HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis

Cell Death & Disease
Xusheng DingJun Zhang

Abstract

Cancer-associated fibroblasts (CAFs) are important components of tumor stroma and play a key role in tumor progression. CAFs involve in crosstalk with tumor cells through various kinds of cytokines. In the present study, we screened hepatocyte growth factor (HGF) as a cytokine predominantly originating from CAFs. CAFs-derived HGF was found to promote MET-unamplified gastric cancer (GC) proliferation, migration, and invasion through the activation of HGF/c-Met/STAT3/twist1 pathway. It also activated interleukin (IL)-6/IL-6R/JAK2/STAT3/twist1 pathway by up-regulating IL-6R expression. As IL-6 was also found to upregulate c-Met expression, we identified the cooperation of HGF and IL-6 in enhancing the characteristics of CAFs. In vivo experiments revealed that CAFs-derived HGF promoted tumorigenesis and metastasis of MET-unamplified GC. Gene set enrichment analysis (GSEA) was performed to confirm our findings. Our study found that the increased expression of HGF in CAFs induced by MET-unamplified GC contributed to the malignant phenotype of both MET-unamplified GC and CAFs in tumor microenvironment.

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Citations

Sep 9, 2019·Cancer Science·Shamaine Wei Ting Ho, Patrick Tan
Nov 7, 2019·Cancers·Kelsey L PolakMark W Jackson
Sep 8, 2020·Cancer Metastasis Reviews·Rachel E SextonAsfar S Azmi
Apr 3, 2020·Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association·Cheong A BaeHoon Hur
Jan 4, 2021·Acta Biomaterialia·Xiaobei LuoSide Liu
Jan 29, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Ji-Min LiChing-Hsien Chen
Jun 9, 2021·Biochemical Society Transactions·Nishanth Belugali NatarajYosef Yarden
Jun 3, 2021·Cancers·Mamatha KakarlaOmar E Franco
Jun 11, 2021·Signal Transduction and Targeted Therapy·Fanglong WuHongmei Zhou

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Datasets Mentioned

BETA
GSE62254

Methods Mentioned

BETA
PCR
enzyme-linked immunosorbent assay
ELISA
RNA-seq
immunoprecipitation
transfection
Flow cytometry
electrophoresis

Software Mentioned

ALGGEN
PROMO
FlowJo
GraphPad Prism6
GSEA

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