Department of Gastroenterology, Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, P.R. China.
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China.
Oncol Rep. 2018 Sep;40(3):1684-1694. doi: 10.3892/or.2018.6566. Epub 2018 Jul 12.
An early diagnosis of colitis‑associated colorectal cancer (CAC) is important for its clinical management. However, it is currently difficult to distinguish the different stages of CAC development. MicroRNA dysregulation is common in human colorectal disorders, however little is known regarding whether miRNA affects tumor progression by regulating inflammation. In the present study, we identified a novel miRNA (miR‑449a), the expression of which was significantly reduced in CAC tissues than in paired adjacent non‑cancerous tissues (ANTs). Notably, the level of miR‑449a was in a markedly decreased pattern during the neoplastic transformation of ulcerative colitis (UC)‑to‑CAC, as demonstrated by both clinical investigations and the experimental mouse model induced by AOM/DSS treatment. In addition, we observed that decreased miR‑449a expression was associated with advanced T or N status, later clinical stage and poor histological differentiation of CAC. Mechanistic studies revealed that miR‑449a inhibited the growth and metastasis of human colon cancer cells by directly binding to the 3'‑UTR of Notch‑1 and thereby, suppressed the activation of the Notch signaling pathway. Therefore, these findings provide strong evidence for the translational potential of miR‑449a in the discrimination of patients with UC that is likely to progress into CAC, from those unlikely to progress, as well as in the prognosis and diagnosis of CAC.
结直肠型结肠炎相关癌症（CAC）的早期诊断对其临床管理很重要。然而，目前很难区分 CAC 发展的不同阶段。miRNA 失调在人类结直肠疾病中很常见，但关于 miRNA 是否通过调节炎症来影响肿瘤进展知之甚少。在本研究中，我们鉴定了一种新型 miRNA（miR-449a），其在 CAC 组织中的表达明显低于配对的相邻非癌组织（ANTs）。值得注意的是，miR-449a 的水平在溃疡性结肠炎（UC）向 CAC 的肿瘤转化过程中呈明显下降趋势，这一点通过临床研究和 AOM/DSS 处理诱导的实验小鼠模型得到了证实。此外，我们观察到，miR-449a 表达降低与 CAC 的 T 或 N 分期较晚、临床分期较晚和组织学分化不良有关。机制研究表明，miR-449a 通过直接结合 Notch-1 的 3'UTR 抑制人结肠癌细胞的生长和转移，从而抑制 Notch 信号通路的激活。因此，这些发现为 miR-449a 在鉴别可能进展为 CAC 的 UC 患者与不太可能进展的患者，以及在 CAC 的预后和诊断方面具有潜在的转化应用提供了有力证据。
