Μolecular impact of bone morphogenetic protein�7, on lung cancer cells and its clinical significance

Abstract

Abstract. The aim of this study was to investigate the expression of bone morphogenetic protein 7 (BMP7), in human pulmonary cancer tissues/cells and to evaluate the cellular impact of bone morphogenetic proteins on pulmonary cancer cells. BMP7 expression was determined in human lung cancer cell lines. The invasiveness and growth of cells transfected with BMP7, in vitro, were evaluated using the in vitro invasion assay and in vitro tumour models. Cellular migration was analysed using wounding assays. BMP7-positive tumours correlated with the absence of bone metastasis (P=0.040). In this analysis, we identified that 4 of 4 small cell lung cancer (SCLC) tissue specimens had no BMP7 expression, which illustrated that BMP7 may have no role in SCLC. BMP7 expression was not correlated with the overall survival time in lung cancer patients. Downregulation of BMP7 expression significantly inhibited the invasiveness of SPC-A1 cells (P<0.001) and forced-expression of BMP7 dramatically increased the motility of A549 cells. Overexpression of BMP7 in A549 cells and its knockdown in SPC-A1 cells did not significantly alter proliferation compared with the control cells (P>0.5 respectively). In conclusion, we have demonstrated that BMP7 has an important role in controlling lung cancer cell motility and invasiveness, without affecting the growth process, cell proliferation and cell apoptosis. A higher BMP7 expression may be an indicator for bone metastasis. The therapeutic role of BMP7 warrants further investigation. IntroductionLung cancer is one of the most fatal tumours worldwide. Distant metastasis is an important cause for the poor prognosis. Of the factors related to metastasis, bone morphogenetic proteins (BMPs) have been recently shown to regulate the aggressiveness of cancer cells (1-7). BMPs are multifunctional signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily, which play important roles in multiple cellular processes such as cell growth, differentiation, migration and apoptosis in various types of cancer (8-12). The Smad-dependent signaling pathway has been proven to be the canonical pathway for BMP function (13). In lung cancer, expression of the BMP family members has also been reported (1,14). For example, BMP2 protein could stimulate growth, migration and invasion of lung cancer cells, and is overexpressed in virtually all types of lung cancers, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Silencing of BMP3b expression during NSCLC development has been reported and the BMP3b promoter has been found to be methylated. Activation of the BMP4 signaling pathway negatively regulates the growth, and induces senescence of A549 lung adenocarcinoma cells. Thus, there may be a contrasting response to any given BMP, depending on the tumour and cell type. Despite the discordant results defining the specific effects of BMP7 in various types of cancer, published data underscore the important role that BMP7 plays in tumour development and metastasis. The expre...

Oncogenic features of the bone morphogenic protein 7 (BMP7) in pheochromocytoma

“…Moreover, shRNA-mediated Bmp7 gene silencing reduced the viability of rat primary PCC cells, suggesting that in this experimental system Bmp7 sustains cell survival. Thus, similar to what has been reported for lung cancer [ 41 ], melanoma [ 42 ] and, albeit controversial, for breast cancer [ 25 ], BMP7 exerts a tumor-promoting action in PCC.…”

BMP-7 Enhances Cell Migration and αvβ3 Integrin Expression via a c-Src-Dependent Pathway in Human Chondrosarcoma Cells

“…These results are consistent with our findings in chondrosarcoma cells. Clinical reports have also indicated that a high-expression level of BMP-7 may serve as a biomarker for metastasis and poor prognosis in various malignancies, such as esophageal cancer [38], lung cancer [18], gastric cancer [3], colorectal cancer [15], liver cancer [39], and melanoma [5].…”

“…Accumulating evidence reveals that high-level expression of BMP-7 correlates with increased invasion and metastasis in various malignancies, including breast cancer [14], colorectal cancer [15], prostate cancer [16], esophageal cancer [17], gastric cancer [3], lung cancer [18], liver cancer [6], and melanoma [5]. Although the roles of BMP-7 have emerged as an important factor in the regulation of cell motility across diverse cancer, the influence of BMP-7 on the motility of chondrosarcoma cells still remains largely unknown.…”

Bone morphogenetic protein 7 promotes resistance to immunotherapy

“…BMP7 has been reported in a wide range of human cancers and is associated with metastasis and poor prognosis 8 – 13 . In lung cancer, BMP7 overexpression was associated with lymph node involvement and an indicator of bone metastasis 14 , 15 . The immune-regulatory functions of BMPs are not well understood.…”