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Targeting retinoid receptors with dysregulated microNRAs in pancreatic duct adenocarcinoma
Targeting retinoid receptors with dysregulated microNRAs in pancreatic duct adenocarcinoma
Retinoid (i.e., vitamin A, all-trans retinoic acid and other synthetic derivatives of vitamin A) induce cell differentiation and growth via the interaction of retinoid receptors in various normal and malignant cells. In addition to the success of all-trans-retinoic acid -based differentiation therapy in acute promyelocytic leukemia, emerging attempt in the combination of RA therapy and traditional chemotherapy has been studied in various solid cancer. Retinoid receptors (RARA, RARB, RXRA, and RXRB) and retinoic acid were reported to be down-regulated in pancreatic duct adenocarcinoma (PDAC) compared to normal pancreas. Moreover, the reduced expression of retinoid receptors correlates with the expression of these markers involved in the cell differentiation and the epithelial-mesenchymal transition. Further analysis revealed that the expressions of RARA and RXRB are associated with the overall survival in PDAC patients. Reduced level of retinoid and their receptors is associated with worse survival outcomes in PDAC patients. Yet, the mechanism of the down-regulation of retinoid receptors is not well defined. miRNA, as a class of small non-coding RNAs, can incorporate into the RNA-induced silencing complex and post-transcriptionally regulate the mRNA expression typically by binding to the 3’ untranslated region (3’-UTR) of the complementary mRNA sequence. The aim of this study was to find out whether selected dysregulated miRNAs in PDAC are responsible for the decreased level of retinoid receptors. For this purpose, we first performed a bioinformatics research to reveal conserved target sequences for deregulated miRNAs within the 3’UTR region of retinoid receptor mRNA. Next, we investigated the expression of selected retinoid receptors and miRNAs in BxPC-3, DanG, MiaPaCa-2, Panc-1 cell lines and the Human Pancreatic Duct Epithelial (HPDE) cell line. Further, we investigated the expression level by manipulating the expression of selected miRNAs. We demonstrated that none of these miRNAs can target the selected retinoid receptors in vitro. Therefore, we conclude that dysregulated miR-138, miR-206, miR-613, miR-9 and miR-27a/b are not involved in the regulation of the expression of retinoid receptors in PDAC patients.
Not available
Yin, Shuai
2018
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Yin, Shuai (2018): Targeting retinoid receptors with dysregulated microNRAs in pancreatic duct adenocarcinoma. Dissertation, LMU München: Faculty of Medicine
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Abstract

Retinoid (i.e., vitamin A, all-trans retinoic acid and other synthetic derivatives of vitamin A) induce cell differentiation and growth via the interaction of retinoid receptors in various normal and malignant cells. In addition to the success of all-trans-retinoic acid -based differentiation therapy in acute promyelocytic leukemia, emerging attempt in the combination of RA therapy and traditional chemotherapy has been studied in various solid cancer. Retinoid receptors (RARA, RARB, RXRA, and RXRB) and retinoic acid were reported to be down-regulated in pancreatic duct adenocarcinoma (PDAC) compared to normal pancreas. Moreover, the reduced expression of retinoid receptors correlates with the expression of these markers involved in the cell differentiation and the epithelial-mesenchymal transition. Further analysis revealed that the expressions of RARA and RXRB are associated with the overall survival in PDAC patients. Reduced level of retinoid and their receptors is associated with worse survival outcomes in PDAC patients. Yet, the mechanism of the down-regulation of retinoid receptors is not well defined. miRNA, as a class of small non-coding RNAs, can incorporate into the RNA-induced silencing complex and post-transcriptionally regulate the mRNA expression typically by binding to the 3’ untranslated region (3’-UTR) of the complementary mRNA sequence. The aim of this study was to find out whether selected dysregulated miRNAs in PDAC are responsible for the decreased level of retinoid receptors. For this purpose, we first performed a bioinformatics research to reveal conserved target sequences for deregulated miRNAs within the 3’UTR region of retinoid receptor mRNA. Next, we investigated the expression of selected retinoid receptors and miRNAs in BxPC-3, DanG, MiaPaCa-2, Panc-1 cell lines and the Human Pancreatic Duct Epithelial (HPDE) cell line. Further, we investigated the expression level by manipulating the expression of selected miRNAs. We demonstrated that none of these miRNAs can target the selected retinoid receptors in vitro. Therefore, we conclude that dysregulated miR-138, miR-206, miR-613, miR-9 and miR-27a/b are not involved in the regulation of the expression of retinoid receptors in PDAC patients.