Objective

MicroRNAs are a class of small, non-coding RNAs that play a key role in several biological and molecular processes, including tumorigenesis. We previously identified that MIR452 is upregulated in both colorectal cancer (CRC) and colitis. However, the functional mechanisms of MIR452 and its target genes in CRC and colitis are not well understood. So, we hypothesize that MIR452 can influence CRC and DSS-induced colitis model through the regulation of IL20RA and its downstream JAK-STATs signaling pathway.

Methods

We used a luciferase reporter assay to confirm the effect of MIR452 on IL20RA expression. The protein and mRNA expression of a target gene and its associated molecules were measured by western blot, quantitative RT-PCR, and immunohistochemistry.

Results

We found that the IL20RA was a direct target gene of MIR452. Overexpression of MIR452 in CRC cell lines significantly decreased IL20RA and its downstream Janus kinase 1 (JAK1), Signal transducer and activator of transcription 1 (STAT1) and STAT3. Knockdown of IL20RA in CRC cell lines by IL20RA gene silencing also decreased the expression of IL20RA, JAK1, and STAT3, but not of STAT1.

Conclusion

Our results suggest that MIR452 regulates STAT3 through the IL20RA-mediated JAK1 pathway, but not STAT1. Overall, MIR452 acts as tumor suppressor in human CRC and in a mouse colitis model. These findings suggest that MIR452 is a promising therapeutic target in the treatment of cancer and colitis.

中文翻译：

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MicroRNA 452 在炎症性结肠炎和结直肠癌中调节 IL20RA 介导的 JAK1/STAT3 通路

客观的

MicroRNA 是一类小的非编码 RNA，在包括肿瘤发生在内的多种生物和分子过程中发挥关键作用。我们之前发现MIR452在结直肠癌 (CRC) 和结肠炎中均上调。然而，MIR452及其靶基因在CRC和结肠炎中的功能机制尚不清楚。因此，我们假设 MIR452 可以通过调节 IL20RA 及其下游 JAK-STATs 信号通路影响 CRC 和 DSS 诱导的结肠炎模型。

方法

我们使用荧光素酶报告基因测定来确认MIR452对IL20RA表达的影响。通过蛋白质印迹、定量 RT-PCR 和免疫组织化学测量靶基因及其相关分子的蛋白质和 mRNA 表达。

结果

我们发现IL20RA是MIR452的直接靶基因。MIR452在 CRC 细胞系中的过表达显着降低了 IL20RA 及其下游 Janus 激酶 1 (JAK1)、信号转导和转录激活因子 1 (STAT1) 和 STAT3。通过 IL20RA 基因沉默敲低CRC 细胞系中的 IL20RA 也降低了 IL20RA、JAK1 和 STAT3 的表达，但不降低 STAT1 的表达。

结论

我们的结果表明，MIR452通过 IL20RA 介导的 JAK1 途径调节 STAT3，而不是 STAT1。总体而言，MIR452在人类 CRC 和小鼠结肠炎模型中充当肿瘤抑制因子。这些发现表明，MIR452是治疗癌症和结肠炎的有希望的治疗靶点。