MicroRNA-101-3p reverses gemcitabine resistance by inhibition of ribonucleotide reductase M1 in pancreatic cancer

Fan, Pei; Liu, Li; Yin, Yanping; Zhao, Zhong; Zhang, Yiyao; Amponsah, Prince Saforo; Xiao, Xi; Bauer, Nathalie; Abukiwan, Alia; Nwaeburu, Clifford C.; Gladkich, Jury; Gao, Chao; Schemmer, Peter; Groß, Wolfgang; Herr, Ingrid

doi:10.1016/j.canlet.2016.01.038

Cited by 54 publications

(35 citation statements)

References 21 publications

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“…In addition, a recent study found that downregulation of miR-130a-3p can induce the EMT and malignancy of hepatocellular carcinoma cells via inhibition of Smad4 [3]. Also, miR-101-3p reverses gemcitabine resistance by inhibiting ribonucleotide reductase M1 in pancreatic cancer [4]. …”

Section: Introductionmentioning

confidence: 99%

Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p

et al. 2017

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BackgroundAlthough gemcitabine-based chemotherapy has been established as a core multimodal therapy for non-small cell lung cancer (NSCLC) treatment, its clinical efficacy remains limited by the development of acquired resistance following tumor metastasis and relapse. In this study, we investigated how gemcitabine-resistant (GR) cells contribute to the development of NSCLC tumor malignancy via exosome-mediated transfer of microRNAs.MethodsWe first studied the mechanism of exosome internalization via PKH-67 staining and an immunofluorescence assay, then confirmed our finding by transmission electron microscopy and western blot analysis. Candidate miRNAs were identified through microarray analysis. Thereafter, RT-PCR, MTS, Transwell and soft agar assays were performed to assess the role of exosomic miR-222-3p in vitro. A 3’ untranslated region reporter assay was applied to identify the target of miR-222-3p. A lung metastasis mouse model was constructed to evaluate tumor growth and metastasis in vivo. Finally, clinical samples were used for correlation analysis between exosomic miR-222-3p levels and patients’ response to gemcitabine.ResultsA549-GR–derived exosomes were internalized by receipt cells via caveolin- and lipid raft-dependent endocytosis, which allowed the transfer of miR-222-3p. Exosomic miR-222-3p enhanced the proliferation, gemcitabine resistance, migration, invasion, and anti-anoikis of parental sensitive cells by directly targeting the promoter of SOCS3. In addition, a higher level of exosomic miR-222-3p in sera usually predicted worse prognosis in NSCLC patients.ConclusionOur data demonstrate that exosomic-miR-222-3p functions as a principal regulator of gemcitabine resistance and malignant characteristics by targeting SOCS3. The exosomic miR-222-3p level in sera may be a potential prognostic biomarker for predicting gemcitabine sensitivity in NSCLC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0694-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p

et al. 2017

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“…For instance, the combination of miR-223 inhibitor/genistein [27] and overexpression of miR-210/miR-101 [28,29] inhibited tumor growth by targeting EMT phenotype and multidrug resistance proteins ABCC5/RRM1, respectively. Therefore, we generated miR-205 overexpressing MIA PaCa-2R cells using lentiviral particles to study the long-term impact brought after its restoration (Fig.…”

Section: Discussionmentioning

confidence: 99%

Chemosensitization and inhibition of pancreatic cancer stem cell proliferation by overexpression of microRNA-205

et al. 2017

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Treatment of pancreatic cancer with gemcitabine (GEM) is limited due to its rapid plasma metabolism and development of chemoresistance. MicroRNA (miRNA) regulates cancer stem cell (CSC) maintenance and induces chemoresistance in cancer cells. In this study, we observed differential downregulation of miR-205 (miR-205-5p) in human pancreatic cancer tissues and cells. Compared to GEM-sensitive MIA PaCa-2 cells, miR-205 was highly downregulated in GEM-resistant MIA PaCa-2R cells. Lentivirus-mediated overexpression of miR-205 inhibits MIA PaCa-2R cell proliferation after GEM-treatment. Further investigation confirmed that miR-205 alone significantly reduces the proliferation of CSCs and tumor growth in mouse models. However, miR-205 in combination with GEM was more efficient in reducing the proliferation of CSCs and 3D spheroids. Moreover, miR-205 overexpressing MIA PaCa-2R cells induced orthotopic tumor growth was significantly inhibited after intravenous administration of GEM-conjugated methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate)-graft-gemcitabine-graft-dodecanol (mPEG-b-PCC-g-GEM-g-DC) (mPEG-b-PCC-g-GEM-g-DC) polymeric micelles. Also, a reduction in CSCs, EMT and chemoresistance markers was observed in miR-205 overexpressing MIA PaCa-2R cells. Immunohistochemical analysis of orthotopic tumors showed a decrease in drug resistance protein caveolin-1 and cell proliferation marker Ki-67 in combination treatment. Overall, our findings suggest that miR-205 resensitizes GEM-resistant pancreatic cancer cells to GEM and acts as a tumor suppressor miRNA.

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“…Likewise, miR-101 inhibits autophagy and enhances chemo-sensitivity to doxorubicin of osteosarcoma cells in vitro (172). In pancreatic cancer, miR-101 up-regulation reverts gemcitabine resistance by inhibiting the expression of ribonucleotide reductase M1 (RRM1) (173). Moreover, recent studies demonstrate that miR-101 interacts with lncRNA MALAT1 in regulatory networks that modulate cisplatin and temozolomide resistance, in lung cancer (174) and glioblastoma (80), respectively.…”

Section: A Network Analysis: the Most Central Ncrnas In Chemoresistancementioning

confidence: 99%

The Network of Non-coding RNAs in Cancer Drug Resistance

et al. 2018

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Non-coding RNAs (ncRNAs) have been implicated in most cellular functions. The disruption of their function through somatic mutations, genomic imprinting, transcriptional and post-transcriptional regulation, plays an ever-increasing role in cancer development. ncRNAs, including notorious microRNAs, have been thus proposed to function as tumor suppressors or oncogenes, often in a context-dependent fashion. In parallel, ncRNAs with altered expression in cancer have been reported to exert a key role in determining drug sensitivity or restoring drug responsiveness in resistant cells. Acquisition of resistance to anti-cancer drugs is a major hindrance to effective chemotherapy and is one of the most important causes of relapse and mortality in cancer patients. For these reasons, non-coding RNAs have become recent focuses as prognostic agents and modifiers of chemo-sensitivity. This review starts with a brief outline of the role of most studied non-coding RNAs in cancer and then highlights the modulation of cancer drug resistance via known ncRNAs based mechanisms. We identified from literature 388 ncRNA-drugs interactions and analyzed them using an unsupervised approach. Essentially, we performed a network analysis of the non-coding RNAs with direct relations with cancer drugs. Within such a machine-learning framework we detected the most representative ncRNAs-drug associations and groups. We finally discussed the higher integration of the drug-ncRNA clusters with the goal of disentangling effectors from downstream effects and further clarify the involvement of ncRNAs in the cellular mechanisms underlying resistance to cancer treatments.

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MicroRNA-101-3p reverses gemcitabine resistance by inhibition of ribonucleotide reductase M1 in pancreatic cancer

Cited by 54 publications

References 21 publications

Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p

Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p

Chemosensitization and inhibition of pancreatic cancer stem cell proliferation by overexpression of microRNA-205

The Network of Non-coding RNAs in Cancer Drug Resistance

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