Hypoxia-induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway.
Hypoxia-induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway.
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缺氧诱导的cofilin 1通过调节PLD1/AKT通路促进肝细胞癌进展
DOI：
10.1002/ctm2.366
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发表时间：
2021-03
影响因子：
10.6
通讯作者：
Tu K
中科院分区：
文献类型：
--
作者：
Yao B;Li Y;Chen T;Niu Y;Wang Y;Yang Y;Wei X;Liu Q;Tu K
肝细胞癌是世界上第四大致命性恶性肿瘤。然而，参与肝细胞癌进展的确切分子机制仍不清楚。采用等压相对和绝对定量(ITRAQ)技术对3对肝细胞癌和配对的门静脉癌栓(PVTT)组织标本进行分析，以研究差异表达的蛋白质。采用实时荧光定量聚合酶链式反应、免疫染色和免疫印迹等方法检测肝细胞癌和非肿瘤组织中的胶原蛋白1(CFL1)。CCK8、EDU和Transwell检测分别确定了肝癌细胞的增殖、迁移和侵袭。在此基础上，采用裸鼠皮下和尾静脉注射的方法研究了裸鼠体内的肝癌生长和肺转移情况。染色质免疫沉淀(ChIP)法证实低氧诱导因子-1α(HIF-1α)对CFL1的调节作用。最后，用免疫沉淀(IP)法研究了CFL1与磷脂酶D 1(PLD 1)的相互作用。ITRAQ分析发现CFL1在PVTT中的表达显著高于在肝细胞癌组织中的表达。CFL1的高表达与不良的临床特征密切相关，是肝细胞癌患者总生存期的独立风险预测因子。CFL1基因敲除抑制了肝癌细胞的生长活力、侵袭力和上皮间质转化(EMT)。此外，CFL1沉默显著抑制了裸鼠肝癌细胞的生长和肺转移。接下来，缺氧诱导因子-1α通过与启动子中的缺氧反应元件结合来直接调节CFL1的转录。此外，我们还利用免疫印迹技术揭示了CFL1和PLD1在肝癌细胞中的相互作用。机制上，CFL1通过抑制泛素介导的蛋白质降解，从而激活肝癌细胞中的AKT信号，从而维持PLD1的表达。值得注意的是，CFL1/PLD1轴被发现介导了低氧诱导的AKT通路和EMT的激活。分析表明，低氧诱导的CFL1通过激活PLD1/AKT通路增加肝癌细胞的增殖、迁移、侵袭和EMT。Cofilin 1在肝细胞癌组织中过表达，尤其在PVTT组织中表达更明显。Cofilin 1在低氧条件下上调，促进肝细胞癌的进展。CFL1与PLD1结合，维持PLD1蛋白的稳定性。HIF-1α调控肝细胞癌CFL1转录，激活CFL1-PLD1AKT轴。
Hepatocellular carcinoma (HCC) is the fourth fatal malignant tumour type worldwide. However, the exact molecular mechanism involved in HCC progression remains unclear. Three pairs of HCC and matched portal vein tumour thrombus (PVTT) tissue samples were analysed by isobaric tags for relative and absolute quantification (iTRAQ) assay to investigate the differentially expressed proteins. Real‐time quantitative PCR, immunostaining, and immunoblotting were performed to detect cofilin 1 (CFL1) in HCC and non‐tumour tissues. CCK8 and EdU, and Transwell assays, respectively, determined cell proliferation, migration, and invasion of HCC cells. Further, subcutaneous and tail vein injection were performed in nude mice for investigating HCC growth and lung metastasis in vivo. Regulatory effect of hypoxia‐inducible factor‐1α (HIF‐1α) on CFL1 was confirmed by chromatin immunoprecipitation (ChIP) assay. Finally, interaction between CFL1 and phospholipase D1 (PLD1) was studied using immunoprecipitation (IP) assay. The iTRAQ analysis identified expression of CFL1 to be significantly upregulated in PVTT than in HCC tissues. Increased expression of CFL1 was closely associated with unfavourable clinical features, and was an independent risk predictor of overall survival in HCC patients. The knockdown of CFL1 inhibited cell growth viability, invasiveness, and epithelial‐mesenchymal transformation (EMT) in HCC cells. Furthermore, CFL1 silencing significantly suppressed the growth and lung metastasis of HCC cells in nude mice. Next, HIF‐1α directly regulated CFL1 transcription by binding to the hypoxia‐responsive element (HRE) in the promoter. Moreover, we disclosed the interaction between CFL1 and PLD1 in HCC cells using IP assay. Mechanistically, CFL1 maintained PLD1 expression by repressing ubiquitin‐mediated protein degradation, thereby activating AKT signalling in HCC cells. Notably, the CFL1/PLD1 axis was found mediating the hypoxia‐induced activation of the AKT pathway and EMT. The analysis suggests that hypoxia‐induced CFL1 increases the proliferation, migration, invasion, and EMT in HCC by activating the PLD1/AKT pathway. Cofilin 1 is overexpressed in HCC, especially in PVTT tissues. Cofilin 1 is up‐regulated in hypoxia condition and promotes HCC progression. CFL1 binds to PLD1 and maintains PLD1 protein stability. HIF‐1α regulates CFL1 transcription and activates CFL1‐PLD1‐AKT axis in HCC.
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影响因子：
5.7
作者：
Satoh M;Takano S;Sogawa K;Noda K;Yoshitomi H;Ishibashi M;Mogushi K;Takizawa H;Otsuka M;Shimizu H;Miyazaki M;Nomura F
通讯作者：
Nomura F
磷脂酶D抑制剂减少了人类前列腺癌细胞的增殖和菌落形成。
影响因子：
8.8
作者：
Noble AR;Maitland NJ;Berney DM;Rumsby MG
通讯作者：
Rumsby MG
Supervillin通过激活RhoA/ROCK-ERK/p38通路促进缺氧条件下肝细胞癌的上皮间质转化和转移
DOI：
10.1186/s13046-018-0787-2
发表时间：
2018-06-28
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Chen X;Zhang S;Wang Z;Wang F;Cao X;Wu Q;Zhao C;Ma H;Ye F;Wang H;Fang Z
通讯作者：
Fang Z
影响因子：
3.7
作者：
Baker, Tabari M.;Waheed, Sana;Syed, Viqar
通讯作者：
Syed, Viqar
影响因子：
4.6
作者：
Hoffmann C;Mao X;Brown-Clay J;Moreau F;Al Absi A;Wurzer H;Sousa B;Schmitt F;Berchem G;Janji B;Thomas C
通讯作者：
Thomas C