Open AccessARL4C might serve as a prognostic factor and a novel therapeutic target for gastric cancer: bioinformatics analyses and biological experiments
Author(s) -
Xie Ning,
Bai Yunfan,
Qiao Lu,
Bai Yuru,
Wu Jian,
Li Yan,
Jiang Mingzuo,
Xu Bing,
Ni Zhen,
Yuan Ting,
Shi Yongquan,
Wu Kaichun,
Xu Feng,
Wang Jinhai,
Dong Lei,
Liu Na
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.16366
Subject(s) - biology , cancer , gene knockdown , cancer research , carcinogenesis , gene silencing , bioinformatics , computational biology , cell culture , genetics , gene
Abstract The ADP‐ribosylation factor‐like proteins (ARLs) have been proved to regulate the malignant phenotypes of several cancers. However, the exact role of ARLs in gastric cancer (GC) remains elusive. In this study, we systematically investigate the expression status, interactive relations, potential pathways, genetic variations and clinical values of ARLs in GC. We find that ARLs are significantly dysregulated in GC and involved in various cancer‐related pathways. Subsequently, machine learning models identify ARL4C as one of the two most significant clinical indicators among ARLs for GC. Furthermore, ARL4C silencing remarkably inhibits the growth and metastasis of GC cells both i n vitro and in vivo. Moreover, enrichment analysis indicates that ARL4C is highly correlated with TGF‐β1 signalling. Correspondingly, TGF‐β1 treatment dramatically increases ARL4C expression and ARL4C knockdown inhibits the phosphorylation level of Smads, downstream factors of TGF‐β1. Meanwhile, the coexpression of ARL4C and TGF‐β1 worsens the prognosis of GC patients. Our work comprehensively demonstrates the crucial role of ARLs in the carcinogenesis of GC and the specific mechanisms underlying the GC‐promoting effects of TGF‐β1. More importantly, we uncover the great promise of ARL4C‐targeted therapy in improving the efficacy of TGF‐β1 inhibitors for GC patients.