Adenovirus Mediated Knockdown and Bone Morphogenetic Protein 2 Inhibits Human Lung Cancer Growth and Invasion In Vitro and in Vivo

Abstract

The first two authors contributed equally to this work Bone morphogenetic protein 2 (BMP-2) is a member of the TGF-IJ superfamily of signaling molecules, and has been shown to function as a tumor suppressor involved in development and progression of many malignancies. BMP-2 has previously been reported to be closely correlated with lung cancer. But, the role and molecular mechanisms of BMP-2 in lung cancer have not yet been comprehensively explained. The present study aims to elucidate the role of BMP-2 in growth and invasion of human lung adenocarcinoma (LAC) in vitro and in vivo. Adenovirus vector-mediated BMP-2 small hairpin RNA (shBMP-2) was used to transfect into A549 LAC cells to determine the functional relevance of BMP-2 and tumor growth and invasion in vitro and in vivo, and further investigate the expression levels of BMP-2, vascular endothelial growth factor (VEGF), matrix metallopeptidase-9 (MMP-9), phosphatidylinositol 3-kinase p85a (PI3Kp85a) and phosphorylated AKT (P-AKT). As a result, LAC cell proliferation and invasion were significantly diminished by knockdown of BMP-2 indicated by MTT and Transwell assays, and cell apoptosis and cycle arrest were markedly induced indicated by flow cytometry. When BMP-2 expression was knocked down, the expression of PI3Kp85a, p-AKT, VEGF and MMP-9 was also down-regulated in LAC cells. In addition, the tumor volumes in LAC subcutaneous nude mouse model treated with shBMP-2 were significantly smaller than those in control and ad-GFP groups. Taken together, our findings indicate that knockdown of BMP-2 inhibits growth and invasion of LAC cells possibly via blockade of the PI3KJ AKT signaling pathway, and BMP-2 may be a potential therapeutic target for lung cancer.Lung cancer was the most commonly diagnosed cancer as well as the leading cause of cancer death in males in 2008 globally. Among females, it was the fourth most commonly diagnosed cancer and the second leading cause of cancer death (1). The current best approach for treatment of cancer is complete surgical removal of the tumor with the adjacent lymph nodes. However, the efficacy of this therapeutic approach, as well as hormone-, radio-, and chemo-therapy, is very limited (2). Tumor is also a genetic disease developing from a multi-step process. Single or multiple gene mutations is related to growth control, invasion and metastasis form the molecular genetic basis of malignant transformation and tumor progression. Therefore, identification of key genes or targets related to tumorigenesis is

Silencing BMP-2 expression inhibits A549 and H460 cell proliferation and migration

“…Blocking BMP signaling with the inhibitor DMH1 reduced lung cell proliferation, promoted cell death, and decreased cell migration and invasion in NSCLC cells [31]. BMP-2 knockdown by adenovirus inhibited growth and invasion of human lung adenocarcinoma cells by blocking PI3K/AKT signaling [32]. In this study, we suppressed BMP-2 activity by siRNA.…”

Follistatin-like Protein 1 Inhibits Lung Cancer Metastasis by Preventing Proteolytic Activation of Osteopontin

“…Fstl1-deficient mice have impaired alveolar maturation due to dysfunctional distal alveolar differentiation and insufficient surfactant production (3). Because many developmental pathways involved in embryogenesis play critical roles in oncogenesis and cancer progression (4,5) and the dysregulation of BMP pathways has been detected during tumorigenesis and the malignant evolution of lung cancer (6)(7)(8)(9), perturbations in the FSTL1/BMP4 pathway during lung cancer development are worth investigating.…”

Effect of recombinant human bone morphogenetic protein‐2 on a novel lung cancer spine metastasis model in rodents

“…The effect of rhBMP-2 on cancer growth represents an important and controversial topic in spine surgery because of equivocal evidence in the literature. 14 Although in vitro data suggest that BMP-2 increases the migration and invasion of breast, prostate, and lung cancer cells, 19,[23][24][25][26] BMP-2 also inhibits cell proliferation and promotes differentiation in breast cancer and medulloblastoma cells. [27][28][29][30] Carragee et al 44 concluded that the use of AMPLIFY (Medtronic Sofamor Danek, Memphis, TN), which contains rhBMP-2, leads to a significantly greater risk of cancer in exposed individuals; however, population-based database studies have reported no difference in malignancy rates with BMP exposure.…”

“…Recombinant human BMP‐2 (rhBMP‐2) has been FDA‐approved for use in the spine in an anterior lumbar interbody cage and is commercially available (INFUSE ™ ; Medtronic Sofamor Danek, Memphis, TN). Although rhBMP‐2 has been shown to increase arthrodesis rates and decrease the need for re‐operation in the general population, its use in patients with a history of cancer is currently not recommended due to concerns over possible tumorigenic effects on lung and other cancer cells . Authors have linked this mechanism to a mitogenic rather than a mutagenic effect .…”

“…Although rhBMP-2 has been shown to increase arthrodesis rates and decrease the need for re-operation in the general population, 17,18 its use in patients with a history of cancer is currently not recommended due to concerns over possible tumorigenic effects on lung and other cancer cells. [19][20][21][22][23][24][25][26] Authors have linked this mechanism to a mitogenic rather than a mutagenic effect. 21 On the other hand, there is also evidence that rhBMP-2 may actually inhibit tumorigenesis through the tumorsuppressive action of TGF-b.…”