MiR-221 Promotes Capan-2 Pancreatic Ductal Adenocarcinoma Cells Proliferation by Targeting PTEN-Akt

Yang, Weiming; Yang, Yanning; Xia, Lu; Yang, Yuefeng; Wang, Fei; Song, Meiyi; Chen, Xiaoyu; Liu, Jingqi; Song, Yang; Zhao, Yingying; Chen, Yang

doi:10.1159/000445589

Cited by 33 publications

(33 citation statements)

References 46 publications

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“…In human umbilical vein endothelial cells, miR-221 is found to inhibit autophagy by modulating a PTEN/Akt signaling pathway (12). miR-221 targeting PTEN/Akt is also reported in several cancer cells during cancer development (33)(34)(35). Our results implicated a potential role of TP53INP1 on the effect of miR-221 on autophagy of CRC.…”

Section: Discussionsupporting

confidence: 64%

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Liao¹,

Li²,

Ye³

et al. 2017

Exp Ther Med

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Abstract. Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated mortalities worldwide. MicroRNAs (miRNAs/miRs) serve important roles in tumor development, progression and metastasis. miR-221 has been reported to modulate proliferation, apoptosis, cell cycle distribution and cell migration in a variety of cancers. However, the function of miR-221 in the autophagy of cancer is unclear. In the present study, the role of miR-221 in the autophagy of CRC cells was investigated and its associated target was identified. Survival analysis using The Cancer Genome Atlas data suggested that a higher expression of miR-221 was associated with poor survival in patients with CRC. A Cell Counting kit-8 assay revealed that miR-221 promoted CRC cell proliferation. Autophagy flux analyzed by microtubule-associated protein 1 light chain 3 (LC3) turnover indicated that miR-221 reduced autophagy in CRC cells using different protease inhibitors (E64d and pepstatin A; Bafilomycin A1) in nutrient-rich medium or under starvation conditions. Tumor protein 53-induced nuclear protein 1 (TP53INP1) was identified as a potential novel target of miR-221 by bioinformative prediction. The protein expression of TP53INP1 was inversely regulated by miR-221 in CRC cells. Furthermore, luciferase activity assays were performed and indicated that miR-221 may regulate the luciferase activity of wild-type TP53INP1 without interfering with the activity of mutant TP53INP1. These data suggested that miR-221 may promote the cell proliferation of CRC via the inhibition of autophagy and targeted TP53INP1. IntroductionColorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated death worldwide (1). The morbidity rates of CRC are increasing substantially in a number of countries within Eastern Asia and Eastern Europe which were previously at low risk (2). The multifactorial etiology of CRC involves lifestyle and dietary factors, such as smoking, red and processed meat consumption, and excessive alcohol consumption (3). Autophagy is a vital transformational switch among mechanisms that are involved in the pathogenesis of CRC (4). Autophagy may act as a suppressor during early stages and as a promoter during advanced stages of CRC (4,5). It is important to determine the regulative mechanisms of autophagy in CRC.Recent studies suggests that the post-transcription and translation regulation mediated by microRNAs (miRNAs/miRs) contribute significantly to autophagy in cancer (6). It is found that miR-23b-3p inhibits autophagy in gastric cancer cells (7) and miR-26 suppresses autophagy in hepatocellular carcinoma cells (8). Whereas miR-193b is suggested to induce autophagy in oesophageal cancer cells (9). It is interesting that different miRNAs play diverse roles in the regulation of autophagy through various targets.

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Section: Discussionsupporting

confidence: 64%

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Liao¹,

Li²,

Ye³

et al. 2017

Exp Ther Med

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“…Previous studies showed that miR-221 was overexpressed in PaCa tissues and associated with distant metastasis [53,54], which suggested that this miRNA might serve as a biomarker for the diagnosis of PaCa [55]. In addition, it was reported that miR-221/222 induced the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 [56], targeting the phosphatase and tensin homolog-protein kinase B (PTEN-Akt) pathway [57]. In pancreatic cells, miR-221 was essential for the PDGF-mediated EMT phenotype [58], and overexpression of mir-221-3p promoted 5-FU resistance [59].…”

Section: Discussionmentioning

confidence: 99%

Integrating MicroRNA Expression Profiling Studies to Systematically Evaluate the Diagnostic Value of MicroRNAs in Pancreatic Cancer and Validate Their Prognostic Significance with the Cancer Genome Atlas Data

