BMP4 enhances hepatocellular carcinoma proliferation by promoting cell cycle progression via ID2/CDKN1B signaling.

Bone morphogenetic protein-4 (BMP4) plays a crucial role in carcinogenesis, but the effects and signaling mechanisms of BMP4 in hepatocellular carcinoma (HCC) are not clearly clarified. The present study aimed to identify the roles of BMP4 in the proliferation of human HCC. In this study, BMP4 expression and its correlation with clinicopathological characteristics and the survival of HCC patients were analyzed in two independent cohorts consisting of 310 subjects. Functional analysis of BMP4 on HCC proliferation was performed in vitro and in vivo in human HCC specimens, HCC cells of Bel-7402 and HCCLM3, and subcutaneous tumor model. The downstream signaling targets of BMP4 in HCC were investigated by PCR Array and Western blot. The results indicated that BMP4 expression was significantly increased in HCC tissues and closely related with unfavorable prognosis of HCC. BMP4 treatment increased cell proliferation and promoted G1/S cell cycle progression. In vivo subcutaneous tumor of nude mice model supported that BMP4 overexpression promoted the growth of HCC cells and BMP4 knockdown hold the opposite trend. Id2 was directly upregulated by BMP4, resulting in the mediated expression of cell cycle regulatory protein of CDKN1B. Blocking of Id2 attenuated BMP4-induced proliferation, confirming the important roles of Id2 in BMP4-mediated proliferation in HCC. So BMP4 is overexpressed in HCC tissues and acts as a poor prognostic factor of HCC patients. BMP4-induced ID2/CDKN1B signaling facilitates proliferation of HCC.