1. Cancer-associated fibroblasts-derived exosomal miR-3656 promotes the development and progression of esophageal squamous cell carcinoma via the ACAP2/PI3K-AKT signaling pathway
- Author
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Jieqiong Cao, Yiqi Yang, Xue Chen, Baoqing Tian, Xiaojia Chen, Size Chen, Tsung-Chieh Shih, Xin Yuan Guan, Chen Xie, Yibo Zhang, Bihui Zhang, Yuan Jin, Jiakang Wang, An Hong, and Qilin Meng
- Subjects
Esophageal Neoplasms ,Biology ,Exosomes ,Applied Microbiology and Biotechnology ,Exosome ,Cancer-associated Fibroblast (CAF) ,Mice ,Phosphatidylinositol 3-Kinases ,Downregulation and upregulation ,microRNA ,Animals ,Humans ,Molecular Biology ,Protein kinase B ,Ecology, Evolution, Behavior and Systematics ,PI3K/AKT/mTOR pathway ,Tumor microenvironment ,Mice, Inbred BALB C ,Esophageal Squamous Cell Carcinoma (ESCC) ,High-Throughput Nucleotide Sequencing ,Membrane Proteins ,Cell Biology ,Fibroblasts ,Microvesicles ,digestive system diseases ,MicroRNA miR-3656 ,MicroRNAs ,Cancer research ,Disease Progression ,Cancer-Associated Fibroblasts ,ACAP2 ,Female ,Esophageal Squamous Cell Carcinoma ,Proto-Oncogene Proteins c-akt ,Developmental Biology ,Research Paper ,Signal Transduction - Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common gastrointestinal tumors, accounting for almost half a million deaths per year. Cancer-associated fibroblasts (CAFs) are the major constituent of the tumor microenvironment (TME) and dramatically impact ESCC progression. Recent evidence suggests that exosomes derived from CAFs are able to transmit regulating signals and promote ESCC development. In this study, we compared different the component ratios of miRNAs in exosomes secreted by CAFs in tumors and with those from normal fibroblasts (NFs) in precancerous tissues. The mRNA level of hsa-miR-3656 was significantly upregulated in the former exosomes. Subsequently, by comparing tumor cell development in vitro and in vivo, we found that the proliferation, migration and invasion capabilities of ESCC cells were significantly improved when miR-3656 was present. Further target gene analysis confirmed ACAP2 was a target gene regulated by miR-3656 and exhibited a negative regulatory effect on tumor proliferation. Additionally, the downregulation of ACAP2 triggered by exosomal-derived miR-3656 further promotes the activation of the PI3K/AKT and β-catenin signaling pathways and ultimately improves the growth of ESCC cells both in vitro and in xenograft models. These results may represent a potential therapeutic target for ESCC and provide a new basis for clinical treatment plans.
- Published
- 2021