Dysregulation of key microRNAs in pancreatic cancer development

Baradaran, Behzad; Shahbazi, Roya; Khordadmehr, Monireh

doi:10.1016/j.biopha.2018.10.177

Cited by 53 publications

(40 citation statements)

References 119 publications

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“…A lower Z-score for a miRNA family reflects preferential loss of its binding sites due to 3’-UTR shortening. Interestingly, 6 of the top 8 identified miRNAs have been implicated as tumor suppressors in PDA, including miR-329 and miR-133a 78–82 (Fig. 6B).…”

Section: Resultsmentioning

confidence: 99%

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Venkat

Tisdale

Schwarz

et al. 2019

Preprint

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Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3’-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDAs). We report widespread, recurrent and functionally relevant 3’-UTR alterations associated with gene expression changes of known and newly identified PDA growth-promoting genes and experimentally validate the effects of these APA events on expression. We find enrichment for APA events in genes associated with known PDA pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3’-UTR forms of metabolic genes. Survival analyses reveal a subset of 3’-UTR alterations that independently characterize a poor prognostic cohort among PDA patients. Finally, we identify and validate the casein kinase CK1α as an APA-regulated therapeutic target in PDA. Knockdown or pharmacological inhibition of CK1α attenuates PDA cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of pro-tumorigenic gene expression in PDA via the loss of miRNA regulation.

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Section: Resultsmentioning

confidence: 99%

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Venkat

Tisdale

Schwarz

et al. 2019

Preprint

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“…Furthermore, Sato et al [30] reported that TLR4 is a target of miR-642a-5p in THP-1 cells, but LPS stimulation did not significantly enhance miR-642a-5p expression in THP-1 cells. Dysregulation of miR-642a-5p has also been identified in human prostate, bladder, pancreatic and liver cancer [15,31,32]. However, the information about the biological roles of miR-642a-5p in these cancers is still lacking, and more importantly, whether miR-642a-5p plays a role in LPS-induced ALI/ARDS is obscure.…”

Section: Discussionmentioning

confidence: 99%

miR‐642a‐5p partially mediates the effects of lipopolysaccharide on human pulmonary microvascular endothelial cells via eEF2

2020

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“…The recent, wide-ranging progression of miRNA-based diagnostic and therapeutic approaches for cancer patients is encouraging, and has been widely reported, including in pancreatic cancer [66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86]. Intriguingly, the clinical applications have advanced mainly in diagnostic fields instead of with treatment options.…”

Section: Micrornamentioning

confidence: 99%

The Clinical Potential of Oligonucleotide Therapeutics against Pancreatic Cancer

Takakura

Kawamura

Torisu

et al. 2019

IJMS

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Although many diagnostic and therapeutic modalities for pancreatic cancer have been proposed, an urgent need for improved therapeutic strategies remains. Oligonucleotide therapeutics, such as those based on antisense RNAs, small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are promising agents against pancreatic cancer, because they can identify a specific mRNA fragment of a given sequence or protein, and interfere with gene expression as molecular-targeted agents. Within the past 25 years, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Several clinical and preclinical studies of oligonucleotides have been conducted for patients with pancreatic cancer. To support the discovery of effective diagnostic or therapeutic options using oligonucleotide-based strategies, in the absence of satisfactory therapies for long-term survival and the increasing trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients, with underlying preclinical and scientific data, and focus on the possibility of oligonucleotides for targeting pancreatic cancer in clinical implications.

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Dysregulation of key microRNAs in pancreatic cancer development

Cited by 53 publications

References 119 publications

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

miR‐642a‐5p partially mediates the effects of lipopolysaccharide on human pulmonary microvascular endothelial cells via eEF2

The Clinical Potential of Oligonucleotide Therapeutics against Pancreatic Cancer

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