Hypoxia-induced NIPP1 activation enhances metastatic potential and predicts poor prognosis in hepatocellular carcinoma.

Hypoxia is known to promote hepatocellular carcinoma (HCC) invasion and metastasis and nuclear inhibitor of protein phosphatase 1 (NIPP1) overexpression contributes to the malignant phenotype in HCC. The aim of this study was to investigate the role of NIPP1 in HCC development under hypoxia. We first conducted a study with 106 cases to explore the association of NIPP1 and/or enhancer of zeste homolog 2 (EZH2) expression with poor prognosis in HCC. Then additional 352 independent cases were recruited to validate the results in the first stage. Hypoxia was induced by culturing HCC cells in 1 % O₂ or of the treatment with hypoxic agent. The expression levels of NIPP1/EZH2 in both HCC tissues and HCC cell lines were detected by RT-PCR, Western blot, or immunohistochemistry. We also studied the effects of the loss of function of NIPP1 and EZH2 on malignant phenotypes, downstream pathway, and inflammatory factors activities using gene silencing strategy. Overall, we found that NIPP1 and EZH2 were overexpressed in both HCC tissue samples and HCC cell lines. High expression of HIPP1 was associated with poor prognosis and clinicopathological features in patients with advanced HCC. HIPP1 expression positively correlated with the expression of hypoxia marker (carbonic anhydrase IX). Hypoxia induced high expression of NIPP1. NIPP1/EZH2 knockdown in HCC cell lines under hypoxia suppressed the malignant phenotypes, reduced the expression of hypoxia-inducible Factor 1α, downstream molecules of EZH2, and inhibit the activity of inflammatory factors. In conclusion, we found that NIPP1 could be activated by hypoxia and contributed to hypoxia-induced invasive and metastatic potential in HCC.

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