ACTN1 supports tumor growth by inhibiting Hippo signaling in hepatocellular carcinoma.
ACTN1 supports tumor growth by inhibiting Hippo signaling in hepatocellular carcinoma.
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ACTN1 通过抑制肝细胞癌中的 Hippo 信号传导来支持肿瘤生长
DOI：
10.1186/s13046-020-01821-6
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发表时间：
2021-01-07
期刊：
影响因子：
--
通讯作者：
He K
中科院分区：
文献类型：
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作者：
Chen Q;Zhou XW;Zhang AJ;He K
α肌动蛋白（actn）是主要的细胞骨架蛋白，具有许多非肌肉功能。新出现的证据已经揭示了ACTN1在肿瘤发生中的调节作用，然而，ACTN1在肝细胞癌（HCC）中的表达模式、生物学功能和潜在机制在很大程度上仍未被探索。方法采用肝细胞癌组织芯片（n= 157）进行免疫组化分析，以确定ACTN1在肝细胞癌中的表达模式和预后价值。我们在HCC细胞中进行了体外功能丧失研究，以研究ACTN1敲低对细胞增殖的影响。通过建立体内皮下异种移植模型和肝内移植模型来破译ACTN1在HCC肿瘤生长中的作用。采用基因集富集分析、实时荧光定量PCR、免疫共沉淀、免疫荧光和western blotting等方法对其分子机制进行鉴定。结果研究发现，ACTN1在HCC组织中表达显著上调，并与甲胎蛋白水平、肿瘤血栓形成、肿瘤大小、TNM分期及患者预后密切相关。敲低ACTN1可抑制肝癌细胞的体外增殖和体内肿瘤生长。机制上，敲低ACTN1增加了Hippo信号通路的活性，降低了Rho GTPases的活性。机制上，ACTN1可与MOB1竞争性相互作用，降低LATS1和YAP的磷酸化。由ACTN1诱导的促生长作用被维替波芬或super-TDU对YAP的药理学抑制显著抵消。结论sactn1在HCC组织中高表达，并通过与MOB1的物理相互作用抑制Hippo信号传导，起到肿瘤启动子的作用。ACTN1可能作为HCC的潜在预后标志物和治疗靶点。
BackgroundAlpha actinins (ACTNs) are major cytoskeletal proteins and exhibit many non-muscle functions. Emerging evidence have uncovered the regulatory role of ACTNs in tumorigenesis, however, the expression pattern, biological functions, and underlying mechanism of ACTN1 in hepatocellular carcinoma (HCC) remain largely unexplored.MethodsImmunohistochemical analysis of a HCC tissue microarray (n= 157) was performed to determine the expression pattern and prognostic value of ACTN1 in HCC. In vitro loss-of-function study in HCC cells were carried out to investigate ACTN1 knockdown on cell proliferation. In vivo subcutaneous xenograft model and intrahepatic transplantation model were generated to decipher the contribution of ACTN1 in the tumor growth of HCC. Gene set enrichment analysis, quantitative real-time PCR, Co-immunoprecipitation, immunofluorescence and western blotting were performed to identify the underlying molecular mechanism.ResultsIt was found that ACTN1 was significantly upregulated in HCC tissues and closely related to llpha-fetoprotein level, tumor thrombus, tumor size, TNM stage and patient prognoses. Knockdown of ACTN1 suppressed in vitro cell proliferation and in vivo tumor growth of HCC cells. Mechanistically, knockdown of ACTN1 increased Hippo signaling pathway activity and decreased Rho GTPases activities. Mechanistically, ACTN1 could competitively interact with MOB1 and decrease the phosphorylation of LATS1 and YAP. The growth-promoting effect induced by ACTN1 was significantly abrogated by pharmacological inhibition of YAP with verteporfin or super-TDU.ConclusionsACTN1 is highly expressed in HCC tissues and acts as a tumor promoter by suppressing Hippo signaling via physical interaction with MOB1. ACTN1 may serve as a potential prognostic marker and therapeutic target for HCC.
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影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
Guan KL
影响因子：
2.3
作者：
Hartke, Justin;Johnson, Matthew;Ghabril, Marwan
通讯作者：
Ghabril, Marwan
影响因子：
7.5
作者：
Murphy AC;Young PW
通讯作者：
Young PW
影响因子：
24.5
作者：
Kim W;Khan SK;Liu Y;Xu R;Park O;He Y;Cha B;Gao B;Yang Y
通讯作者：
Yang Y
DOI：
10.1038/nrd4161
发表时间：
2014-01
期刊：
Nature reviews. Drug discovery
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作者：
通讯作者：
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