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.
Bibliographical noteFunding Information:
The authors thank Dr. Jonathan M. Kurie (University of Texas MD Anderson Cancer Center) for his valuable suggestions. This research was supported by grants of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI17C0666 to Y-HA; HI20C0461 to SL), and by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (NRF-2020R1A5A2019210 to Y-HA; NRF-2018R1D1A1A02085738 to YHK; 2017R1C1B2011072 to JHH). This work was also supported by the LG Yonam Foundation of Korea (to Y-HA) and by an Ewha Womans University scholarship in 2019 (to SL).
- Cancer-associated fibroblasts
- Lung adenocarcinomas
- Tumor microenvironment