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

Cancer Res Commun. 2022 Oct 18;2(10):1197-1213. doi: 10.1158/2767-9764.CRC-22-0233. eCollection 2022 Oct.


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.

Significance: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Animals
  • Cell Line, Tumor
  • Down-Regulation / genetics
  • Fibrosis
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inflammation / genetics
  • Intracellular Signaling Peptides and Proteins
  • Lung Neoplasms* / genetics
  • Mice
  • Mucins
  • Smoking
  • Tumor Microenvironment


  • FILIP1L protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mucins
  • Filip1l protein, mouse