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miRNA-320 inhibits colitis-associated colorectal cancer by regulating the IL-6R/STAT3 pathway in mice
Meng-Yao Wu1, Yu-Xin Luo1, Wen-Xiu Jia1
1Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Hebei Medical University, Shijiazhuang, China.
Background:
Colitis-associated colorectal cancer (CAC) is a serious complication of inflammatory bowel disease (IBD). microRNA-320 (miRNA-320) promotes intestinal mucosal barrier repair in IBD and inhibits tumor progression. However, the role of miRNA-320 in the progression of CAC remains to be defined. We studied the mechanisms of miRNA-320 in the progression of CAC in mice.
Methods:
CAC was induced in mice (C57BL/B6) by the administration of azoxymethane (AOM) and dextran sulfate sodium (DSS), and the mice were given a lentiviral vector (LV) overexpressing mmu-miRNA-320. The level of miRNA-320 was analyzed by quantitative real-time polymerase chain reaction (qPCR). Colonic inflammation, histological analysis, and tumorigenesis were evaluated. Ki-67 in colonic tissues was examined by immunohistochemistry. B-cell lymphoma-extra large (BCL-xl) and proliferating cell nuclear antigen (PCNA) expression was examined by Western blot. Furthermore, the proliferation, migration, and invasion of colorectal cancer (CRC) cells were evaluated. The levels of interleukin-6 receptor (IL-6R), signal transducer and activator of transcription 3 (STAT3), and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) were examined by Western blot and qPCR.
Results:
miRNA-320 was downregulated in CAC mice (0.57±0.13 vs. 1.00±0.12, t=-5.95, P<0.001). miRNA-320 decreased the disease activity index (DAI) scores, improved colonic inflammation, and inhibited tumor formation (tumor number: 8.00±2.90 vs. 13.67±2.73, t=-3.49, P<0.01) in mice with CAC. miRNA-320 suppressed the expression of BCL-xl, PCNA, and Ki-67 (0.38±0.07 vs. 0.69±0.08, t=-7.30, P<0.001). miRNA-320 inhibited colon cancer cell proliferation, migration, and invasion. miRNA-320 significantly inhibited the levels of IL-6R [colon tissue messenger RNA (mRNA): 4.06±1.44 vs. 10.05±1.55, t=-6.94, P<0.001], STAT3, and p-STAT3 in vivo and in vitro. Silencing IL-6R expression partially reversed the IL-6R/STAT3-suppressing and tumor-inhibiting effect of miRNA-320.
Conclusions:
miRNA-320 inhibits tumorigenesis in mice with CAC by suppressing IL-6R/STAT3 expression, and IL-6R is a target gene of miRNA-320.
Insights
MicroRNA-320 (miRNA-320) suppresses tumor growth in colitis-associated colorectal cancer (CAC) by inhibiting the IL-6R/STAT3 pathway. This study reveals miRNA-320 as a potential therapeutic target for CAC.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD).
- MicroRNA-320 (miRNA-320) plays a role in intestinal healing and tumor suppression.
- The specific function of miRNA-320 in CAC progression requires further investigation.
Purpose of the Study:
- To elucidate the role and underlying mechanisms of miRNA-320 in the progression of CAC.
- To investigate whether miRNA-320 can inhibit CAC development in a mouse model.
- To identify potential molecular targets of miRNA-320 in CAC.
Main Methods:
- CAC was induced in mice using azoxymethane (AOM) and dextran sulfate sodium (DSS).
- Mice were treated with a lentiviral vector overexpressing miRNA-320.
- Key molecular markers, including miRNA-320 levels, inflammation, tumor formation, cell proliferation (Ki-67, PCNA), and the IL-6R/STAT3 pathway, were assessed.
Main Results:
- miRNA-320 levels were significantly downregulated in CAC mice.
- Overexpression of miRNA-320 reduced disease activity, colonic inflammation, and tumor burden.
- miRNA-320 suppressed proliferation, migration, and invasion of cancer cells by downregulating BCL-xl, PCNA, and Ki-67.
- miRNA-320 inhibited the IL-6R/STAT3 signaling pathway, and IL-6R was identified as a direct target.
Conclusions:
- miRNA-320 exhibits anti-tumorigenic effects in CAC by suppressing the IL-6R/STAT3 pathway.
- Interleukin-6 receptor (IL-6R) is a direct target gene of miRNA-320 in the context of CAC.
- miRNA-320 represents a potential therapeutic strategy for managing CAC.
