Medical Biochemistry Department, Medical Research Division, National Research Centre, Cairo, Egypt; Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt.
Pathology Department, Medical Research Division, National Research Centre, Cairo, Egypt.
Mol Cell Probes. 2019 Oct;47:101442. doi: 10.1016/j.mcp.2019.101442. Epub 2019 Aug 31.
Inflammatory bowel disease (IBD) is mostly responsible for the development of colitis-associated colon cancer. Of the several signaling pathways involved in colonic inflammation, the activation and crosstalk between NF-κB and STAT3 serve as the pivotal regulatory hubs that regulate epithelial tumorigenesis by linking inflammation with cancer development. Understanding the molecular mechanisms regulating the crosstalk between NF-κB and STAT3 will help in targeting these signaling pathways and halt epithelial tumorigenesis. MicroRNAs (miRNAs) play important role in the regulation of NF-κB and STAT3 and function in a positive- or negative feedback loop to regulate the crosstalk of these transcription factor. In the present study we evaluated the aberrant expression of a selected panel of miRNAs (miR-181b, miR-31, miR-34a, miR-146b, miR-221, and miR-155) that regulate the crosstalk between NF-κB and STAT3 during colitis-associated tumorigenesis. We used the stepwise colorectal carcinogenesis murine model known as Azoxymethane (AOM)/Dextran sodium sulphate (DSS) to recapitulate the different stages of tumorigenesis. Our results revealed that the expression of the selected miRNAs changed dynamically in a stepwise pattern as colonic tissue transforms from normal to actively inflamed to neoplastic state, in accordance with the gradual activation of NF-κB and STAT3, suggesting that the aberrant expression of these miRNAs could function as the epigenetic switch between inflammation and colorectal tumorigenesis. We were able to elucidate the contribution of miRNAs in the NF-κB - STAT3 crosstalk during the stepwise development of colitis-associated carcinoma, and this could improve our understanding of the molecular pathology of colorectal tumorigenesis and even suggesting a therapeutic strategy by modulating the expression of these regulating miRNAs.
炎症性肠病（IBD）是导致结肠炎相关结肠癌发展的主要原因。在涉及结肠炎症的几个信号通路中，NF-κB 和 STAT3 的激活和串扰作为关键调节枢纽，通过将炎症与癌症发展联系起来，调节上皮肿瘤发生。了解调节 NF-κB 和 STAT3 串扰的分子机制将有助于靶向这些信号通路并阻止上皮肿瘤发生。microRNAs（miRNAs）在调节 NF-κB 和 STAT3 中发挥重要作用，并通过正反馈或负反馈回路发挥作用，以调节这些转录因子的串扰。在本研究中，我们评估了一组选定的 miRNAs（miR-181b、miR-31、miR-34a、miR-146b、miR-221 和 miR-155）的异常表达，这些 miRNAs 调节结肠炎相关肿瘤发生过程中的 NF-κB 和 STAT3 串扰。我们使用已知的逐步结直肠癌变小鼠模型，即氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS），来重现肿瘤发生的不同阶段。我们的结果表明，随着结肠组织从正常状态向活跃炎症状态再到肿瘤状态的逐步转化，所选 miRNAs 的表达呈动态变化，与 NF-κB 和 STAT3 的逐渐激活一致，这表明这些 miRNAs 的异常表达可能作为炎症和结直肠肿瘤发生之间的表观遗传开关。我们能够阐明 miRNA 在 NF-κB-STAT3 串扰中在结肠炎相关癌的逐步发展中的作用，这可以提高我们对结直肠肿瘤发生的分子病理学的理解，甚至通过调节这些调节 miRNA 的表达来提出治疗策略。