Zhang

Pan

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNAs (miRNAs) are promising biomarkers for pancreatic cancer (PaCa). However, systemic and unified evaluations of the diagnostic value of miRNAs are lacking. Therefore, we performed a systematic evaluation based on miRNA expression profiling studies. Methods: We obtained miRNA expression profiling studies from Gene Expression Omnibus (GEO) and ArrayExpress (AE) databases and calculated the pooled sensitivity, specificity, and summary area under a receiver operating characteristic (ROC) curve for every miRNA. According to the area under the curve (AUC), we identified the miRNAs with diagnostic potentiality and validated their prognostic role in The Cancer Genome Atlas (TCGA) data. Gene Ontology (GO) annotations and pathway enrichments of the target genes of the miRNAs were evaluated using bioinformatics tools. Results: Ten miRNA expression profiling studies including 958 patients were used in this diagnostic meta-analysis. A total of 693 miRNAs were measured in more than 9 studies. The top 50 miRNAs with high predictive values for PaCa were identified. Among them, miR-130b had the best predictive value for PaCa (pooled sensitivity: 0.73 [95% confidence intervals (CI) 0.44-0.91], specificity: 0.81 [95% CI 0.59–0.93], and AUC: 0.84 [95% CI 0.73–0.95]). We identified nine miRNAs (miR-23a, miR-30a, miR-125a, miR-129-1, miR-181b-1, miR-203, miR-221, miR-222, and miR-1301) associated with overall survival in PaCa patients by combining our results with TCGA data. The results of a Cox model revealed that two miRNAs (miR-30a [hazard ratio (HR)=2.43, 95% CI 1.05-5.59; p=0.037] and miR-203 [HR=3.14, 95% CI 1.28-7.71; p=0.012]) were independent risk factors for prognosis in PaCa patients. In total, 405 target genes of the nine miRNAs were enriched with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and cancer-associated pathways such as Ras signaling pathways, phospholipase D signaling pathway, and AMP-activated protein kinase (AMPK) signaling pathway were revealed among the top 20 enriched pathways. There were significant negative correlations between miR-181b-1 and miR-125a expression levels and the methylation status of their promoter region. Conclusion: Our study performed a systematic evaluation of the diagnostic value of miRNAs based on miRNA expression profiling studies. We identified that miR-23a, miR-30a, miR-125a, miR-129-1, miR-181b-1, miR-203, miR-221, miR-222, and miR-1301 had moderate diagnostic value for PaCa and predicted overall survival in PaCa patients.

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“…Until now, a large number of microRNAs (miRNAs) have been shown to be potentially effective in the treatment of malignancies [6][7][8][9]. MiRNAs are a group of endogenous evolutionarily conserved small non-coding RNAs, which have been proven to be essential in the development of PDAC, including cell proliferation, cell death, differentiation, angiogenesis, migration, metabolism, and invasion [6,10,11].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-224 Promotes Pancreatic Cancer Cell Proliferation and Migration by Targeting the TXNIP-Mediated HIF1α Pathway

Zhu

Zhou

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNAs (miRNAs) have been shown to participate in the development of pancreatic ductal adenocarcinoma (PDAC) by modulating multiple cellular processes. Increased miR-224 expression enhances proliferation and metastasis in human cancers. This study aimed to investigate the role of miR-224 and its underlying mechanism of action in PDAC. Methods: BrdU, MTT, and cell migration assays were performed to determine cell proliferation, viability, and migration, respectively. The binding sites of miR-224 were identified using a luciferase reporter system, whereas protein expression of target genes was determined by immunoblotting and immunofluorescence analyses. A BALB/c nude mouse xenograft model was used to evaluate the role of miR-224 in vivo. Results: We demonstrated that miR-224 expression was enhanced in PDAC cells and tissues, and was related to migration and proliferation. Noticeably, miR-224 overexpression promoted the proliferation, migration, and metastasis of Panc1 cells, while miR-224 inhibition had the reverse effect on PDAC cells. Moreover, we found that thioredoxin-interacting protein (TXNIP) is a target of miR-224. The results also indicated that miR-224 inversely regulated TXNIP by binding directly to its 3′-untranslated region, which resulted in the activation of hypoxia-inducible factor 1α (HIF1α). Further, either TXNIP re-expression or HIF1α depletion abolished the effects of miR-224 on the proliferation and migration of PDAC cells in vitro and in vivo. Regarding the relationship of TXNIP and HIF1α, we found that TXNIP mediated the nuclear export of HIF1α and its degradation by forming a complex with HIF1α. Conclusion: The miR-224-TXNIP-HIF1α axis may be useful in developing novel therapies for PDAC.

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MiR-221 Promotes Capan-2 Pancreatic Ductal Adenocarcinoma Cells Proliferation by Targeting PTEN-Akt

Cited by 33 publications

References 46 publications

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Integrating MicroRNA Expression Profiling Studies to Systematically Evaluate the Diagnostic Value of MicroRNAs in Pancreatic Cancer and Validate Their Prognostic Significance with the Cancer Genome Atlas Data

MicroRNA-224 Promotes Pancreatic Cancer Cell Proliferation and Migration by Targeting the TXNIP-Mediated HIF1α Pathway

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