PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism.
PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism.
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PTPRO 通过重新编程脂肪酸代谢来抑制结直肠癌肿瘤的发生和进展
DOI：
10.1002/cac2.12341
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发表时间：
2022-09
影响因子：
16.2
通讯作者：
Cai, Guoxiang
中科院分区：
文献类型：
--
作者：
Dai, Weixing;Xiang, Wenqiang;Han, Lingyu;Yuan, Zixu;Wang, Renjie;Ma, Yanlei;Yang, Yongzhi;Cai, Sanjun;Xu, Ye;Mo, Shaobo;Li, Qingguo;Cai, Guoxiang
关键词：
据报道，蛋白酪氨酸磷酸酶（PTPs）的异常表达是癌症的一个关键病因。作为PTPs的一员，蛋白酪氨酸磷酸酶受体O型（PTPRO）已被发现在几种癌症中发挥肿瘤抑制作用，然而其在结直肠癌（CRC）中的作用仍有待阐明。因此，我们旨在探究PTPRO在CRC发生和进展中的作用及机制。
在体外和体内评估了PTPRO对CRC细胞生长和肝转移以及不同脂质代谢酶表达模式的影响。进行了分子和生物学实验以揭示从头脂肪生成和脂肪酸β - 氧化失调的潜在机制。
与原发性癌症相比，PTPRO在CRC肝转移中的表达显著下调，且这种下调与CRC患者的不良预后相关。PTPRO沉默显著促进细胞生长和肝转移。与PTPRO野生型小鼠相比，在偶氮甲烷和葡聚糖硫酸钠处理下，PTPRO敲除小鼠产生更多肿瘤且肿瘤负荷更大。基因集富集分析显示，PTPRO下调与脂肪酸代谢途径显著相关。阻断脂肪酸合成消除了PTPRO沉默对细胞生长和肝转移的影响。进一步的实验表明，PTPRO沉默诱导AKT丝氨酸/苏氨酸激酶（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）信号轴的激活，从而通过激活AKT/mTOR信号通路增强甾醇调节元件结合蛋白1（SREBP1）及其靶脂肪生成酶乙酰辅酶A羧化酶α（ACC1）的表达来促进从头脂肪生成。此外，PTPRO减弱通过激活p38/细胞外信号调节激酶（ERK）丝裂原活化蛋白激酶（MAPK）信号通路抑制过氧化物酶体增殖物激活受体α（PPARα）及其下游酶过氧化物酶体酰基辅酶A氧化酶1（ACOX1）的表达，从而降低脂肪酸氧化速率。
PTPRO可通过调节AKT/mTOR/SREBP1/ACC1和MAPK/PPARα/ACOX1途径以及重新编程脂质代谢来抑制CRC的发展和转移。
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. 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. 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. PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.
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结直肠癌癌细胞和肿瘤浸润淋巴细胞中程序性细胞死亡 1 (PD-1) 和 PD-配体 1 (PD-L1) 表达的预后影响
影响因子：
37.3
作者：
Li Y;Liang L;Dai W;Cai G;Xu Y;Li X;Li Q;Cai S
通讯作者：
Cai S
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
PTPRO 通过 ERBB2 的去磷酸化和内体内化来抑制 ERBB2 驱动的乳腺肿瘤发生
影响因子：
8
作者：
Dong H;Ma L;Gan J;Lin W;Chen C;Yao Z;Du L;Zheng L;Ke C;Huang X;Song H;Kumar R;Yeung SC;Zhang H
通讯作者：
Zhang H
DOI：
10.1186/s40880-018-0301-4
发表时间：
2018-05-21
期刊：
Cancer communications (London, England)
影响因子：
--
作者：
Cheng C;Geng F;Cheng X;Guo D
通讯作者：
Guo D
影响因子：
2.7
作者：
Dana, Nasim;Vaseghi, Golnaz;Javanmard, Shaghayegh Haghjooy
通讯作者：
Javanmard, Shaghayegh Haghjooy