Mechanism of Long Non-coding RNAs Action in leiomyoma

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Uterine leiomyoma (fibroids) are benign tumors afflicting a significant number of reproductive age women and without a known cause. Our laboratory has focused on understanding how miRNAs impact pro-inflammatory and pro-fibrotic pathways in leiomyoma, and identified two miRNAsmiR-200c and miR-29c which primarily target cell cycle, inflammation and extracellular matrix (ECM) component genes respectively as key in the development of leiomyoma. Our recent findings using next generation sequencing has demonstrated a whole host of non-coding RNAs including long non-coding RNAs (lncRNAs) are dysregulated in fibroids. LncRNAs can act as sponge for miRNAs and therefore may be a driver of gene dysregulation in leiomyomas. Our previous work demonstrated that tranilast, an anti- inflammatory drug approved for the treatment of asthma in Japan and Korea, has potent effects in fibroid cells by inhibiting cell proliferation and stimulating the expression of two key miRNAs that are down regulated in fibroids (miR-200c and miR-29c)15, 16. These key miRNAs play a pivotal role in fibroid pathogenesis by targeting the expression of cell cycle regulatory proteins and inflammation (miR-200c), and composition and remodeling of the ECM (miR-29c). Furthermore, recent reports showed that H19 also can act as sponge for miR-29 and miR-200 family18-20 in various malignancies. In this project we propose to determine if H19 can act as a sponge for miR-29/miR-200 family in fibroids and if tranilast can decrease the expression of H19 and thereby increase the expression of miR-29 and miR-200 family. This project clearly falls within the scope of our R01 funded project exploring the interaction of H19 with miR-29 and miR-200 family. We hypothesize that H19 sponges miR-29 and miR-200 family in fibroids and that tranilast upregulates the expression of miR-29/miR-200 family by inhibiting the expression of H19. This hypothesis will be tested in two Aims. Aim 1: Determine if lncRNA H19 functions as a sponge for miR-29 and miR-200 family in fibroids, and determine the effects of tranilast on the expression of H19 in vitro and in vivo. Aim 2: Determine if the effect of tranilast on the expression of miR-29 and miR-200 family is mediated by H19. Completion of these aims will not only advance our knowledge of the role of long non-coding RNAs in fibroid pathogenesis and potential targeting them as a therapeutic approach but will also provide the opportunity for our candidate Mr. Quintanilla to learn a host of new molecular and surgical techniques and prepare him for a career in the biomedical research.