MicroRNA-135a Inhibits Cell Proliferation by Targeting Bmi1 in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal solid tumor due to the lack of reliable early detection markers and effective therapies. MicroRNAs (miRNAs), noncoding RNAs that regulate gene expression, are involved in tumorigenesis and have a remarkable potential for the diagnosis and treatment of malignancy. In this study, we investigated aberrantly expressed miRNAs involved in PDAC by comparing miRNA expression profiles in PDAC cell lines with a normal pancreas cell line and found that miR-135a was significantly down-regulated in the PDAC cell lines. The microarray results were validated by qRT-PCR in PDAC tissues, paired adjacent normal pancreatic tissues, PDAC cell lines, and a normal pancreas cell line. We then defined the tumor-suppressing significance and function of miR-135a by constructing a lentiviral vector to express miR-135a. The overexpression of miR-135a in PDAC cells decreased cell proliferation and clonogenicity and also induced G1 arrest and apoptosis. We predicted Bmi1 may be a target of miR-135a using bioinformatics tools and found that Bmi1 expression was markedly up-regulated in PDAC. Its expression was inversely correlated with miR-135a expression in PDAC. Furthermore, a luciferase activity assay revealed that miR-135a could directly target the 3'-untranslated region (3'-UTR) of Bmi1. Taken together, these results demonstrate that miR-135a targets Bmi1 in PDAC and functions as a tumor suppressor. miR-135a may offer a new perspective for the development of effective miRNA-based therapy for PDAC.

Circular RNA Expression Profile of Pancreatic Ductal Adenocarcinoma Revealed by Microarray

“…The gene and noncoding RNA, such as miRNA and lncRNA, expression microarrays have been recognized as a feasible and useful approach to profile the molecular signatures of PDAC [37,38]. Increasing studies are continuing to prove that noncoding RNAs, including miRNAs and lncRNAs, are involved in the development and procession of PDAC [38][39][40]. However, the tumorigenesis mechanisms of PDAC are far more elucidated.…”

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

“…miR-216a overexpression markedly inhibits the JAK2/STAT3 signaling pathway and xenograft tumor growth in vivo [116]. Furthermore, stably miR-135a overexpressing cells display reduced proliferation and clonogenicity, at least in part via the regulation of BMI1 [117]. Restoring the expression of miR-218 in pancreatic cancer resulted in downregulation of ROBO1 and efficient attenuation of cell migration and invasion [118].…”

“…Tumor suppressor miRNA mimic Inhibition of invasive growth [112] miR-148b Tumor suppressor miRNA mimic and lentiviral system Remarkably suppresses growth and invasion and enhances chemosensitivity/inhibits tumorigenicity in nude mice [113] miR-204 Tumor suppressor miRNA mimic or triptolide treatment Decrease in cell viability and cell death [114] miR-137 Tumor suppressor Lentiviral system Inhibits cell invasion/increases sensitivity to Fluorouracil/suppresses tumor growth in vivo [115] miR-216a Tumor suppressor miRNA mimic Inhibition of the JAK2/STAT3 signaling pathway and xenograft tumor growth in vivo [116] miR-135a Tumor suppressor Lentiviral system Reduced proliferation and clonogenicity/ induced G1 arrest and apoptosis [117] miR-218 Tumor suppressor miRNA mimic and lentiviral system Attenuation of cell migration/invasion [118] miR-663 Tumor suppressor Lentiviral system Antiproliferative, anti-invasive and pro-apoptotic effects in vivo and in vitro [119] The oncogenic or tumor-suppressive effect of miRNA-based targeting is denoted in several pancreatic adenocarcinoma settings. ASO: Antisense oligonucleotide; EMT: Epithelial-mesenchymal transition; HCC: Hepatocellular carcinoma cell.…”

MiR-940 Inhibited Pancreatic Ductal Adenocarcinoma Growth by Targeting MyD88

“…The median overall survival is less than 6 months and, despite surgery, the 5-year survival rate is a dismal 3 to 5%, with chemotherapeutic options having only a limited impact. Cancer is a complex disease involving numerous genetic and epigenetic changes, thus as a better understanding of the molecular mechanism of PDAC is urgently needed to develop an effective diagnosis and treatment [3], these cancer related changes need to be investigated.…”