xia
Oncology Letters.2018;[Epub] CrossRef
‘Lnc’‐ing Wnt in female reproductive cancers: therapeutic potential of long non‐coding RNAs in Wnt signalling
Mei S Ong, Wanpei Cai, Yi Yuan, Hin C Leong, Tuan Z Tan, Asad Mohammad, Ming L You, Frank Arfuso, Boon C Goh, Sudha Warrier, Gautam Sethi, Nicholas S Tolwinski, Peter E Lobie, Celestial T Yap, Shing C Hooi, Ruby Y Huang, Alan P Kumar
British Journal of Pharmacology.2017; 174(24): 4684. CrossRef
Long non-coding RNA HOXA11-AS in human cancer: A meta-analysis
Na Li, Meilan Yang, Ke Shi, Wei Li
Clinica Chimica Acta.2017; 474: 165. CrossRef
Dysregulated expression of homeobox family genes may influence survival outcomes of patients with epithelial ovarian cancer: analysis of data from The Cancer Genome Atlas
Kyung Jin Eoh, Hee Jung Kim, Jung-Yun Lee, Eun Ji Nam, Sunghoon Kim, Sang Wun Kim, Young Tae Kim
Oncotarget.2017; 8(41): 70579. CrossRef

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Synergistic Effect of COX-2 Inhibitor on Paclitaxel-Induced Apoptosis in the Human Ovarian Cancer Cell Line OVCAR-3: Hee Jung Kim, Ga Won Yim, Eun Ji Nam, Young Tae Kim; Cancer Res Treat. 2014;46(1):81-92. Published online January 15, 2014; DOI: https://doi.org/10.4143/crt.2014.46.1.81

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PURPOSE
Celecoxib, a highly selective cyclooxygenase-2 inhibitor, regulates apoptosis of several types of human cancer cells. The purpose of this study was to investigate whether celecoxib in combination with paclitaxel modulates apoptosis of ovarian cancer cells, and to identify the signal pathway by which celecoxib mediates apoptosis.
MATERIALS AND METHODS
OVCAR-3 cells were exposed to paclitaxel (20 microM) in the absence or presence of celecoxib (10 microM). Cell viability was evaluated using a Cell Counting Kit-8 assay. Apoptosis was evaluated using Annexin-V/7-aminoactinomycin D staining and a cellular DNA fragmentation enzyme-linked immunosorbent assay. Caspase-3, -9, and cleavage of poly ADP-ribose polymerase (PARP) were determined by western blotting. Expression of nuclear factor-kappaB (NF-kappaB) and vascular endothelial growth factor (VEGF) and Akt activation were assessed using reverse transcriptase-polymerase chain reaction and western blotting.
RESULTS
Celecoxib enhanced paclitaxel-induced growth inhibition of OVCAR-3 cells. Celecoxib significantly increased paclitaxel-induced apoptosis of OVCAR-3 cells. Pretreatment with celecoxib also increased activation of caspase-9, -3 and cleaved PARP following paclitaxel-treatment. Exposure of OVCAR-3 cells to celecoxib in combination with paclitaxel resulted in downregulation of NF-kappaB activation and VEGF expression. Furthermore, combining celecoxib and paclitaxel inhibited phosphorylation of Akt.
CONCLUSION
OVCAR-3 cells were sensitized to paclitaxel-induced apoptosis by celecoxib through downregulation of NF-kappaB and Akt activation, suggesting that celecoxib may work synergistically with paclitaxel to inhibit different targets and ultimately produce anticancer effects. Combining celecoxib with paclitaxel may prove beneficial in the clinical treatment of ovarian cancer.

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Concomitant effects of paclitaxel and celecoxib on genes involved in apoptosis of triple-negative metastatic breast cancer cells
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