Department of Molecular Medicine, College of Medicine, Ewha Womans University, Seoul, 07804, South Korea; Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul, 07804, South Korea.
Division of Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
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.
肿瘤微环境中的成纤维细胞，即癌相关成纤维细胞（CAFs），在通过多种过程被激活后，会促进癌细胞的迁移、侵袭和转移，这些过程包括 microRNAs（miRNAs）的转录后调控。为了鉴定调控 CAF 激活的 miRNAs，我们使用 NanoString 对正常小鼠肺成纤维细胞（LFs）和 CAFs 中的 miRNA 表达进行了谱分析。基于 NanoString 谱分析，选择 miR-196a 作为 CAFs 中上调的候选 miRNA。过表达 miR-196a 的 LF（LF-196a）在共培养系统中促进肺癌细胞的迁移和侵袭（Transwell 迁移和球体侵袭测定）。ANXA1 被确认为 miR-196a 的直接靶标，并且将 ANXA1 添加回 LF-196a 中恢复了 miR-196a 促进的癌细胞侵袭。miR-196a 增加了成纤维细胞中 CCL2 的分泌，而 ANXA1 则抑制了这种分泌。此外，阻断 CCL2 会阻碍癌症球体的侵袭。在肺腺癌患者中，高表达 miR-196a 与预后不良相关。总之，我们的结果表明，CAF 特异性的 miR-196a 通过 ANXA1 和 CCL2 促进肺癌在肿瘤微环境中的进展，并且 miR-196a 将成为肺腺癌的一个良好治疗靶点或生物标志物。
