Cancer Research and Treatment

Original Articles

WNT3A Upregulates the RIP1/HIF-1α/GDF-15 Pathway to Induce Epithelial-Mesenchymal Transition 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 16, 2025 Accepted October 17, 2025 Published online October 20, 2025; DOI: https://doi.org/10.4143/crt.2025.620 [Epub ahead of print]

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Purpose
We previously demonstrated that WNT signaling, a key regulator of epithelial-mesenchymal transition (EMT), promotes malignancy via receptor-interacting protein 1 (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 and HCT116) and mouse embryonic fibroblasts (MEFs; wtMEF and RIP1−/− MEF) were used in this study. Expression levels of growth differentiation factor 15 (GDF-15) and GDNF receptor alpha-like (GFRAL) were assessed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and enzyme-linked immunosorbent assay (ELISA). RIP1 and hypoxia-inducible factor-1α (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 increased levels 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.

Citations

Citations to this article as recorded by

Resveratrol Attenuates Obesity by Inducing GDF15 Expression via the p38‐ATF3 Signaling Pathway
Liufeng Mao, Yunliang Hou, Weifang Liu, Jianbin Chen, Wanli Hu, Wengong Jiang, Tao Nie
Food Science & Nutrition.2026;[Epub] CrossRef

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CNS cancer

CYBC1 Drives Glioblastoma Progression via Reactive Oxygen Species and NF-κB Pathways: Hyeon Ji Kim, Tae-Jun Kim, Jin-Hwa Cho, Mee-Seon Kim, Jin-Seok Byun, Do-Yeon Kim; Cancer Res Treat. 2025;57(4):951-967. Published online December 24, 2024; DOI: https://doi.org/10.4143/crt.2024.827

Abstract PDF Supplementary Material PubReader ePub: Purpose
This study aims to investigate the role of cytochrome b-245 chaperone 1 (CYBC1) in glioblastoma (GBM) progression, focusing on its involvement in reactive oxygen species (ROS) production and associated signaling pathways. Understanding the molecular mechanisms driven by CYBC1 could provide new therapeutic targets and prognostic markers for GBM.
Materials and Methods
Publicly available datasets were analyzed to assess CYBC1 expression in GBM and its correlation with patient survival. GBM cell lines were genetically manipulated using the CRISPR/Cas9 system to deplete CYBC1. The effects of CYBC1 deficiency on cell proliferation, migration, invasion, and cell cycle dynamics were experimentally evaluated. Additionally, the impact of CYBC1 on the expression of NOXA1, a subunit of NADPH oxidase, and downstream signaling pathways such as nuclear factor кB (NF-κB) was explored.
Results
CYBC1 expression was significantly elevated in GBM tissues and correlated with poor patient survival. CYBC1 deficiency in GBM cells resulted in reduced cell viability, migration, and invasion. Mechanistically, CYBC1 positively regulated NOXA1 expression, which in turn enhanced ROS production and activated the ERK·AKT/NF-κB pathways. The suppression of CYBC1 led to decreased ROS levels, reduced phosphorylation of NF-κB, and downregulation of genes involved in epithelial-mesenchymal transition.
Conclusion
CYBC1 is implicated in GBM progression by regulating NOXA1-mediated ROS production and activating the ERK·AKT/NF-κB pathways. This study suggests that CYBC1 could serve as a potential therapeutic target and prognostic marker in GBM, warranting further investigation into its molecular mechanisms and therapeutic potential.

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