MicroRNA-20a Overexpression Inhibited Proliferation and Metastasis of Pancreatic Carcinoma Cells

Hua, Yan; Wu, Jiangxue; Liu, Wensong; Zuo, Yufang; Chen, Shupeng; Zhang, Shineng; Zeng, Mu‐Sheng; Huang, Wenlin

doi:10.1089/hum.2010.061

Cited by 61 publications

(54 citation statements)

References 41 publications

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“…STAT3 is activated in primary pancreatic cancer and is involved in various physiologic functions [64], including apoptosis, cell cycle regulation, angiogenesis and metastasis. Mechanistic studies showed that miR-20a regulates STAT3 at the post-transcriptional level, leading to attenuation of cell proliferation and invasion of pancreatic carcinoma [65]. Dual luciferase assays revealed that STAT3 is directly targeted by miR130b, which was further confirmed by the inverse expression of miR-130b and STAT3 in pancreatic cancer specimens [66].…”

Section: • Crosstalk Between Mirnas and Transcription Factors In Pancrementioning

confidence: 82%

“…A preclinical in vivo experiment has been described, according to Oncogenic Anti-miRNA Significant increase in cell apoptosis [71] miR-21/mir-221 Oncogenic ASO Increases cell apoptosis/cell cycle arrest [92] miR-21 Oncogenic HIV-1-based lentiviral vectors Inhibits pancreatic cancer tumor growth both in vitro and in vivo [104] miR-27a Oncogenic Anti-miRNA Suppresses growth, colony formation and migration [105] miR-371-5p Oncogenic Anti-miRNA Proliferative inhibition [106] miR-21/miR-23a/miR-27a Oncogenic Anti-miRNA Synergistic effects in reducing cell proliferation both in vivo and in vitro [107] miR-200 and let-7 families Downregulated in gemcitabineresistant cells miRNA mimic or isoflavone Reversal of EMT phenotype leading to epithelial morphology [26] ↑ miR-22 and ↓ miR-199a -miRNA mimic or curcumin Suppressed expression SP1 transcription factor and ESR1 [60] Let-7 Tumor suppressor Plasmid-based synthetic miRNAs or by lentiviral transduction Strongly diminishes cell proliferation [108] miR-34a Tumor suppressor Lentiviral system Inhibits clonogenic cell growth and invasion and induces apoptosis and cell cycle arrest at G1 and G2/M phase [27] miR-217 Tumor suppressor miRNA-expressing plasmids Suppresses tumor cell growth in vivo [36] miR-20a Tumor suppressor Lentiviral system Inhibits proliferation and metastasis [65] miR-96 Tumor suppressor miRNA mimic and miRNA-expressing plasmid…”

Section: Manipulation Of Mirna Expression Levels As a Therapeutic Strmentioning

confidence: 99%

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Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

2016

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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

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Section: • Crosstalk Between Mirnas and Transcription Factors In Pancrementioning

confidence: 82%

Section: Manipulation Of Mirna Expression Levels As a Therapeutic Strmentioning

confidence: 99%

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

2016

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“…The reduction of all miR-17 family members simultaneously in the hypoxic retina as well as other tissues and tumors might be an early response to contextual signals within the tissue microenvironment that triggers neovascularization. In this context, it is interesting to note that overexpression of some of the miRs evaluated here (namely miR-17 and miR-20a) inhibits metastasis (also an angiogenesis-dependent process) in pancreatic carcinoma cells (35) as well as breast cancer (36).…”

Section: Low Levels Of Mir-17 Family In the Initial Steps Of The Angimentioning

confidence: 89%

Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch

Nunes

Dias-Neto

Cardó-Vila

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3′ UTRs of Hif1a and Vegfa. Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response. In humans, the miR-17 family is composed of six distinct mature miRs located on three chromosomes: miR-17-5p and miR-20a are located on chromosome 13q31.3, miR-20b and miR106a are located on chromosome Xq26.2, and miR-106b and miR-93 are located on chromosome 7q22.1. Members of this family seem to be derived from gene duplication events (9), and despite some divergences in length and nucleotide composition, their seed sequence (AAAGUG) is identical, an attribute suggestive of functional redundancy (10). Although the miR-17-92 cluster has been well-characterized, the regulatory role of the miR-17 family members has not been extensively studied (11,12). Distinct prediction algorithms (13-16) indicate that the miR-17 miR family may target the 3′ UTRs of genes encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Therefore, by simultaneously targeting these two key genes, miR-17 family members could, in theory, be important concerted regulators of angiogenesis. As proof of concept, we tested this hypothesis in the experimental mouse model of retinopathy of prematurity (ROP), where Vegfa seems to be a pivotal factor that modulates the angiogenic switch (17)(18)(19). In this model, the expression of retinal Vegfa mRNA increases sharply 12 h after the animals are returned from 75% oxygen (O 2 ) back to room air (∼21% O 2 ), a process that induces a relative hypoxic condition and leads to retinal neovascularization in the subsequent 9 d (17-19).Here, we show the synchronous down-regulation of all members of the miR-17 family in the critical early steps of neovascularization in the ROP model. We propose an miR regulatory network, in which distinct and partially redundant miR-17 family members simultaneously affect the levels of the Hif1a transcription factor to posttranscriptionally (either directly and/or indirectly) increase the expres...

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“…Studies have shown that miR-20a exhibits different expression profiles in different types of cancer (11)(12)(13)(15)(16)(17)(18). Upregulation of miR-20a has been found in GBC (13), colon adenocarcinoma (15) and gliomas (16), while miR-20a down- regulation has been reported in primary HCC (11), OSCC (12), breast cancer (17) and pancreatic carcinoma (18).…”

Section: Discussionmentioning

confidence: 99%

microRNA-20a enhances the epithelial-to-mesenchymal transition of colorectal cancer cells by modulating matrix metalloproteinases

Jing

Shi

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The mortality rates associated with colorectal cancer (CRC) are high due to metastasis. Epithelial-to-mesenchymal transition (EMT) is a key step in tumor metastasis. The aim of the present study was to investigate the function of microRNA-20a (miR-20a) in EMT. The expression of miR-20a was analyzed in CRC tissues and cell lines using the reverse transcription-quantitative polymerase chain reaction. Plasmids containing miR-20a short hairpin RNA and miR-20a mimics were transfected into SW620 and LS174T cell lines, respectively. Cell counting kit-8, Transwell ® and wound healing assays were performed to assess the effects of miR-20a on cell proliferation, invasion and migration. EMT markers and matrix metalloproteinases (MMPs) were identified using western blotting. The results showed that increased expression of miR-20a in CRC tissues was associated with tumor invasion and lymph node metastasis (P<0.05). Further experiments indicated that miR-20a-knockdown inhibited the proliferation, invasion and migration of CRC cells, upregulated the expression of vimentin and tissue inhibitor of metalloproteinases-2 (TIMP-2) and downregulated the expression of E-cadherin, MMP-2 and MMP-9. The opposite effects were observed in CRC cell lines overexpressing miR-20a. In conclusion, these results have shown that the upregulation of miR-20a suppresses TIMP-2 expression, which subsequently increases the expression of MMP-2 and MMP-9, thereby promoting the EMT of CRC cells. These findings suggest that miR-20a represents a potential therapeutic target for patients with CRC.

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MicroRNA-20a Overexpression Inhibited Proliferation and Metastasis of Pancreatic Carcinoma Cells

Cited by 61 publications

References 41 publications

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch

microRNA-20a enhances the epithelial-to-mesenchymal transition of colorectal cancer cells by modulating matrix metalloproteinases

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