CSR1 suppresses tumor growth and metastasis of human hepatocellular carcinoma via inhibition of HPIP

OBJECTIVE: Cellular stress response 1 (CSR1) is a tumor suppressor gene that was frequently down-regulated in prostate cancer. CSR1 has critical roles in the regulation of cell apoptosis via inactivation of CPSF3 or preventing the interaction of XIAP with caspases. However, whether CSR1 plays a role in human hepatocellular carcinoma (HCC) is completely unknown.

PATIENTS AND METHODS: The expression of CSR1 in HCC clinic samples and cell lines was detected by Real-time PCR and Western blot. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system was used to knockout CSR1 gene in HepG2 cells. The proliferation of HCC cells was measured by MTT assay. The migration and invasion abilities of HepG2 cells were determined by in vitro scratch wounding and matrigel invasion assays. Co-immunoprecipitation assay was used to determine the interaction between CSR1 and hematopoietic PBX interacting protein (HPIP).

RESULTS: The mRNA and protein levels of CSR1 were down-regulated in human HCC cell lines and clinic HCC tissues. Over-expression of CSR1 inhibited cell proliferation, migration and invasion in human HCC cell lines. Knockout of CSR1 gene by CRISPR-Cas9 in HepG2 cells achieved the opposite effects. At the molecular level, we found that CSR1 associated with HPIP and inhibited the activation PI3K/AKT pathway.

CONCLUSIONS: For the first time we demonstrated that CSR1 inhibited HCC cell proliferation, migration and invasion through inactivation of HPIP and its downstream PI3K/AKT signaling pathway and suggested CSR1 as a potential therapy target for HCC treatment.

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