Nuclear Ikk Alpha Mediates Microrna-7/-103/107/21 Inductions To Downregulate Maspin Expression In Response To Hbx Overexpression

Maspin is a tumor suppressor that stimulates apoptosis and inhibits metastasis in various cancer types, including hepatocellular carcinoma (HCC). Our previous study has demonstrated that HBx induced microRNA-7, 103, 107, and 21 expressions to suppress maspin expression, leading to metastasis, chemoresistance, and poor prognosis in HCC patients. However, it remains unclear how HBx elicits these microRNA expressions. HBx has been known to induce aberrant activation and nuclear translocation of inhibitor-kappa B kinase-alpha (IKK alpha) to promote HCC progression. In this study, our data further revealed that nuclear IKK alpha expression was inversely correlated with maspin expression in HBV-associated patients. Nuclear IKK alpha but not IKK beta reduced maspin protein and mRNA expression, and inhibition of IKK alpha reverses HBx-mediated maspin downregulation and chemoresistance. In response to HBx overexpression, nuclear IKK alpha was further demonstrated to induce the gene expressions of microRNA-7, -103, -107, and -21 by directly targeting their promoters, thereby leading to maspin downregulation. These findings indicated nuclear IKK alpha as a critical regulator for HBx-mediated microRNA induction and maspin suppression, and suggest IKK alpha as a promising target to improve the therapeutic outcome of HCC patients.