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Hypoxic microenvironment activates GLI2 through synergistic action of TGF-β2 and HIF-1α to confer chemoresistance and poor clinical outcome in colorectal cancer

ABSTRACT: Hypoxic microenvironment activates GLI2 through synergistic action of TGF-β2 and HIF-1α to confer chemoresistance and poor clinical outcome in colorectal cancer

PROVIDER: PRJNA360422 | ENA |

REPOSITORIES: ENA

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Hypoxic microenvironment activates GLI2 through synergistic action of TGF-β2 and HIF-1α to confer chemoresistance and poor clinical outcome in colorectal cancer [IlluminaExpr_2_CAF_SF_SD208]

Project description:Microenvironment has been suggested as an important factor contributing to how the colorectal cancer cells escape therapy, but the exact mechanism leading to chemoresistance remains elusive. Here, through modeling in vitro by cocultivation of patient-derived cancer associated fibroblasts (CAFs) with cancer stem cells (CSCs), we show that CAFs-secreted TGF-β2 is a key stromal factor that coordinates with hypoxia to promote CSC stemness and resistance to chemotherapy. GLI2, a key transcription factor of Hedgehog pathway, was identified as both necessary and sufficient in this process in which TGF-β and hypoxia-inducible factor (HIF-1α) synergize to directly induce GLI2 expression. Conversely, CSC-secreted TGF-β is also important to support the growth of CAFs but instead induce death of normal fibroblasts, suggesting a reciprocal mechanism to selectively support the CAF-CSC interaction. Small molecule inhibition of both TGF-β and GLI2 effectively reversed the chemoresistance. Finally, expression of TGFB2/HIF1A/GLI2 gene signature as a functional readout of this resistance pathway defines worse clinical outcomes and predicts patients relapse. Our observations uncover a key role of TGF-β/HIF-1α/GLI2 in microenvironment-mediated chemoresistance and reveal novel biomarker and targeting strategies to identify and treat the high risk CRC patients.

2019-01-30 | GSE93254 | GEO

Hypoxic microenvironment activates GLI2 through synergistic action of TGF-β2 and HIF-1α to confer chemoresistance and poor clinical outcome in colorectal cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

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Hypoxic microenvironment activates GLI2 through synergistic action of TGF-β2 and HIF-1α to confer chemoresistance and poor clinical outcome in colorectal cancer [IlluminaExpr_1_CAF_NF]

Project description:Analysis of gene expression profiles of three cancer-associated fibroblasts (CAFs) and four normal fibroblasts (NFs), which are derived from tumor tissues and adjacent normal mucosa of colorectal cancer patients, respectively.

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Overexpression of GLI2 induces genomic instability

Project description:We used genome-wide microarray comparative genomic hybridization to investigate the response of control HT1080 cells and HT1080 cells infected with a lentivirus expressing eGFP, GLI2-eGFP or CCND1-RFP to challenge with methotrexate to address the question if GLI2 overexpression induces genomic instability. Keywords: aCGH Array CGH experiments of cell line genomic DNA as test samples and normal human genomic DNA as reference sample.

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Mitochondrial hTERT rewires glucose metabolism to confer cancer chemoresistance by binding to MT-ND1

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Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion

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Overexpression of GLI2 induces genomic instability

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Hypoxic tumor microenvironment activates GLI2 via HIF-1? and TGF-?2 to promote chemoresistance in colorectal cancer.

Project description: Not available

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