Abstract
Simple SummaryThe 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.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.
Highlights
Colorectal cancer (CRC), known as colon, bowel, or rectal cancer, is a type of cancer that develops in the colon or rectum
The mature miRNA sequence region in the stem-loop of dre-mir-30e-2 was replaced by the mature dre-mir-21 sequence (Figure 1B)
We demonstrated that miR-21 regulates at least three molecular and pathophysiological pathways during CAC development: Akt/Nf-κb, Pdcd4/Tnf-α, and Il-6/Stat3
Summary
Colorectal cancer (CRC), known as colon, bowel, or rectal cancer, is a type of cancer that develops in the colon or rectum. CRCs develop from polyps on the inner lining of the colon or rectum. Not all polyps become malignant, but some can transform into cancer over time. Adenomatous polyps (adenoma, a precancerous condition) are an example of polyps that can transform into cancer. Hyperplastic and inflammatory polyps are more common than adenomas but are generally not precancerous. Sessile serrated polyps (SSPs) and traditional serrated adenomas (TSAs) have a higher risk of tumorigenesis of CRC [2]. CRC can occur at any age, it is more common in older adults. People with a family history of CRC, adenomatous polyps, and inflammatory bowel disease (IBD) are at a high risk of developing CRC
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