miR-17-5p Inhibitor Enhances Chemosensitivity to Gemcitabine Via Upregulating Bim Expression in Pancreatic Cancer Cells

Background/Aims: Oogenesis is a highly complex process that is intricately regulated by interactions of multiple genes and signaling molecules. However, the underlying molecular mechanisms are poorly understood. There is emerging evidence that microRNAs contribute to oogenesis. Here, we aimed to investigate the role of miR-17-92 cluster in regulating oogenesis. Methods: The miR-17-92 cluster was genetically ablated in germ cells of female mice by applying the Cre-loxp system for conditional gene knockout. Mating experiment, superovulation and histological analysis were used to assess the fertility of the model female mice. TUNEL assay was used to identify apoptotic cells in ovaries. The expression level of apoptosis- and follicular atresia- related genes was evaluated by qRT-PCR. Western blotting was performed to detect protein expression. Bioinformatics software and dual luciferase reporter assay were applied to predict and verify the target of miR-17-92 cluster. Results: Deletion of miR-17-92 cluster in germ cells of female mice caused increased oocyte degradation and follicular atresia, perturbed oogenesis, and ultimately led to subfertility. Genes involved in follicular atresia and the mitochondrial apoptotic pathway were obviously up-regulated. Furthermore, we verified that miR-19a regulated oogenesis at the post-transcriptional level by targeting Bmf in the ovaries of miR-17-92 cluster conditional knockout female mice. Conclusion: The miR-17-92 cluster is an important regulator of oogenesis. These findings will assist in better understanding the etiology of disorders in oogenesis and in developing new therapeutic targets for female infertility.

show abstract

“…10). Previous studies identified Bim as direct targets of miR-17 [40, 45], miR-20a [27, 40], and miR-92a [40]. Xie et al .…”

Section: Discussionmentioning

confidence: 99%

Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice

Wang

Tian

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Nagano and colleagues suggested that activation of the Wnt/beta-catenin signaling pathway mediates the miR-29a-induced resistance to gemcitabine in PDAC cells [95]. In another study, transfection of PANC-1 and BxPC-3 cells with an miR-17-5p inhibitor showed growth inhibition, spontaneous apoptosis, higher caspase-3 activation and increased chemosensitivity to gemcitabine [96]. Additionally, miR-205 was found to be consistently downregulated across pancreatic cancer specimens, making it a suitable therapeutic target.…”

Section: Mirnas Relate To Chemotherapy Treatment In Pdacmentioning

confidence: 99%

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

2016

View full text Add to dashboard Cite

Pancreatic cancer is a devastating malignancy that ranks as the fourth leading cause of cancerrelated deaths worldwide. Dismal prognosis is mainly attributable to limited knowledge of the molecular pathogenesis of the disease. miRNAs have been found to be deregulated in pancreatic cancer, affecting several steps of initiation and aggressiveness of the disease by regulating important signaling pathways, such as the KRAS and Notch pathways. Moreover, the effect of miRNAs on regulating cell cycle events and expression of transcription factors has gained a lot of attention. Recent studies have highlighted the application of miRNAs as biomarkers and therapeutic tools. The current review focuses on latest advances with respect to the roles of miRNAs in pancreatic ductal adenocarcinoma associated signaling pathways and miRNA-based therapeutics. KEYWORDS• antisense oligonucleotides • miRNAs • pancreatic cancer Pancreatic cancer overview Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic neoplasms and accounts for greater than 85% of the clinical cases [1]. The disease develops via acinar-ductal metaplasia and neoplastic precursor lesions [2]. In the USA alone, 48,960 new cases of pancreatic cancer were expected to occur in 2015, with an estimated 40,560 deaths, about the same number in women (19,850) as in men (20,710). Over 96% are cancers arising from exocrine pancreas. Endocrine carcinomas are often diagnosed at a younger age and exhibit a better prognosis. From 2007 to 2011, mortality rates increased slightly by 0.3% per year. For all stages combined, the 1-and 5-year relative survival rates are 28 and 7%, respectively. For the small percentage of people diagnosed with local disease (9%), the 5-year survival is 26%, while more than half of patients (53%) are diagnosed at a late stage for which 1-and 5-year survival rates reach 15 and 2%, respectively [3]. These numbers are a staggering example of the poor prognosis associated with PDAC.While new therapeutic options are emerging for nonhematologic malignancies, molecular-targeted therapies for pancreatic cancer have failed to make any positive impact on patient survival. In 1993, the Nobel Prize-winning discovery of small interference RNAs (siRNAs) led to an outburst of knowledge on RNA interference and gene regulation [4]. Since then, thousands of research studies have described the functional role of small noncoding RNAs, named miRNAs, in a vast panel of human pathologies. In 2002, a small genomic region in chromosome 13q14 comprising miR-15a and miR-16-1 genes was found to be commonly deleted in chronic lymphocytic leukemia, For reprint orders, please contact: reprints@futuremedicine.com

show abstract

“…Conversely, miR-17-5p downregulates the proapoptotic member of the Bcl-2 protein family Bim, and PDAC cells transfected with miR-17-5p inhibitor showed growth inhibition, spontaneous apoptosis, higher caspase-3 activation, and increased chemosensitivity to gemcitabine [126]. Pathways delivering an antiapoptotic signal, such as PI3K/Akt, play also a pivotal role in the balance between proapoptotic and survival signals, which determines the fate of cancer cells.…”

Section: Microrna-based Mechanisms Of Anticancer Drug Resistance Imentioning

confidence: 99%

Molecular Mechanisms Underlying the Role of MicroRNAs in the Chemoresistance of Pancreatic Cancer

Garajová

Large

Frampton

et al. 2014

BioMed Research International

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is an extremely severe disease where the mortality and incidence rates are almost identical. This is mainly due to late diagnosis and limited response to current treatments. The tumor macroenvironment/microenvironment have been frequently reported as the major contributors to chemoresistance in PDAC, preventing the drugs from reaching their intended site of action (i.e., the malignant duct cells). However, the recent discovery of microRNAs (miRNAs) has provided new directions for research on mechanisms underlying response to chemotherapy. Due to their tissue-/disease-specific expression and high stability in tissues and biofluids, miRNAs represent new promising diagnostic and prognostic/predictive biomarkers and therapeutic targets. Furthermore, several studies have documented that selected miRNAs, such as miR-21 and miR-34a, may influence response to chemotherapy in several tumor types, including PDAC. In this review, we summarize the current knowledge on the role of miRNAs in PDAC and recent advances in understanding their role in chemoresistance through multiple molecular mechanisms.

show abstract

miR-17-5p Inhibitor Enhances Chemosensitivity to Gemcitabine Via Upregulating Bim Expression in Pancreatic Cancer Cells

Abstract: These results prove that miR-17-5p negatively regulates Bim at the posttranscriptional level. We suggest that miR-17-5p inhibitor gene therapy would be a novel approach to chemosensitization for human pancreatic cancer.

Cited by 54 publications

References 27 publications

Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice

Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

Molecular Mechanisms Underlying the Role of MicroRNAs in the Chemoresistance of Pancreatic Cancer

Contact Info

Product

Resources

About