EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling

Abstract

Background Somatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2. Methods Whole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2−/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis. Results A new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway. Conclusions In our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.

Pyroptosis-Related LncRNA Signature Predicts Prognosis and Is Associated With Immune Infiltration in Hepatocellular Carcinoma

“…The pathogenesis of HCC is very complicated, involving transcriptional misregulation and cell cycle disorder ( 26 , 27 ), somatic mutation ( 27 ) and abnormal pyroptosis ( 28 ). LncRNAs can affect tumorigenesis and tumor progression in a variety of ways, including regulation of cell proliferation and apoptosis ( 29 ), influencing drug sensitivity ( 30 ), and regulation of cell pyroptosis ( 31 ).…”

N6-methyladenosine-mediated changes in SOCS3 expression regulate skeletal muscle stem cell senescence

“…As a protein coding regulator, SOCS3 can directly interact with JAK2, suppressing the JAK2/STAT3 signaling pathway and thus plays roles in regulating cell signaling connectivity under physiological and pathological conditions. [24][25][26] . Consistently, reduction of SOCS3expression in cells causes abnormal epigenetic and metabolic reprogramming 27,28 .…”

Bioinformatics analysis of differentially expressed genes in non alcoholic fatty liver disease using next generation sequencing data

“…Pathways and GO annotation include signal transduction [ [108], SOCS1 [109], GPR183 [110], AKR1B10 [111], TREM2 [112], SCD (stearoyl-CoA desaturase) [113], GCK (glucokinase) [114], LPL (lipoprotein lipase) [115], ANGPTL8 [116], UGT1A1 [117], IL2RA [118], CDKN1A [119], GAS6 [120], ACE2 [121], NLRP6 [122], S1PR4 [123], FADS2 [124], FASN (fatty acid synthase) [125], TIMP3 [126], CHI3L1 [127], ADAMTSL2 [128], FNDC5 [129], MMP9 [130] and TMC4 [131] were involved in progression of NAFLD. EGR1 [132], NR4A2 [133], DUSP1 [134], DLK1 [135], SIK1 [136], CCN1 [137], CEBPD (CCAAT enhancer binding protein delta) [138], SOCS2 [139], IRS2 [91], GADD45B [140], CXCL2 [141], ZFAND5 [142], EGR3 [143], PTGS2 [144], KL (klotho) [145], SOCS3 [146], MMP1 [147], CXCR4 [148], THBS1 [149], SLC7A11 [150], FAM83A [151], EGR2 [152], ZFP36 [153], NR0B2 [154], CCN2…”