Wnt5a-Regulator Of Molecular Events Leading To Inflammation And Cancer In The Lung

Clinical and experimental data have demonstrated a robust correlation between chronic inflammation and cancer development. However, the molecular mechanisms are still need clarification. Several pathways have emerged as modulators in both inflammation and carcinogenesis including NF-κB, mTOR, and Wnt. Studies have shown elevated activation of the non-canonical Wnt pathway both in inflammatory diseases and squamous cell lung carcinomas. Wnt5a, a non-canonical Wnt is de-regulated in lung diseases As tobacco smoke induces inflammation and carcinogenesis, we have investigated the cigarette smoke induced Wnt pathway modulation in the lung. In in vivo studies C57BL/6 mice were exposed to cigarette smoke for several months. To investigate the effect of tobacco smoke on human lung tissues, a three-dimensional (3D) human lung tissue model consisting of epithelial cells, fibroblasts and monocytes have been created. Cell sorting, qRT-PCR, immunofluorescent staining, western-blotting proved that cigarette smoke exposure amplified Wnt5a expression at both mRNA and protein levels in mouse and human tissues. While increased Wnt5a levels were evident in both species, inflammatory cytokine regulation appeared different. Both TNF-α and IL-1β levels decreased in vivo and in vitro, IL-6 expression decreased in vivo and increased in vitro in human tissues. As IL6 was characterized as a regulator of immune and inflammatory responses, showed elevated expression in epithelial tumors including breast and lung adenocarcinomas. Our in vivo and in vitro studies have traced cigarette smoke induced molecular events leading to alteration in the microenvironment favoring chronic inflammatory conditions and cancer development.