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KLF4-mediated upregulation of CD9 and CD81 suppresses hepatocellular carcinoma development via JNK signaling.

ABSTRACT: Tetraspanins CD9 and CD81 frequently serve as the surface markers of exosomes, which are involved in intercellular communication during tumor progression. KLF4 is a well-known tumor suppressor in various cancers. This study aims to investigate the relationship between KLF4 and CD9/CD81 in hepatocellular carcinoma (HCC). The results showed that CD9 and CD81 were transcriptionally activated by KLF4 in HCC cell lines. Decreased expressions of CD9 and CD81 were found in most HCC tumor tissues and predicted advanced stages. Furthermore, KLF4 expression was positively associated with CD9 and CD81 expression in HCC specimens. Functionally, overexpression of CD9 and CD81 inhibited HCC cell proliferation in vitro and in vivo and silencing CD9 and CD81 displayed opposite phenotypes. Mechanistically, we found that JNK signaling pathway may be involved in the growth suppression mediated by CD9 and CD81. In addition, increased expression of KLF4, CD9 or CD81 had no obvious impact on exosome secretion from HCC cells. Collectively, we identified CD9 and CD81 as new transcriptional targets of KLF4 and the dysregulated KLF4-CD9/CD81-JNK signaling contributes to HCC development. Our findings will provide new promising targets against this disease.

SUBMITTER: Li Y

PROVIDER: S-EPMC7190708 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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KLF4-mediated upregulation of CD9 and CD81 suppresses hepatocellular carcinoma development via JNK signaling.

Li Yandong Y Yu Shijun S Li Li L Chen Jingde J Quan Ming M Li Qinchuan Q Gao Yong Y

Cell death & disease 20200429 4

Tetraspanins CD9 and CD81 frequently serve as the surface markers of exosomes, which are involved in intercellular communication during tumor progression. KLF4 is a well-known tumor suppressor in various cancers. This study aims to investigate the relationship between KLF4 and CD9/CD81 in hepatocellular carcinoma (HCC). The results showed that CD9 and CD81 were transcriptionally activated by KLF4 in HCC cell lines. Decreased expressions of CD9 and CD81 were found in most HCC tumor tissues and pr ...[more]

PMID: 32350244

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Project description: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.

Dataset Information

KLF4-mediated upregulation of CD9 and CD81 suppresses hepatocellular carcinoma development via JNK signaling.

Publications

KLF4-mediated upregulation of CD9 and CD81 suppresses hepatocellular carcinoma development via JNK signaling.

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