PPP1R26 drives hepatocellular carcinoma progression by controlling glycolysis and epithelial-mesenchymal transition.
PPP1R26 drives hepatocellular carcinoma progression by controlling glycolysis and epithelial-mesenchymal transition.
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PPP1R26通过控制糖酵解和上皮间质转化驱动肝细胞癌进展
DOI：
10.1186/s13046-022-02302-8
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发表时间：
2022-03-15
期刊：
影响因子：
--
通讯作者：
Xing B
中科院分区：
文献类型：
--
作者：
Yang Y;Ren P;Liu X;Sun X;Zhang C;Du X;Xing B
背景肝细胞癌（HCC）由于进展迅速，通常在晚期才被诊断.糖酵解支持合成代谢生长和转移以促进HCC进展。方法采用免疫组织化学方法检测PPP 1 R26在人肝癌组织中的表达，分析PPP 1 R26在肝癌进展和预后中的临床意义。通过质谱分析测定PPP 1 R26结合蛋白。在HCC细胞中评价PPP 1 R26在糖酵解、EMT和肿瘤发生中的功能。在小鼠体内异种移植物中使用PET成像评估葡萄糖摄取和肿瘤生长。通过免疫共沉淀和免疫荧光共定位确认蛋白结合。通过RNA免疫沉淀（RIP）实验测定蛋白质-RNA结合。结果PPP 1 R26在人肝癌组织中表达上调，且其表达上调与患者的转移和生存率显著相关。PPP 1 R26在体内激活HCC细胞和小鼠异种移植物中的糖酵解。PPP 1 R26通过与PTBP 1结合促进PKM 2的mRNA剪接来驱动糖酵解。同时，PPP 1 R26过表达诱导PKM 2在细胞核内积聚，抑制E-cadherin的表达，进而驱动EMT。结论PPP 1 R26通过增强PKM 2剪接促进糖酵解，同时通过PPP 1 R26-PKM 2-TGIF 2复合物激活EMT，从而促进HCC的进展。因此，靶向PPP 1 R26可减缓HCC进展，并为PPP 1 R26上调的HCC患者提供潜在的治疗策略。
BackgroundHepatocellular carcinoma (HCC) is usually diagnosed at an advanced stage due to rapid progression. Glycolysis supports anabolic growth and metastasis to promote HCC progression. However, the molecular mechanisms linking glycolysis and metastasis in HCC are not completely defined.MethodsThe expression of PPP1R26 in human HCC tissues was evaluated by immunohistochemistry, and the clinical significance of PPP1R26 in the progression and prognosis of the HCC patients were analyzed. The PPP1R26-binding proteins were determined by mass spectrometry analysis. The function of PPP1R26 in glycolysis, EMT and tumorigenesis were evaluated in HCC cells. Glucose uptake and tumor growth were evaluated using PET imaging in mouse xenograftsin vivo. Protein binding was confirmed by co-immunoprecipitation and immunofluorescence co-localization. Protein-RNA binding was determined by RNA-immunoprecipitation (RIP) experiment. The binding of protein on the promoter was evaluated by chromatin immunoprecipitation assay (ChIP).ResultsPPP1R26 is upregulated in human HCC tissues and its upregulation is significantly associated with metastasis and the poor survival of the patients. PPP1R26 activates glycolysis in HCC cells and in mouse xenograftsin vivo. PPP1R26 drives glycolysis by binding to PTBP1 to facilitate the mRNA splicing ofPKM2. Simultaneously, overexpressed PPP1R26 induces the nuclear accumulation of PKM2 to inhibit the expression of E-cadherin further to drive EMT. Mechanistically, PPP1R26 binds with Ser37-phosphorylated PKM2 and TGIF2 in the nucleus and blocks the binding of TGIF2 withCDH1promoter to inhibit the transcription ofCDH1.ConclusionPPP1R26 promotes glycolysis by enhancing PKM2 splicing and simultaneously activates EMT by forming a PPP1R26-PKM2-TGIF2 complex to drive HCC progression. Therefore, targeting PPP1R26 attenuates HCC progression and provides a potential therapeutic strategy for the HCC patients with upregulation of PPP1R26.
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影响因子：
5.9
作者：
Masin M;Vazquez J;Rossi S;Groeneveld S;Samson N;Schwalie PC;Deplancke B;Frawley LE;Gouttenoire J;Moradpour D;Oliver TG;Meylan E
通讯作者：
Meylan E
影响因子：
20.8
作者：
Elia I;Haigis MC
通讯作者：
Haigis MC
影响因子：
3.3
作者：
del Pilar Chantada-Vazquez, Maria;Castro Lopez, Antonio;Nunez, Cristina
通讯作者：
Nunez, Cristina
MiR-199a-5p 与恶性肿瘤呈负相关，并通过靶向肝癌中的己糖激酶 2 来调节糖酵解和乳酸的产生
影响因子：
13.5
作者：
Guo, Weijie;Qiu, Zhaoping;He, Xianghuo
通讯作者：
He, Xianghuo
影响因子：
9.3
作者：
Ben-Haim, Simona;Ell, Peter
通讯作者：
Ell, Peter