Hypoxia inducible factor 3-alpha promotes a malignant phenotype in colorectal cancer cells
Por:
Lopez-Mejia A., Moreno-Londoño A.P., Fonseca Camarillo G., Yamamoto-Furusho J.K., Villanueva-Herrero J.A., de Leon-Rendón J.L., Castañeda Patlán M.C., Robles-Flores M.
Publicada:
1 ene 2025
Resumen:
Colorectal cancer (CRC) is the third most common cancer worldwide. Hypoxia is a hallmark of the tumor microenvironment, and cellular adaptation to it is primarily mediated by the family of Hypoxia-inducible factors (HIFs) HIF-1a, HIF-2a, and HIF-3a. However, in contrast to HIF-1a and HIF-2a, a specific role for HIF-3a in cancer biology has not yet been clearly established. This research was aimed to elucidate the role of HIF-3a in colon cancer. As reported previously for HIF-1a and HIF-2a, we found that HIF-3a is also overexpressed under normoxic conditions in all cancer cell lines examined and in patient-derived tumor tissue samples compared with non-malignant cells and normal tissue, but remarkably, pulse-chase experiments demonstrated that HIF-3a displays high stability in cells compared with HIF-1a and HIF-2a. Progno Scan data analysis showed that overexpression of HIF-3a correlated with a patient's lower survival rate and a poor prognosis in colon adenocarcinoma patients. Knockdown of HIF-3a expression was carried out to investigate the effects derived from its silencing on malignant phenotype. We found a significative decrease in the Hypoxia Response Element (HRE) reporter transcriptional activity mediated by HIF-3a and a reduction in cell viability under oxidative stress in colon cancer cells with HIF-3a knockdown compared with control HIF-3a expressing cells. In addition, HIF-3a silencing also produced an increase in apoptotic rate, decreased clonogenic capacity, altered autophagy flux, and modulated the canonical Wnt/ß pathway in an isoform-dependent and cell context-dependent manner in colon cancer cells. Overall, these data show that transcriptional activity mediated by HI3-3a plays an essential role in promoting the malignant phenotype, cell survival, and resistance to cell death in CRC cells. © 2025 The Author(s). IUBMB Life published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.
Filiaciones:
Lopez-Mejia A.:
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
Moreno-Londoño A.P.:
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
Fonseca Camarillo G.:
Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Clínica de Enfermedad Inflamatoria Intestinal, Ciudad de México, Mexico
Yamamoto-Furusho J.K.:
Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Clínica de Enfermedad Inflamatoria Intestinal, Ciudad de México, Mexico
Villanueva-Herrero J.A.:
Servicio de Coloproctología, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México, Mexico
de Leon-Rendón J.L.:
Servicio de Coloproctología, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México, Mexico
Castañeda Patlán M.C.:
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
Robles-Flores M.:
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
hybrid, All Open Access; Hybrid Gold Open Access
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