Regulation of Lung Cancer by FOSL1 and JUN Transcription Factors: Novel Insights and Implications

There are limited therapeutic strategies to mitigate mutant KRAS activity in lung cancer which is the leading cause of cancer deaths in the US. Constitutively active mutant KRAS in alveolar epithelium promotes lung tumorigenesis. My study focuses on investigating the role of AP-1 transcription factors, FOSL1 and JUN, in human lung adenocarcinoma present downstream of the RAS-ERK1/2 signaling pathway and to further identify if they are the crucial downstream effectors of mutant KRAS and mediate lung tumorigenesis in vivo. In vivo findings in my study suggest that using either Fosl1 or Jun deletion or a combination of both increased survival of mice with activated mutant Kras in lungs, demonstrating its role in promoting mutant KRAS-induced lung cancer in vivo. Mechanistic studies done on mutant KRAS Human Lung adenocarcinoma cells (HLAC) suggest that both FOSL1 and JUN regulates KRAS mutant HLAC cell proliferation by inducing the expression of amphiregulin (AREG), a growth factor that activates the EGFR signaling. In addition, FOSL1 promotes KRAS mutant HLAC cell survival by regulating the expression of antioxidant genes (such as NQO1 and HMOX1) and apoptotic genes (such as BCL2 and BCLXL) but JUN does not alter their expression levels. Furthermore, in non-mutant KRAS HLAC cells FOSL1 regulates various chemokines which are known regulators of tumor survival. These results enable us to potentially target either FOSL1 or JUN individually or as a combinatorial therapy against human lung adenocarcinoma.