Jung Kwang Hwa, Zhang Jing, Zhou Chong, Shen Hong, Gagea Mihai, Rodriguez-Aguayo Cristian, Lopez-Berestein Gabriel, Sood Anil K, Beretta Laura
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX.
Hepatology. 2016 Mar;63(3):864-79. doi: 10.1002/hep.28367. Epub 2016 Jan 14.
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.
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.
肝细胞癌（HCC）的死亡率正在上升，肝癌是全球癌症相关死亡的第二大主要原因。大多数HCC患者伴有潜在的肝硬化和肝功能受损，限制了治疗选择。肝硬化与细胞去分化和肝内胆管祖细胞的扩增有关。我们鉴定出一种与HCC和祖细胞肝细胞分化相关的微小RNA特征。我们进一步确定miR-148a是肝细胞分化的诱导剂，在HCC中表达下调。体内给予miR-148a模拟物可抑制肿瘤生长，降低肿瘤恶性程度和肝纤维化，并预防肿瘤发生。这些作用与增加的分化表型相关，并由IκB激酶α/NUMB/Notch信号介导。
miR-148a是IκB激酶α/NUMB/Notch通路的抑制剂和肝细胞分化的诱导剂，其失调时会促进HCC的起始和进展。靶向分化治疗可能是治疗和预防HCC的一种有前景的策略。
