NRBP2 promotes HCC cell chemosensitivity

Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy. Research data supported that cancer stem cells (CSCs) may be responsible for the chemoresistance, and strategies that suppress CSCs stemness could also inhibit the drug resistance. In this study, we found that NRBP2 expression was downregulated in the CD133+ HCC CSCs. Most adjacent non-cancerous liver tissue analyzed expressed higher level of NRBP2 compared with cancerous tissue in HCC patients, and high NRBP2 expression indicated a better prognosis. Realtime PCR results showed that NRBP2 negatively correlated with stemness-related genes, including Oct3/4, Nanog, Notch1, Ep300 and CD133 mRNA expression. High NRBP2 expression in HCC cells downregulated CK19 protein expression, inhibited tumorsphere formation and tumorigenesis ability, indicates that high NRBP2 expression restrains the HCC cell stemness. Overexpression of NRBP2 reduced the IC50 of sorafenib in HCC cells, and NRBP2 expression was negatively correlated with HCC cell resistance to the chemotherapy agents, including cisplatin and the Akt signaling inhibitor perifosine. Co-immunoprecipitation results showed that NRBP2 could bind with annexin A2 (ANXA2) and inhibit ANXA2 expression. Co-expression of ANXA2 restored the chemoresistant ability in NRBP2-overexpressing HCC cells. Further analysis showed that that NRBP2 downregulated Akt and its downstream signaling target Bad phosphorylation level. ANXA2 co-expression partially restored the Akt phosphorylation. Analysis of the expression of Bcl2 family proteins showed that NRBP2 may increase HCC cell chemosensitivity by regulating expression of survival proteins involved in the Akt and Bcl2 pathway. These results suggest that NRBP2 plays an important role in the tumor progression and chemotherapeutic resistance of HCC.

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