The Role of Bone Morphogenetic Protein (BMP) Signalling in Lung Cancer and Lung Regeneration

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta (TGFβ) super-family of signalling molecules. BMPs play crucial roles in developing and adult tissues during processes including proliferation, differentiation, apoptosis and epithelial-mesenchymal transition (EMT). However, little is known regarding the role of BMPs in adult lungs during health and disease. In the present study, the role of BMP signalling in lung cancer and lung regeneration processes was examined. Early lung cancer tumours were isolated by laser capture microdissection from Kras G12D mouse lungs and microarray analysis was carried out on RNA from the purified populations of cells. Microarray and qPCR analyses revealed differential BMP pathway expression during early tumour formation. BMPR expression was decreased compared to normal lung epithelial cells while BMP4, BMP5, Smad4 and Id-1 expression were increased. We hypothesized BMPR-IB plays an anti-proliferative role during early tumour progression. To characterise the function of BMPR-IB in lung cells, the gene was cloned from mouse lung cDNA and an over-expression vector was generated. Viral and nonviral delivery methods were assessed for their ability to efficiently transfect normal and tumour-derived lung cells. Lipofectamine-2000 was the most efficient non-viral method of gene delivery. This mode of transfection was utilised to transfect BMPR-IB gene into the human BEAS-2B cell line, which is devoid of endogenous BMPR-IB expression. The effects of BMPR-IB expression on proliferation, BMP signalling, and differentiation were assessed. BMPR-IB expression caused a reduction in viable cell number, an increase in non-viable cell number and an increase in cell death by apoptosis. Given the loss of expression of BMPR-IB at the early stages of cancer, these data suggest that BMPR-IB may have anti-proliferative properties during this stage in cancer. The role of BMP signalling in lung regeneration processes was also examined in the 1-NN acute lung damage. BMP signalling was up-regulated during the inflammatory stage of lung damage. These data suggest that the BMP pathway plays an integral role during regeneration and disease processes in the adult lung