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Gastric Cancer
Published in: Gastric Cancer 2/2022

01-03-2022 | Gastric Cancer | Original Article

Cancer-associated fibroblasts-derived HAPLN1 promotes tumour invasion through extracellular matrix remodeling in gastric cancer

Authors: Tiancheng Zhang, Xiang Li, Yani He, Yaohui Wang, Jiajia Shen, Shoulin Wang, Qiang You, Jing Zhai, Lizong Shen

Published in: Gastric Cancer | Issue 2/2022

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Abstract

Background

Cancer-associated fibroblasts (CAFs) are the most principal cells of depositing and remodeling extracellular matrix (ECM) within solid tumours. Both CAFs and ECM have been demonstrated to play critical roles in tumour development. However, the functional roles of CAFs-associated ECM or ECM remodeling in the pathogenesis of gastric cancer remain unclear.

Methods

Bioinformatics analysis of the differentially expressed genes between CAFs and corresponding normal fibroblasts (NFs) in gastric cancer was performed. The clinical relevance of hyaluronan and proteoglycan link protein 1 (HAPLN1) was investigated using TCGA data and human gastric cancer specimens. Spheroid cell invasion assay and nude mouse xenograft model were introduced to assay cell invasion. Second harmonic generation (SHG) was used to image and analyze the changes of collagen fibers in ECM.

Results

HAPLN1 was identified as the most significantly up-regulated gene in CAFs of gastric cancer, and higher HAPLN1 levels were associated with shorter overall survival. HAPLN1 was prominently produced by CAFs, and its levels were correlated positively with tumor T staging (P < 0.0001), lymph node metastasis (P = 0.0006) and TNM stage (P = 0.0063). Mechanically, gastric cancer cells activate fibroblasts to up-regulate HAPLN1 expression via activation of TGF-β1/Smad2/3 signaling, which in turn promotes tumour migration and invasion. Importantly, SHG assays with mouse xenograft models and human samples further demonstrated CAFs-derived HAPLN1 increased tumour invasiveness through ECM remodeling.

Conclusions

This study sheds light on the role of CAFs-derived HAPLN1 in the pathogenesis of gastric cancer, and provides insights for the development of novel strategies for prevention and treatment of gastric carcinoma.
Appendix
Available only for authorised users
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Metadata
Title
Cancer-associated fibroblasts-derived HAPLN1 promotes tumour invasion through extracellular matrix remodeling in gastric cancer
Authors
Tiancheng Zhang
Xiang Li
Yani He
Yaohui Wang
Jiajia Shen
Shoulin Wang
Qiang You
Jing Zhai
Lizong Shen
Publication date
01-03-2022
Publisher
Springer Singapore
Published in
Gastric Cancer / Issue 2/2022
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-021-01259-5

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