MicroRNA 23b Regulates Autophagy Associated With Radioresistance of Pancreatic Cancer Cells

Wang, Peng; Zhang, Juan; Zhang, Li; Zhu, Zhengfei; Fan, Jia; Chen, Lianyu; Zhuang, Liping; Luo, Jianmin; Chen, Hao; Liu, Luming; Chen, Zheng; Meng, Zhiqiang

doi:10.1053/j.gastro.2013.07.048

Cited by 216 publications

(144 citation statements)

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“…In fact, MIR23B regulates autophagy, associated with radio-resistance in pancreatic cancer cells, through the targeting of ATG12 and HMGB2. 37 By contrast, the other predicted MIRNAs (MIR7-3HG, MIR9 and MIR200B) we identified could be potentially novel regulators of autophagy. To determine whether these MIRNAs' binding sites were functional on the full-length AMBRA1 3 0 -UTR, HeLa cells were cotransfected with MIRNA overexpressing plasmids and a reporter plasmid, containing Renilla luciferase fused to the AMBRA1 full-length 3 0 -UTR sequence.…”

Section: Resultsmentioning

confidence: 71%

MIR7–3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1

et al. 2017

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Macroautophagy/autophagy is a tightly regulated intracellular catabolic pathway involving the lysosomal degradation of cytoplasmic organelles and proteins to be recycled into metabolic precursors. AMBRA1 (autophagy and Beclin 1 regulator 1) has a central role in the autophagy signaling network; it acts upstream of MTORC1-dependent autophagy by stabilizing the kinase ULK1 (unc-51 like autophagy activating kinase 1) and by favoring autophagosome core complex formation. AMBRA1 also regulates the cell cycle by modulating the activity of the phosphatase PPP2/PP2A (protein phosphatase 2) and degradation of MYC. Of note, post-transcriptional regulation mediated by noncoding microRNAs (MIRNAs) contributes significantly to control autophagy. Here we describe a new role for the microRNA MIR7-3HG/MIR-7 as a potent autophagy inhibitor. Indeed, MIR7-3HG targets the 3 0 untranslated region (UTR) of AMBRA1 mRNA, inducing a decrease of both AMBRA1 mRNA and protein levels, and thus causing a block in autophagy. Furthermore, MIR7-3HG, through AMBRA1 downregulation, prevents MYC dephosphorylation, establishing a positive feedback for its own transcription. These data suggest a new and interesting role of MIR7-3HG as an antiautophagic MIRNA that may affect oncogenesis through the regulation of the tumor suppressor AMBRA1.

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Section: Resultsmentioning

confidence: 71%

MIR7–3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1

et al. 2017

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“…The authors proposed that reduced miR-23b levels increase levels of its target AGT12 and autophagy to promote radioresistance [98]. Treatment of cells with a combination of the tumor suppressor miR-205 and gemcitabine micelles reduced cell invasion and restored the gemcitabine chemosensitivity, while intratumoral injection of the combinatorial treatment in mice bearing gemcitabine-resistant xenografts potently arrested tumor growth [99].…”

Section: Mirnas Relate To Chemotherapy Treatment In Pdacmentioning

confidence: 99%

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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“…18), including miR-23a and let-7e, whose family members have been demonstrated to be associated with tumor radioresponse (11,12,41). We were interested in reduced miR-203 in the CNE2-IR cells, because the function and mechanism of which in tumor radioresistance have not been characterized.…”

Section: Reduced Mir-203 Expression Is Correlated With Npc Radioresismentioning

confidence: 99%

MiRNA-203 Reduces Nasopharyngeal Carcinoma Radioresistance by Targeting IL8/AKT Signaling

et al. 2015

Molecular Cancer Therapeutics

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Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA (miR) regulates this phenomenon. In this study, we investigated the function and mechanism of miR-203 in NPC radioresistance, one of downregulated miRs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-203 was frequently downregulated in the radioresistant NPC tissues compared with radiosensitive NPC tissues, and its decrement significantly correlated with NPC radioresistance and poor patient survival, and was an independent predictor for reduced patient survival. In vitro radioresponse assays showed that miR-203 mimic markedly decreased NPC cell radioresistance. In a mouse model, therapeutic administration of miR-203 agomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we confirmed that IL8 was a direct target of miR-203, and found that reduced miR-203 promoted NPC cell radioresistance by activating IL8/ AKT signaling. Moreover, the levels of IL8 and phospho-AKT were significantly increased in the radioresistant NPC tissues compared with radiosensitive NPC tissues, and negatively associated with miR-203 level. Our data demonstrate that miR-203 is a critical determinant of NPC radioresponse, and its decrement enhances NPC radioresistance through targeting IL8/AKT signaling, highlighting the therapeutic potential of the miR-203/IL8/AKT signaling axis in NPC radiosensitization. Mol Cancer Ther; 14(11); 2653-64. Ó2015 AACR.

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MicroRNA 23b Regulates Autophagy Associated With Radioresistance of Pancreatic Cancer Cells

Cited by 216 publications

References 43 publications

MIR7–3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1

MIR7–3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

MiRNA-203 Reduces Nasopharyngeal Carcinoma Radioresistance by Targeting IL8/AKT Signaling

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