miR-23a-3p is a Key Regulator of IL-17C-Induced Tumor Angiogenesis in Colorectal Cancer

Abstract

MicroRNAs (miRNAs) have emerged as key players in tumor angiogenesis. Interleukin-17C (IL-17C) was identified to promote colorectal cancer (CRC) progression. Therefore, we aimed to investigate the effect of IL-17C on tumor angiogenesis, the involvement of miR-23a-3p in IL-17C signaling, and the direct target gene of miR-23a-3p in CRC. In vitro and ex vivo angiogenesis, a mouse xenograft experiment, and immunostaining were performed to test the effect of IL-17C on tumor angiogenesis. ELISA, quantitative real time PCR, and gene silencing were used to uncover the underlying mechanism. IL-17C induced angiogenesis of intestinal endothelial cells, subsequently enhancing cell invasion and migration of DLD-1 cells. IL-17C-stimulated DLD-1 cells produced vascular endothelial growth factor (VEGF) to enhance angiogenesis. Moreover, IL-17C markedly accelerated xenograft tumor growth, which was manifested by substantially reduced tumor growth when treated with the VEGF receptor 2 inhibitor Ki8751. Accordingly, Ki8751 suppressed the expression of IL-17C-stimulated PECAM and VE-cadherin in xenografts. Furthermore, IL-17C activated STAT3 to increase the expression of miR-23a-3p that suppressed semaphorin 6D (SEMA6D) expression, thereby permitting VEGF production. Taken together, our study demonstrates that IL-17C promotes tumor angiogenesis through VEGF production via a STAT3/miR-23a-3p/SEMA6D axis, suggesting its potential as a novel target for anti-CRC therapy.

Interplay between the Gut Microbiota and Inflammatory Mediators in the Development of Colorectal Cancer

“…Dual [28] ↑ [29,30] ↓ in tumor under immunotherapy [33] ↑ in serum [74] ↓ by FMT under DSS [27] NF-κB Promote [ ↑ [134] ↓ in colon [94] ↑ by FMT [27,94,95] IL-17 Promote [106,135] ↑ [114,135] ↓ in CD4 + T cell [113] ↓ in colon [94] ↓ by FMT under DSS [75] IFNs Suppress (α, β) [122] Controversial (γ) [124,129,130] ↓ IFNAR1 [122] ↓ α, β in ileum under viral infection [131] ↓ γ in T cells under viral infection [132] ↓ β, γ in SI under T. gondii infection [60] ↑ γ by L. delbrueckii, S. thermophilus under DMH-induced CRC [133] ↓ γ by FMT under DSS [75] ↑, up-regulated; ↓, down-regulated; CRC, colorectal cancer; GF, germ-free; ABX, antibiotics cocktail; TNF, tumor-necrosis factor; FMT, fecal microbiota transplantation; DSS, dextran sulfate sodium; NF-κB, nuclear factor kappa B; P. anaerobius, Peptostreptococcus anaerobius; IL-1, interleukin-1; LP, lamina propria; SI, small intestine; T. gondii, Toxoplasma gondii; VSL#3, probiotic mixture; CD, Crohn's disease; IL-6, interleukin-6; UC, ulcerative colitis; LPS, lipopolysaccharide; IL-10, interleukin-10; IL-17, interleukin-17; IFNs, interferons; IFNAR, interferon-α/β receptor; L. delbrueckii, Lactobacillus delbrueckii; S. thermophilus, Streptococcus thermophilus; DMH, 1,2-dimethylhydrazine.…”

“…IL-17 can also promote tumor proliferation via the MAPK/extracellular signal-regulated kinase pathway and angiogenesis by stimulating the production of VEGF. In addition to angiogenesis, IL-17 directly stimulates the migration of CRC cells, suggesting a role in the promotion of CRC metastasis and invasion [ 103 , 104 , 105 , 106 ].…”

Mast Cells, microRNAs and Others: The Role of Translational Research on Colorectal Cancer in the Forthcoming Era of Precision Medicine

“…Recently, some studies have shown the interaction of miRNAs with other biomarkers, such as KRAS [ 89 , 90 ], and their consequent role in predicting treatment response to classical cytotoxic chemotherapy or targeted therapy (anti-epidermal growth factor receptor (EGFR) and anti-VEGF) [ 91 , 92 , 93 , 94 ].…”

“…An inhibitor of this miRNA is under evaluation for the treatment of hepatocellular carcinoma [ 97 ]. High levels of miRNA-203 have been correlated with oxaliplatin resistance [ 93 ], and the deregulation of other miRNAs, such as miRNA-10b [ 98 ], is associated with 5-fluorouracil (FU) and irinotecan resistance [ 99 ].…”

Long Noncoding RNA ZEB1-AS1 Downregulates miR-23a, Promotes Tumor Progression, and Predicts the Survival of Oral Squamous Cell Carcinoma Patients

“…Accumulating evidences indicate that miRNA-23a may be a critical regulator in carcinogenesis and aberrant miR-23a expression has been detected in many cancers. 16 , 17 Advances in cancer research have highlighted the cancer-promoting function of miR-23a in regulating cell proliferation, apoptosis, EMT and angiogenesis progress 16 , 18 However, some recent studies reported that miR-23a is downregulated in certain cancer types, including nephroblastomas and osteosarcoma. 19 , 20 Another group of researchers showed that miR-23a can exhibit pro-apoptotic functions.…”