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

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 26 Pg. E5990-E5999 (06 26 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 29891662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GLI2 protein, human
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• Nuclear Proteins
• TGFB2 protein, human
• Transforming Growth Factor beta2
• Zinc Finger Protein Gli2

Topics

• Cell Hypoxia
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Drug Resistance, Neoplasm
• Female
• Fibroblasts (metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, genetics)
• Male
• Neoplasm Proteins (biosynthesis, genetics)
• Nuclear Proteins (biosynthesis, genetics)
• Transforming Growth Factor beta2 (biosynthesis, genetics)
• Tumor Microenvironment
• Zinc Finger Protein Gli2 (biosynthesis, genetics)