miR-29a-5p/STAT3 Positive Feedback Loop Regulates TETs in Colitis-Associated Colorectal Cancer.

BACKGROUND:Interleukin (IL)-6/signal transducers and activators of transcription 3 signaling plays an important role in the development of colitis-associated colorectal cancer (CAC). The mechanism of CAC formation remains unclear, and the relationship between miRNAs and the signaling pathway in the development of CAC is not well understood. In this study, we investigated the relationship between miR-29a-5p and the IL-6/duanyu18133 signaling pathway in the development of CAC and alterations in 10-11 translocations (TETs) regulated by this network. METHODS:miR-29a-5p was screened in a CAC mouse model by high-throughput microarray analysis and investigated in human colorectal cancer tissue samples and colon cell lines by quantitative reverse transcription polymerase chain reaction (Q-RTPCR). The expression of miR-29a and TETs was detected by Q-RTPCR, and the expression of and TET3 was detected via Western blot assay. The expression of TET1 and 5-hydroxymethylcytosine (5hmC) was detected through immunofluorescence. RESULTS:Our results showed that miR-29a-5p was significantly upregulated and was accompanied by activation in the colon tissues of CAC mouse and human colorectal cancer tissues, as compared with normal colon tissues. In contrast, the levels of TETs and 5hmC were decreased. In vitro, overexpression of miR-29a-5p in colonic cell lines (HCT-116 and IEC-6) and RAW264.7 cells increased duanyu18133 expression, but decreased that of TET3, TET1, and 5hmC. miR-29a-5p downregulation in HCT-116 and IEC-6 cell lines could rescue the expression of duanyu18133 and TET3. Notably, duanyu18133 activation induced by IL-6 upregulated miR-29a-5p expression and reduced TET expression in vitro, although duanyu18133 inhibitor treatment downregulated miR-29a-5p expression, which was induced by IL-6. CONCLUSIONS:Our studies showed that tumor development occurred with inflammation. The signaling axis could play an important role in the development of CAC, and the miR-29a-5p/duanyu18133 positive feedback loop may amplify the effects of inflammation, lead to decreased levels of TET and 5hmC, and eventually lead to the development of CAC.

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