MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish

SIMPLE SUMMARY: The PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks, regulated by the microRNA (miR)-21, are critical for inflammatory regulation, tumor suppressor modulation, and oncogenic activation. We developed a zebrafish model (ImiR-21) with an inducible overexpression of miR-21, specifically in the intestine. The miR-21 overexpression resulted in the development of colorectal cancer (CRC) due to inflammatory bowel disease. Furthermore, the physiological, metabolic, and histological aspects of CRC were similar to those of colitis-associated cancer (CAC) induced by the intestinal carcinogens azoxymethane or dextran sodium sulfate in this model. Thus, miR-21 is critical to the pathogenesis of CRC/CAC and could serve as a novel therapeutic target to treat CRC/CAC. ABSTRACT: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Patients with inflammatory bowel disease (IBD) have a high risk of developing CRC. Inflammatory cytokines are regulated by complex gene networks and regulatory RNAs, especially microRNAs. MicroRNA-21 (miR-21) is amongst the most frequently upregulated microRNAs in inflammatory responses and cancer development. miR-21 has become a target for genetic and pharmacological regulation in various diseases. However, the association between inflammation and tumorigenesis in the gut is largely unknown. Hence, in this study, we generated a zebrafish model (ImiR-21) with inducible overexpression of miR-21 in the intestine. The results demonstrate that miR-21 can induce CRC or colitis-associated cancer (CAC) in ImiR-21 through the PI3K/AKT, PDCD4/TNF-α, and IL-6/STAT3 signaling network. miR-21 activated the PI3K/AKT and NF-κB signaling pathways, leading to initial inflammation; thereafter, miR-21 and TNF-α repressed PDCD4 and its tumor suppression activity. Eventually, active STAT3 stimulated a strong inflammatory response and activated the invasion/metastasis process of tumor cells. Hence, our findings indicate that miR-21 is critical for the development of CRC/CAC via the PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks.