[Metformin Suppresses Hypoxia-inducible Factor-1 Expression in Cancer-associated Fibroblasts to Block Tumor-stromal Cross-talk in Breast Cancer]

Overview

Journal Nan Fang Yi Ke Da Xue Xue Bao

Specialty General Medicine

Date 2024 Apr 10

PMID 38597433

Authors

S Shao

W Bai

P Zhou

M Luo

X Zhao

J Lei

Affiliations

Soon will be listed here.

Abstract

Objective: To investigate the mechanism of metformin for regulating tumor-stromal cell cross-talk in breast cancer.

Methods: Tumor associated fibroblasts (CAFs) co-cultured with breast cancer cells were treated with metformin, and the changes in expressions of hypoxia-inducible factor-1 (HIF-1), p-AMPK, stroma-derived factor-1 (SDF-1) and interleukin-8 (IL-8) in the CAFs were detected using ELISA, RT-qPCR or Western blotting; Transwell assay was used to evaluate the invasiveness of the tumor cells and its changes following treatment with exogenous SDF-1, IL-8 and TGF-β1. The effects of HIF-1 shRNA or overexpression plasmid, AMPK shRNA, and treatment with OG (a proline hydroxylase inhibitor) or 2-OXO (a proline hydroxylase activator) were examined on p-AMPK, HIF-1, SDF-1 and IL-8 expressions and invasiveness of the CAFs.

Results: Metformin treatment significantly increased the expression levels of p-AMPK, SDF-1 and IL-8 (<0.05) and decreased HIF-1 expression (<0.05) without affecting AMPK expression level (>0.05) in the CAFs. The invasion ability of metformintreated breast cancer cells was significantly decreased (<0.05). Exogenous SDF-1 and IL-8, HIF-1 overexpression, and OGinduced upregulation of HIF-1 all significantly attenuated the inhibitory effects of metformin on breast cancer cell invasion (<0.05) and HIF-1, SDF-1 and IL-8 expressions in CAFs (<0.05). Transfection with HIF-1 shRNA or treatment with 2-OXO significantly decreased the invasiveness of breast cancer cells (<0.05). P-AMPK knockdown significantly suppressed the inhibitory effect of metformin on HIF-1 expression in CAFs and on invasion of breast cancer cells (<0.05). Treatment with TGF-β1 partially decreased the inhibitory effect of metformin on HIF-1 expression in CAFs and invasiveness of the breast cancer cells (<0.05).

Conclusion: Metformin suppresses HIF-1 expression in CAFs to block tumor-stromal cross talk in breast cancer.

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