ACTN1 supports tumor growth by inhibiting Hippo signaling in hepatocellular carcinoma

Journal of Experimental & Clinical Cancer Research

Kang He¹  Xiao-Wei Zhou²  Qian Chen²  Ai-Jun Zhang² 

[1] Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, 200127, Shanghai, China;Reproductive Medical Center, Department of Obstetrics and Gynecology of Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, 197 Ruijin 2nd Road, 200025, Shanghai, China;

关键词: ACTN1;    Poor prognosis;    Tumor growth;    Hepatocellular carcinoma;    Hippo signaling;   

DOI  :  10.1186/s13046-020-01821-6

来源: Springer

【 摘 要 】

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.

【 授权许可】

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