Smoking-associated Downregulation of FILIP1L Enhances Lung Adenocarcinoma Progression Through Mucin Production, Inflammation, and Fibrosis

• Published in: Cancer research communications 2022-10, Vol.2 (10), p.1197-1213
• Main Authors: Kwon, Mijung, Rubio, Genesaret, Wang, Haitao, Riedlinger, Gregory, Adem, Asha, Zhong, Hua, Slegowski, Daniel, Post-Zwicker, Louisa, Chidananda, Anshruta, Schrump, David S, Pine, Sharon R, Libutti, Steven K
• Format: Article
• Language: English
• Subjects: Adenocarcinoma of Lung - genetics; Animals; Cell Line, Tumor; Down-Regulation - genetics; Epigenetics; Fibrosis; Gene Expression Regulation, Neoplastic; Humans; Inflammation - genetics; Intracellular Signaling Peptides and Proteins; Lifestyle Risk Factors; Lung Cancer; Lung Neoplasms - genetics; Mice; Mucins; Oncogenes & Tumor Suppressors; Progression, Invasion & Metastasis; Smoking; Tumor Microenvironment
• ISSN: 2767-9764; 2767-9764
• DOI: 10.1158/2767-9764.CRC-22-0233

Lung adenocarcinoma (LUAD) is the major subtype in lung cancer, and cigarette smoking is essentially linked to its pathogenesis. We show that downregulation of Filamin A interacting protein 1-like (FILIP1L) is a driver of LUAD progression. Cigarette smoking causes its downregulation by promoter methylation in LUAD. Loss of FILIP1L increases xenograft growth, and, in lung-specific knockout mice, induces lung adenoma formation and mucin secretion. In syngeneic allograft tumors, reduction of FILIP1L and subsequent increase in its binding partner, prefoldin 1 (PFDN1) increases mucin secretion, proliferation, inflammation, and fibrosis. Importantly, from the RNA-sequencing analysis of these tumors, reduction of FILIP1L is associated with upregulated Wnt/β-catenin signaling, which has been implicated in proliferation of cancer cells as well as inflammation and fibrosis within the tumor microenvironment. Overall, these findings suggest that down-regulation of FILIP1L is clinically relevant in LUAD, and warrant further efforts to evaluate pharmacologic regimens that either directly or indirectly restore FILIP1L-mediated gene regulation for the treatment of these neoplasms. This study identifies FILIP1L as a tumor suppressor in LUADs and demonstrates that downregulation of FILIP1L is a clinically relevant event in the pathogenesis and clinical course of these neoplasms.