自Virchow提出肿瘤有可能起源于慢性炎症这一假说后，开启了人们对炎症和肿瘤关系的探索之路[1]。目前研究发现TNF-α、IL-6、NF-κB等炎症因子均可促进肝癌的发生、发展[2，3]。在我国，病毒性肝炎以乙型（Hepatitis B Viral，HBV）和...自Virchow提出肿瘤有可能起源于慢性炎症这一假说后，开启了人们对炎症和肿瘤关系的探索之路[1]。目前研究发现TNF-α、IL-6、NF-κB等炎症因子均可促进肝癌的发生、发展[2，3]。在我国，病毒性肝炎以乙型（Hepatitis B Viral，HBV）和丙型（Hepatitis C Viral，HCV）最为常见，而长期慢性炎症可推进肝纤维化及肝硬化的发展，进而诱发肝癌（Hepatocel-lular Carcinoma，HCC）[4，5]。PTPRO基因目前被认为是一种抑癌基因，共有6种变异体，它以全长形式（PT-PRO）存在于人肝脏、肾脏、脑、乳腺，以短截体形式（PTPROt）存在于B淋巴细胞及巨噬细胞中[6]。目前研究表明PTPRO基因在肺癌、乳腺癌、肝癌等肿瘤中因启动子CPG岛甲基化而沉默，并影响肿瘤的转移、增殖等细胞生物学行为[7]。而肝炎、肝硬化被认为是肝癌的癌前病变，目前针对PTPRO基因在肝炎、肝硬化中的作用机制亦受到广泛关注。展开更多
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 t...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 acidβ-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,PTPROknockout 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.展开更多
文摘自Virchow提出肿瘤有可能起源于慢性炎症这一假说后，开启了人们对炎症和肿瘤关系的探索之路[1]。目前研究发现TNF-α、IL-6、NF-κB等炎症因子均可促进肝癌的发生、发展[2，3]。在我国，病毒性肝炎以乙型（Hepatitis B Viral，HBV）和丙型（Hepatitis C Viral，HCV）最为常见，而长期慢性炎症可推进肝纤维化及肝硬化的发展，进而诱发肝癌（Hepatocel-lular Carcinoma，HCC）[4，5]。PTPRO基因目前被认为是一种抑癌基因，共有6种变异体，它以全长形式（PT-PRO）存在于人肝脏、肾脏、脑、乳腺，以短截体形式（PTPROt）存在于B淋巴细胞及巨噬细胞中[6]。目前研究表明PTPRO基因在肺癌、乳腺癌、肝癌等肿瘤中因启动子CPG岛甲基化而沉默，并影响肿瘤的转移、增殖等细胞生物学行为[7]。而肝炎、肝硬化被认为是肝癌的癌前病变，目前针对PTPRO基因在肝炎、肝硬化中的作用机制亦受到广泛关注。
基金National Natural Science Foundation of China,Grant/Award Numbers:81871958,82103554Science and Technology Commission of Shanghai Municipality,Grant/Award Numbers:19140902100,16401970502,17411951100。
文摘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 acidβ-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,PTPROknockout 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.
