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Bone morphogenetic protein 2 inhibits hepatocellular carcinoma growth and migration through downregulation of the PI3K/AKT pathway

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Tumor Biology

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.

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Authors and Affiliations

  1. 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

    Ying Zheng

  2. Department of Ultrasound, Obstetrics and Gynecology Hospital of Fudan University, No.419 Fangxie Rd, Shanghai, 200011, People’s Republic of China

    Xuemei Wang

  3. Department of Obstetrics and Gynecology, Huai’an First People’s Hospital, Nanjing Medical University, 6 Beijing Road West, Huai’an, Jiangsu, 223300, People’s Republic of China

    Haidong Wang

  4. Department of Gastroenterology, Huai’an First People’s Hospital, Nanjing Medical University, 6 Beijing Road West, Huai’an, Jiangsu, 223300, People’s Republic of China

    Wei Yan

  5. Department of Oncology, Huai’an First People’s Hospital, Nanjing Medical University, 6 Beijing Road West, Huai’an, Jiangsu, 223300, People’s Republic of China

    Quan Zhang

  6. Department of Imaging Medicine Center, Huai’an First People’s Hospital, Nanjing Medical University, 6 Beijing Road West, Huai’an, Jiangsu, 223300, People’s Republic of China

    Xin Chang

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  1. Ying Zheng
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  2. Xuemei Wang
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  3. Haidong Wang
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  4. Wei Yan
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  5. Quan Zhang
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  6. Xin Chang
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Correspondence to Xin Chang.

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Ying Zheng and Xuemei Wang contributed equally to this work.

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Zheng, Y., Wang, X., Wang, H. et al. Bone morphogenetic protein 2 inhibits hepatocellular carcinoma growth and migration through downregulation of the PI3K/AKT pathway. Tumor Biol. 35, 5189–5198 (2014). https://doi.org/10.1007/s13277-014-1673-y

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