UCLA

Chronic inflammation is associated with increased lung cancer incidence. The transcription factor Slug is overexpressed in both chronic inflammatory diseases of the lung, such as Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF), and lung cancer. Both of these pulmonary diseases are associated with increased risk for lung cancer. This study demonstrates that Slug overexpression in a model of pulmonary premalignancy, using Human Bronchial Epithelial Cells (HBEC) and 3D lung organotypic cell culture, is able to induce malignant phenotypes. Overexpression of Slug in HBEC cells induces CXCL8, an angiogenic cytokine often expressed in the lungs of patients suffering from COPD, IPF, and lung cancer. Lung organotypic cell culture of Slug overexpressing HBEC cells indicates that an ability to invade into pulmonary fibroblasts, demonstrating Slug's capability to induce early dissemination during premalignancy. Slug overexpressing cells gain the ability to grow in anchorage independent conditions, indicating a shift towards cellular transformation. Additionally, Slug induces expression of the stem cell genes, Oct4, Sox2, and Klf4, which are associated with tumor initiation. The combination of these malignant phenotypes: invasion, anchorage independent growth, stemness, and angiogenesis, indicates Slug expression during premalignancy may mediate the initiation of metastatic lung cancer.