EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling
| Autor: | Yu-Kui Shang, Meng Lu, Ding Wei, Man Liu, Can Li, Zhi-Nan Chen, Huijie Bian, Cai-Xia Hu, Ling-Min Kong, Ze-Kun Liu, Ren-Yu Zhang, Nai-Shan Zheng, Ke Liu, Yu-Le Yong, Xiao-Zhen Yang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Cancer Research Eyes absent homolog 2 Metastasis Unfolded protein response Mice 0302 clinical medicine SOCS3 Tumor suppressor gene RC254-282 Gene knockdown Liver Neoplasms Intracellular Signaling Peptides and Proteins JAK-STAT signaling pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens Nuclear Proteins Middle Aged STAT Transcription Factors Oncology 030220 oncology & carcinogenesis Whole-exome sequencing DNA methylation Disease Progression Molecular Medicine Heterografts Female Signal Transduction Adult Carcinoma Hepatocellular Mice Nude Protein degradation Biology 03 medical and health sciences Germline mutation medicine Animals Humans Aged Janus Kinases JAK/STAT signaling pathway Research Somatic mutation medicine.disease digestive system diseases 030104 developmental biology Suppressor of Cytokine Signaling 3 Protein Cancer research Protein Tyrosine Phosphatases |
| Zdroj: | Molecular Cancer Molecular Cancer, Vol 20, Iss 1, Pp 1-18 (2021) |
| ISSN: | 1476-4598 |
| Popis: | BackgroundSomatic 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.MethodsWhole-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.ResultsA 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.ConclusionsIn our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis. |
| Databáze: | OpenAIRE |
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