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Differentiation therapy for hepatocellular carcinoma: Multifaceted effects of miR‐148a on tumor growth and phenotype and liver fibrosis

The death rate from hepatocellular carcinoma (HCC) is increasing, and liver cancer is the second leading cause of cancer‐related mortality worldwide. Most patients with HCC have underlying liver cirrhosis and compromised liver function, limiting treatment options. Cirrhosis is associated with cell dedifferentiation and expansion of hepatocholangiolar progenitor cells. We identified a microRNA signature associated with HCC and hepatocytic differentiation of progenitor cells. We further identified miR‐148a as an inducer of hepatocytic differentiation that is down‐regulated in HCC. MiR‐148a‐mimetic treatment in vivo suppressed tumor growth, reduced tumor malignancy and liver fibrosis, and prevented tumor development. These effects were associated with an increased differentiated phenotype and mediated by IκB kinase alpha/NUMB/NOTCH signaling. Conclusion: miR‐148a is an inhibitor of the IκB kinase alpha/NUMB/NOTCH pathway and an inducer of hepatocytic differentiation that when deregulated promotes HCC initiation and progression. Differentiation‐targeted therapy may be a promising strategy to treat and prevent HCC. (Hepatology 2016;63:864–879)