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

Cancer Communications

article

Weixing Dai¹  Wenqiang Xiang¹  Lingyu Han¹  Zixu Yuan⁴  Renjie Wang¹  Yanlei Ma¹  Yongzhi Yang¹  Sanjun Cai¹  Ye Xu¹  Shaobo Mo¹  Qingguo Li¹  Guoxiang Cai¹ 

[1] Department of Colorectal Surgery, Fudan University Shanghai Cancer Center;Department of Oncology, Shanghai Medical College, Fudan University;These authors contributed equally to this work;Department of Surgery, Sixth Affiliated Hospital of Sun Yat-sen University

关键词: AKT;    colorectal cancer;    fatty acid oxidation;    fatty acid synthesis;    lipid metabolism;    liver metastasis;    mTOR;    PTPRO;    tumorigenesis;   

DOI  :  10.1002/cac2.12341

学科分类：社会科学、人文和艺术（综合）

来源: Springer

【 摘 要 】

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 silencing induced the activation of the AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling axis, thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element-binding protein 1 (SREBP1) and its target lipogenic enzyme acetyl-CoA carboxylase alpha (ACC1) by activating the AKT/mTOR signaling pathway. Furthermore, PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator-activated receptor alpha (PPARα) and its downstream enzyme peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) via activating the p38/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. Conclusions PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.

【 授权许可】

CC BY|CC BY-NC-ND