title: Bone morphogenetic protein 2 inhibits hepatocellular carcinoma growth and migration through downregulation of the PI3K/AKT pathway.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Previous studies have suggested that abnormal expression of BMP-4, BMP-7, and BMP-9 is correlated with tumor progression in HCC, but the role played by BMP-2 in HCC has not yet been reported. To determine the role of BMP-2 in HCC, we first investigated the effect of exogenous BMP-2 on the growth of the cell lines HCC SK-Hep-1, Hep G2, and Hep 3B. Next, we studied the function of BMP-2 in SK-Hep-1 HCC cell line using a recombinant lentivirus vector to deliver BMP-2. We also used siRNA to silence endogenous BMP-2 expression in the HCC Hep 3B cell line. Then, cell growth and migration were assayed in vitro using WST-8, wound-healing, and transwell invasion assays. Cellular apoptosis and cell-cycle distribution were assessed using flow cytometry. We also investigated the effects of BMP-2 overexpression and knockdown on the expression of proliferating cell nuclear antigen (PCNA), matrix metallopeptidase-2 (MMP-2), phosphorylated AKT (p-AKT), phosphoinositide 3-kinase p85α (PI3Kp85α), Bax, Bcl-2, caspase-3, cleaved caspase-3, p21, and cyclin E. As a result, we observed that BMP-2 inhibited the proliferation of HCC cells. Furthermore, HCC cell proliferation and migration were significantly diminished by BMP-2 overexpression, as was indicated by WST-8, would healing, and transwell assays, while knockdown of BMP-2 led to an increase in proliferation and migration of Hep 3B cells. BMP-2 overexpression significantly increased the susceptibility of SK-Hep-1 cells to low-serum-induced apoptosis, while BMP-2 knockdown reduced the susceptibility of Hep 3B cells. Overexpression of BMP-2 induced G1 phase arrest through upregulation of p21. When BMP-2 expression was elevated in SK-Hep-1 cells, the expression of PI3Kp85α, p-AKT, PCNA, and MMP-2 declined. These results suggest that BMP-2 exerts an inhibitory effect on the growth and migration of HCC cells, possibly via a blockade of PI3K/AKT signaling.
authors.affiliation: Department of Anesthesia, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu, 223300, People's Republic of China, changxin156@sina.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Haidong
authors.initials: H
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Chang
mesh_terms: D017209:Apoptosis; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D055396:Bone Morphogenetic Protein 2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering