Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer

Yen An Tang, Yu feng Chen, Yi Bao, Sylvia Mahara, Siti Maryam J.M. Yatim, Gokce Oguz, Puay Leng Lee, Min Feng, Yu Cai, Ern Yu Tan, Sau Shung Fong, Zi huan Yang, Ping Lan, Xiao jian Wu, Qiang Yu

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2−mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.

Original languageEnglish
Pages (from-to)E5990-E5999
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number26
DOIs
Publication statusPublished - 2018 Jun 26

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer'. Together they form a unique fingerprint.

Cite this