Exosomal miR-27a Derived from Gastric Cancer Cells Regulates the Transformation of Fibroblasts into Cancer-Associated Fibroblasts

Abstract

Background/Aims: The malignant biological behavior of gastric cancer(GC) is not only determined by cancer cells alone, but also closely regulated by the microenvironment. Fibroblasts represent a large proportion of the components in the tumor microenvironment, and they promote the development of disease. Currently, accumulating evidence suggests that exosomes can function as intercellular transport systems to relay their contents, especially microRNAs(miRNAs). Methods: First, we detected the highly-expressed level of miR-27a in exosomes isolated from gastric cancer cells by qRT-PCR. MiR-27a –over-expressed models in vitro and in vivo were established to investigate the transformation of cancer-associated fibroblasts observed by Western blotting, and the malignant behavior of gastric cancer cells using the methods CCK8 and Transwell. Moreover, the downregulation of CSRP2 in fibroblasts was used to evaluate the promotion of malignancy of gastric cancer using the methods CCK8 and Transwell. Results: In this study, we found a marked high level of miR-27a in exosomes derived from GC cells. miR-27a was found to function an oncogene that not only induced the reprogramming of fibroblasts into cancer-associated fibroblasts(CAFs), but also promoted the proliferation, motility and metastasis of cancer cells in vitro and in vivo. Conversely, CAFs with over-expression of miR-27a could pleiotropically increase the malignant behavior of the GC cells. For the first time, we revealed that CSRP2 is a downstream target of miR-27a. CSRP2 downregulation could increase the proliferation and motility of GC cells. Conclusion: Thus, this report indicates that miR-27a in exosomes derived from GC cells has a crucial impact on the microenvironment and may be used as a potential therapeutic target in the treatment of GC

Low abundance of TFPI‐2 by both promoter methylation and miR‐27a‐3p regulation is linked with poor clinical outcome in gastric cancer

“…first proposed that circulating miR‐27a and miR‐130a served as potential prognostic and diagnostic biomarkers in colorectal cancer. Subsequently, the study performed by Wang et al . provided evidence indicating that gastric cancer cell‐derived exosomal miR‐27a modulated transformation of fibroblasts into cancer‐associated fibroblasts.…”

The role of cancer-derived microRNAs in cancer immune escape

“…Immunosuppressive [125] miR-24-3p NPC Immunosuppressive [126] miR-891a NPC Immunosuppressive [126] miR-106a-5p NPC Immunosuppressive [126] miR-20a-5p NPC Immunosuppressive [126] miR-1908 NPC Immunosuppressive [126] TAMs miR-222-3p EOC Immunosuppressive [127] miR-940 EOC Immunosuppressive [128] miR-21-3p EOC Immunosuppressive [129] miR-125b-5p EOC Immunosuppressive [129] miR-181d-5p EOC Immunosuppressive [129] miR-21 Head and neck cancer Immunosuppressive [130] miR-1246 Colon cancer Immunosuppressive [131] miR-16 Breast cancer Immunostimulatory [132] MDSCs miR-107 Gastric cancer Immunosuppressive [133] miR-21 OSCC Immunosuppressive [134] miR-21 Glioma Immunosuppressive [135] miR-10a Glioma Immunosuppressive [135] miR-29a Glioma Immunosuppressive [136] miR-92a Glioma Immunosuppressive [136] miR-155 CLL Immunosuppressive [137] CAFs miR-27a Gastric cancer Immunosuppressive [138] miR-1247-3p HCC Immunosuppressive [139] miR-21 HCC Immunosuppressive [140] NPC nasopharyngeal carcinoma, TAM tumor-associated macrophage, EOC epithelial ovarian cancer, MDSC myeloid-derived suppressor cell, OSCC oral squamous cell carcinoma, CLL chronic lymphocytic leukemia, CAF cancer-associated fibroblast, HCC hepatocellular carcinoma M2-like phenotype and suppressing the expression of M1 phenotype-associated markers [130]. Similarly, Cooks et al observed that cancer cells harboring TP53 mutation could reprogram neighboring TAMs into pro-tumor state via secreting miR-1246-enriched exosomes [131].…”

“…Cancer-derived exosomal miRNA is a vital factor accounting for increased CAFs in the tumor microenvironment. Gastric cancer-derived exosomal miR-27a promoted the transformation from normal fibroblasts toward CAFs [138]. In addition, Fang et al found that metastatic hepatocellular carcinoma cells produced exosomal miR-1247-3p which could target B4GALT3 and activate β1-integrin-NF-κB signaling pathway in CAFs [139].…”

Deregulation of miR‐27a may contribute to canine fibroblast activation after coculture with a mast cell tumour cell line

“…For example, dysregulation of let‐7 family members and miR‐27a, along with several of their target mRNAs, has been found to be involved in regulatory mechanisms of ECM and CAF metabolism [6,9,20]. Some of this intercellular crosstalk occurring within the tumour microenvironment is also attributed to exosomes [21]. Exosomes are small membrane vesicles secreted by all types of cells capable of mediating cell‐to‐cell communication by means of exchanging DNA, proteins, mRNAs and miRNAs [22,23].…”

“…Exosomes are small membrane vesicles secreted by all types of cells capable of mediating cell‐to‐cell communication by means of exchanging DNA, proteins, mRNAs and miRNAs [22,23]. For instance, in vitro and in vivo models for the human disease have shown that exosome‐derived miR‐27a may regulate the transformation of normal fibroblasts into CAFs and also modulate the growth and metastasis of tumour cells [21].…”