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

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.

MicroRNAs in Inflammatory Bowel Disease and Its Complications

“…The chronic inflammation in UC and CD increases the risk of CAC as dysregulated cytokines, miRNAs, transcription factors, inflammatory mediators, and gut dysbiosis participate in the process of transforming chronic colonic injury into neoplasia [ 40 , 41 , 42 , 43 ]. Numerous studies have shown that miRNAs may significantly influence cancer tumorigenesis, proliferation, invasion, and metastasis [ 41 , 44 , 45 ]. Increased expression of TLR4 is a distinctive characteristic of CAC that co-occurs with miR-155 upregulation alongside downregulation of suppressor of cytokine signaling 1 (SOCS1) and Src homology 2 domain-containing inositol-5′-phosphatase 1 in SW480 and HCT116 cancer cells [ 42 , 46 ].…”

“…miR-21 is a major upregulated miRNA that plays a variety of roles in tumor genesis and development. Lai et al illuminated how miR-21 affects the major pathways of PI3K/AKT, IL-6/JAK/STAT3, and PDCD4/NF-κB/TNF-α during carcinogenesis within a zebrafish model [ 45 ]. miR-21 is activated through gut dysbiosis and targets tumor suppressors PDCD4, BTG2, and TPM1, along with modulating the PI3K/AKT pathway by repressing PTEN to activate ERK and AKT, which induces the downstream NF-κB pathway to release inflammatory cytokines TNF-α, IL-6, and IL-1β [ 45 , 51 ].…”

“…Lai et al illuminated how miR-21 affects the major pathways of PI3K/AKT, IL-6/JAK/STAT3, and PDCD4/NF-κB/TNF-α during carcinogenesis within a zebrafish model [ 45 ]. miR-21 is activated through gut dysbiosis and targets tumor suppressors PDCD4, BTG2, and TPM1, along with modulating the PI3K/AKT pathway by repressing PTEN to activate ERK and AKT, which induces the downstream NF-κB pathway to release inflammatory cytokines TNF-α, IL-6, and IL-1β [ 45 , 51 ]. IL-6 is then able to use the JAK signaling pathway to activate STAT3, which enables it to create a positive feedback loop by activating the promoter region of miR-21.…”

The Role and Interactions of Programmed Cell Death 4 and its Regulation by microRNA in Transformed Cells of the Gastrointestinal Tract

“…In mice with DSS induced colitis, PDCD4 knockdown resulted in increased secretion of inflammatory cytokines, such as IL-6, the subsequent induction of STAT-3 expression, with an increase in epithelial cell proliferation and progression to CRC, illustrating an anti-inflammatory and tumour repressor role for PDCD4 ( 103 ). Corroborating a possible inverse association between PDCD4 and inflammation, inducible overexpression of the miRNA-21, a micro-RNA that suppresses translation of the tumour suppressor, results in diminished expression of PDCD4, intestinal inflammation and CRC in transgenic zebrafish ( 104 ). However, further investigation is required to prove a cause-and-effect relationship between PDCD4 expression and inflammation in this model.…”

LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2

“…lncRNAs are deregulated in HCC and exert crucial roles in the occurrence and progression of HCC [11], and some lncRNAs act as vital metabolic regulators that are involved in the etiology of NAFLD [12][13][14][15]. Although lncRNAs may contribute to the progression of NAFLD and HCC [16][17][18][19][20], their role in NAFLD-associated HCC is not well-understood, indicating the need to delineate the relevant mechanisms underlying NAFLD-HCC progression.…”