PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

作者：Weixing Dai, Wenqiang Xiang, Lingyu Han, Zixu Yuan, Renjie Wang, Yanlei Ma, Yongzhi Yang, Sanjun Cai, Ye Xu, Shaobo Mo, Qingguo Li, Guoxiang Cai · 发表于：癌症：英文版 · 年份：2022 · DOI：10.1002/cac2.12341 · 被引用次数：111 · 研究领域：Protein Tyrosine Phosphatases、Cancer, Lipids, and Metabolism、Cancer, Hypoxia, and Metabolism

BACKGROUND: Abnormal expression of protein tyrosine phosphatases (PTPs) has been reported to be a crucial cause of cancer. As a member of PTPs, protein tyrosine phosphatase receptor type O (PTPRO) has been revealed to play tumor suppressive roles in several cancers, while its roles in colorectal cancer (CRC) remains to be elucidated. Hence, we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression. METHODS: The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo. Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acid β-oxidation. RESULTS: PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation was associated with poor prognosis of patients with CRC. PTPRO silencing significantly promoted cell growth and liver metastasis. Compared with PTPRO wild-type mice, PTPRO-knockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium. Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways. Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis. Further experiments indicated that PTPRO silenci...