Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression

Guifang Xu^1*, Bin Zhang^1*, Jiahui Ye^2*, Shouli Cao^1*, Jiajun Shi², Yan Zhao¹, Yongsheng Wang³, Jianfeng Sang², Yongzhong Yao², Wenxian Guan², Jinqiu Tao², Min Feng², Weijie Zhang^2✉

1. Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China;
2. Department of General surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China;
3. Department of Respiratory Medicine, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China.
*Guifang Xu , Bin Zhang, Jiahui Ye and Shouli Cao are co-first authors.

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Citation:
Xu G, Zhang B, Ye J, Cao S, Shi J, Zhao Y, Wang Y, Sang J, Yao Y, Guan W, Tao J, Feng M, Zhang W. Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression. Int J Biol Sci 2019; 15(11):2320-2329. doi:10.7150/ijbs.33750. Available from http://www.ijbs.com/v15p2320.htm

Abstract

Solid tumors consist of various types of stromal cells in addition to cancer cells. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and play an essential role in tumor progression and metastasis in a variety of malignancies, including gastric cancer. However, the effects of CAFs on gastric cancer cells' progression and metastasis are not well studied. Here we show that matrix metalloproteinase 11 (MMP11) in exosomes secreted from CAFs can be delivered into gastric cancer cells. Gastric CAFs promote gastric cancer cell migration partially through exosomal MMP11. Moreover, MMP11 is overexpressed in exosomes purified from plasma of gastric cancer patients and tumor tissues and associated with overall survival of gastric patients. We also find that MMP11 is negatively regulated by exosomal miR-139 in the CAFs of gastric cancer. Exosomal miR-139 inhibits tumor growth and metastasis of gastric cancer cells by decreasing the expression of MMP11 in vitro and in vivo. Thus, we propose that exosomal miR-139 derived from gastric CAFs could inhibit the progression and metastasis of gastric cancer by decreasing MMP11 in tumor microenvironment.

Keywords: Gastric cancer, CAFs, exosome, MMP11, miR-139, cancer progression