PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis
PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis
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DOI：
10.1136/gutjnl-2013-305302
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发表时间：
2014-10-01
期刊：
影响因子：
24.5
通讯作者：
Zhang, Zhiyong
中科院分区：
文献类型：
--
作者：
Hong, Xuehui;Song, Ruipeng;Zhang, Zhiyong
背景越来越多的流行病学证据支持磷酸酶和张力蛋白同源物（PTEN）-T细胞白血病1（Tcl 1）信号失调在肝癌发生中的作用。目的探讨肝细胞癌（HCC）中PTEN/Tcl 1轴调控磷酸戊糖途径（PPP）的分子生物学机制。我们测量PPP流量，葡萄糖消耗，乳酸生产，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）水平和脂质积累。我们采用分子生物学、生物化学和质谱分析方法研究了PTEN/Tcl 1轴。我们评估了增殖，细胞凋亡和衰老在培养的细胞，和肿瘤形成在mice.Results，我们发现，PTEN抑制PPP途径在人类肝脏肿瘤。通过PPP，PTEN抑制葡萄糖消耗和生物合成。从机制上讲，PTEN蛋白结合G6 PD，PPP的第一个和限速酶，并阻止活性G6 PD二聚体的形成。Akt的辅激活因子Tcl 1逆转了PTEN对生物合成的影响。Tcl 1促进G6 PD活性，并以异质核核糖核蛋白（hnRNPK）依赖的方式增加G6 PD前mRNA剪接和蛋白表达。PTEN还与hnRNPK形成复合物，其抑制G6 PD前体mRNA剪接。此外，PTEN通过糖原合成酶激酶-3 β（GSK 3 β）介导的磷酸化使Tcl 1失活。重要的是，Tcl 1敲低增强了肝癌对索拉非尼的敏感性，而G6 PD敲低抑制hepatocarcinogenes.Conclusions这些结果建立了PTEN和Tcl 1之间的反作用作为一个关键的机制，调节PPP，并建议，针对PTEN/Tcl 1/hnRNPK/G6 PD轴可以开辟治疗干预的可能性，并改善肝癌患者的预后。
Background Mounting epidemiological evidence supports a role for phosphatase and tensin homologue (PTEN)-T cell leukaemia 1 (Tcl1) signalling deregulation in hepatocarcinogenesis. Objective To determine the molecular and biochemical mechanisms by which the PTEN/Tcl1 axis regulates the pentose phosphate pathway (PPP) in hepatocellular carcinoma (HCC).Methods We compared levels of PTEN and glucose-6-phosphate dehydrogenase (G6PD) mRNA in human HCC and healthy liver tissue. We measured PPP flux, glucose consumption, lactate production, nicotinamide adenine dinucleotide phosphate (NADPH) levels and lipid accumulation. We investigated the PTEN/Tcl1 axis using molecular biology, biochemistry and mass spectrometry analysis. We assessed proliferation, apoptosis and senescence in cultured cells, and tumour formation in mice.Results We showed that PTEN inhibited the PPP pathway in human liver tumours. Through the PPP, PTEN suppressed glucose consumption and biosynthesis. Mechanistically, the PTEN protein bound to G6PD, the first and rate-limiting enzyme of the PPP and prevented the formation of the active G6PD dimer. Tcl1, a coactivator for Akt, reversed the effects of PTEN on biosynthesis. Tcl1 promoted G6PD activity and also increased G6PD pre-mRNA splicing and protein expression in a heterogeneous nuclear ribonucleoprotein (hnRNPK)-dependent manner. PTEN also formed a complex with hnRNPK, which inhibited G6PD pre-mRNA splicing. Moreover, PTEN inactivated Tcl1 via glycogen synthase kinase-3 beta (GSK3 beta)-mediated phosphorylation. Importantly, Tcl1 knockdown enhanced the sensitivity of HCC to sorafenib, whereas G6PD knockdown inhibited hepatocarcinogenesis.Conclusions These results establish the counteraction between PTEN and Tcl1 as a key mechanism that regulates the PPP and suggest that targeting the PTEN/Tcl1/hnRNPK/G6PD axis could open up possibilities for therapeutic intervention and improve the prognosis of patients with HCC.