|
|||||
|
|
ARL4C might serve as a prognostic factor and a novel therapeutic target for gastric cancer: bioinformatics analyses and biological experiments |
|
| Authors: | Ning Xie Yunfan Bai Lu Qiao Yuru Bai Jian Wu Yan Li Mingzuo Jiang Bing Xu Zhen Ni Ting Yuan Yongquan Shi Kaichun Wu Feng Xu Jinhai Wang Lei Dong Na Liu |
| Affiliation: | 1. Department of Gastroenterology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China Shaanxi Key Laboratory of Gastrointestinal Motility Disorders, Xi’an Jiaotong University, Xi'an, China;2. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan;3. State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, China;4. Department of Gastroenterology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China;5. The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China Bioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong University, Xi’an, China |
| 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 in 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. |
| Keywords: | ARL4C ARLs clinical values gastric cancer TGF-β1 |