Cancer-associated fibroblasts activated by miR-196a promote the migration and invasion of lung cancer cells

Cancer Lett. 2021 Jun 28;508:92-103. doi: 10.1016/j.canlet.2021.03.021. Epub 2021 Mar 26.


Fibroblasts in the tumor microenvironment, known as cancer-associated fibroblasts (CAFs), promote the migration, invasion, and metastasis of cancer cells when they are activated through diverse processes, including post-transcriptional regulation by microRNAs (miRNAs). To identify the miRNAs that regulate CAF activation, we used NanoString to profile miRNA expression within normal mouse lung fibroblasts (LFs) and CAFs. Based on NanoString profiling, miR-196a was selected as a candidate that was up-regulated in CAFs. miR-196a-overexpressed LFs (LF-196a) promoted the migration and invasion of lung cancer cells in co-culture systems (Transwell migration and spheroid invasion assays). ANXA1 was confirmed as a direct target of miR-196a, and adding back ANXA1 to LF-196a restored the cancer cell invasion promoted by miR-196a. miR-196a increased CCL2 secretion in fibroblasts, and that was suppressed by ANXA1. Furthermore, blocking CCL2 impeded cancer spheroid invasion. In lung adenocarcinoma patients, high miR-196a expression was associated with poor prognosis. Collectively, our results suggest that CAF-specific miR-196a promotes lung cancer progression in the tumor microenvironment via ANXA1 and CCL2 and that miR-196a will be a good therapeutic target or biomarker in lung adenocarcinoma.

Keywords: Cancer-associated fibroblasts; Invasion; Lung adenocarcinomas; Tumor microenvironment; miR-196a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / metabolism*
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Annexin A1 / genetics
  • Annexin A1 / metabolism
  • Cancer-Associated Fibroblasts / metabolism*
  • Cancer-Associated Fibroblasts / pathology
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness


  • ANXA1 protein, human
  • Annexin A1
  • CCL2 protein, human
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • MIRN196 microRNA, human
  • MIRN196 microRNA, mouse
  • MicroRNAs
  • annexin A1, mouse