miR-200c Regulates IL8 Expression by Targeting IKBKB: A Potential Mediator of Inflammation in Leiomyoma Pathogenesis

Abstract

We have previously reported that leiomyoma expressed lower levels of miR-200c and elevated IL8 as compared to paired myometrium. Here we addressed the regulatory functions of miR-200c on the expression of inflammatory mediators and cellular viability using leiomyomas and paired myometrium and their isolated primary smooth muscle cells. Our results indicated that gain-of function or knockdown of miR-200c in leiomyoma smooth muscle cells (LSMC) regulated IL8 mRNA and protein expression through direct targeting of IKBKB and alteration of NF-kB activity. Additionally, leiomyoma expressed higher levels of phosphorylated IKBKB with no significant difference in the level of IKBKB mRNA and protein as compared to matched myometrium. Gain-of function of miR-200c in LSMC resulted in decreased IkBαphosphorylation and p65 nuclear translocation, which led to decreased p65 transcriptional activity of IL8 promoter, and increased caspase 3/7 activity which was not reversible following IL8 restoration. Collectively, our results suggest that NF-κB signaling pathway is a target of miR-200c regulatory function, and low level of miR-200c expression in leiomyoma by transcriptional regulation of inflammatory mediators such as IL8, in part account for development of leiomyomas.

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

“…miR-200c directly targets many pro-inflammatory genes, including IL-8, VEGFA, and VEGFR2. Additionally, miR-200c also targets IKK␤ (IKBKB), thereby decreasing Nf-B signaling and inhibiting scores of pro-inflammatory Nf-B-target genes (51)(52)(53). Furthermore, as let-7d, miR-23b, and miR200c are established tumor suppressor genes that are significantly down-regulated in OSCC, our data provide a potential mechanism whereby PAR-2 activation contributes to tumor progression (54 -61).…”

Effects of miRNA-197 overexpression on proliferation, apoptosis and migration in levonorgestrel treated uterine leiomyoma cells

“…Accumulated evidence suggests that microRNAs (miRNA), a member of non-protein coding small RNA, functions as key regulator of protein coding genes expression [28,29], and their deregulation or dysfunction has been associated with the inflammation, fibrosis and tumorigenesis [30,31]. Several miRNAs, including miR-29b [32], miR-93/106b [33], and miR-200c [34,35], are down-regulated in leiomyoma and involved in the development of uterus leiomyoma. In our study, we found that miR-197 was also down-regulated in human uterus leiomyomas in comparison with the adjacent normal uterus myometrium.…”

miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

“…IL-6-mediated suppression of miR-200c led towards activation of its downstream targets JNK2 and p65 (required for constitutive activation of IL-6) whereas loss of IL-6 in a mouse model impaired tumorigenicity due to activation of miR-200c [107]. Overexpressing miR-200c also controls inflammation-associated IL-8 in leiomyoma (smooth muscle tumor) by targeting IKKB at the upstream of NF-κB, thus decreasing p65 binding at IL-8 promoter [108]. Overall, in addition to playing important roles in EMT and metastasis, miR-200c has been adapted to regulate multiple normal growth, development, cancer, and other diseases.…”