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

Abstract

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.

BMP4 promotes hepatocellular carcinoma proliferation by autophagy activation through JNK1-mediated Bcl-2 phosphorylation

“…In our previous study, we have previously testified that application of BMP4 recombinant protein could enhance the proliferation of HCC cells Bel-7402 and HCCLM3 by promoting cell cycle via ID2/CDKN1B signaling [ 14 ]. But the effects of BMP4 on autophagy-regulated HCC growth remain unknown.…”

“…Other studies have identified BMP4 as an onco-protein with frequent overexpression in tumor tissues and positive regulation of proliferation, chemo-resistance and metastasis in several cancer cells such as the breast [ 22 ], ovarian [ 23 ], pancreatic [ 24 ], gastric [ 15 ] and colon [ 25 ] cancers. Our previous studies have found that BMP4 acted as a tumor promotion protein by facilitating HCC proliferation, invasion and chemoresistance, as well as identified its prognostic value in HCC patients [ 13 , 14 , 26 ]. Herein, we investigated the role of BMP4 on autophagy-regulated HCC proliferation.…”

“…Moreover, BMP4 additions have shown inhibitory effects on HCC progression [ 17 ]. In our previous study, we have shown that BMP4 enhanced the proliferation of HCC cells Bel-7402 and HCCLM3 by promoting G1/S cell cycle via ID2/CDKN1B signaling [ 14 ]. However, the exact effect of BMP4 on autophagy-regulated HCC progression needs to be explicit.…”

Knockdown of Beclin‐1 impairs epithelial‐mesenchymal transition of colon cancer cells

“…4 Epithelial-to-mesenchymal transition (EMT) is a significant molecular mechanism in the steps of distant metastasis by suppression of epithelial markers, up-regulation of mesenchymal markers. 5,6 EMT promotes cancer cells switching a polarized epithelium to a highly invasive mesenchymal phenotype, and it requires a succession of complicated cellular events including the loss of polarity and tight junctions, desmosomes and cytokeratin intermediate filaments, and the alteration in cytoskeletal architecture through the modulation of EMT-related factors. 7,8 EMT is considered as a crucial event in cancer metastasis, and many factors can induce or mediate EMT.…”

Comparison of immune profiles between hepatocellular carcinoma subtypes

“…Both BMP4 (bone morphogenetic protein 4) and NODAL encode ligand of the TGF-b superfamily. Recent studies revealed that BMP4 could enhance HCC proliferation and metastasis (Ma et al 2017;Zeng et al 2017) and is associated with poor prognosis in HCC samples (Guo et al 2012). Over-expression of NODAL is involved in promoting invasive phenotypes of tumor cells in vitro (Duan et al 2015;Quail et al 2014).…”