miR-3656 expression enhances the chemosensitivity of pancreatic cancer to gemcitabine through modulation of the RHOF/EMT axis

Yang, Ruimeng; Zhan, Ming; Xu, Sunwang; Long, Manmei; Yang, Linhua; Chen, Wei; Huang, Shuai; Liu, Qiang; Zhou, Jun; Zhu, Jun; Wang, Jian

doi:10.1038/cddis.2017.530

Cited by 37 publications

(29 citation statements)

References 36 publications

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“…RHOF, however, enhances the resistance of pancreatic cancer to gemcitabine through regulation of the epithelial-to-mesenchymal transition. 26 The potential roles of ARL3, RRAS, and RHOF in modulating tamoxifen resistance warrant future investigation.…”

Section: Resultsmentioning

confidence: 99%

Roles of Small GTPases in Acquired Tamoxifen Resistance in MCF-7 Cells Revealed by Targeted, Quantitative Proteomic Analysis

Huang

Wang

2018

Anal. Chem.

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Development of tamoxifen resistance remains a tremendous challenge for the treatment of estrogen-receptor (ER)-positive breast cancer. Small GTPases of the Ras superfamily play crucial roles in intracellular trafficking and cell signaling, and aberrant small-GTPase signaling is implicated in many types of cancer. In this study, we employed a targeted, quantitative proteomic approach that relies on stable-isotope labeling by amino acids in cell culture (SILAC), gel fractionation, and scheduled multiple-reaction-monitoring (MRM) analysis, to assess the differential expression of small GTPases in MCF-7 and the paired tamoxifen-resistant breast cancer cells. The method displayed superior sensitivity and reproducibility over the shotgun-proteomic approach, and it facilitated the quantification of 96 small GTPases. Among them, 13 and 10 proteins were significantly down- and up-regulated (with >1.5-fold change), respectively, in the tamoxifen-resistant line relative to in the parental line. In particular, we observed a significant down-regulation of RAB31 in tamoxifen-resistant cells, which, in combination with bioinformatic analysis and downstream validation experiments, supported a role for RAB31 in tamoxifen resistance in ER-positive breast-cancer cells. Together, our results demonstrated that the targeted proteomic method constituted a powerful approach for revealing the role of small GTPases in therapeutic resistance.

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Section: Resultsmentioning

confidence: 99%

Roles of Small GTPases in Acquired Tamoxifen Resistance in MCF-7 Cells Revealed by Targeted, Quantitative Proteomic Analysis

Huang

Wang

2018

Anal. Chem.

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“…Chemoresistance is a major hurdle in the treatment of many tumor patients. Recent studies have revealed that aberrant miRNA levels are tightly implicated in chemoresistance or chemosensitivity in a host of tumors ( 69 – 74 ), suggesting that targeting miRNAs to eradicate chemoresistance or improve chemosensitivity may be a novel therapeutic strategy for the therapy of tumor patients. Nishida et al found that miR-125a-5p evidently suppressed cell proliferation via targeting ERBB2, and miR-125a-5p markedly enhanced the sensitivity of gastric carcinoma cells to trastuzumab ( 75 ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-125a-5p enhances the sensitivity of esophageal squamous cell carcinoma cells to cisplatin by suppressing the activation of the STAT3 signaling pathway

Zhao

Yang

et al. 2018

Int J Oncol

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Increasing evidence has demonstrated that microRNAs (miRNAs or miRs) play a variety of roles in tumor development, progression and chemosensitivity in a wide range of tumors. In this study, we found that miR-125a-5p exhibited a low expression in esophageal squamous cell carcinoma (ESCC) tissues and cells, and that its low expression was associated with higher tumor staging and shorter a survival time of patients with ESCC. Moreover, miR-125a-5p overexpression contributed to the suppression of cell proliferation, cell cycle arrest, cell apoptosis and a decrease in cell migratory and invasive abilities, whereas the downregulation of miR-125a-5p promoted cell proliferation, accelerated cell cycle progression, suppressed apoptosis and enhanced the migratory and invasive abilities of ESCC EC1 and TE1 cells, which may be tightly associated with the epithelial-mesenchymal transition (EMT) process in ESCC. Importantly, miR-125a-5p enhanced the cytotoxic effects of cisplatin on EC1 and TE1 cells, and co-treatment with miR-125a-5p and cisplatin significantly induced cell apoptosis and reduced the cell migratory and invasive abilities of EC1 and TE1 cells, coupled with an increase in the E-cadherin level and a decrease in the N-cadherin and Vimentin levels. Most notably, signal transducer and activator of transcription-3 (STAT3) was found to be a direct target of miR-125a-5p in ESCC cells, and miR-125a-5p overexpression significantly reduced the protein levels of t-STAT3, p-STAT3 and vascular endothelial growth factor (VEGF) in EC1 and TE1 cells. Furthermore, the combination of miR-125a-5p and cisplatin markedly inactivated the STAT3 signaling pathway; however, interleukin (IL)-6, a widely reported activator of the STAT3 signaling pathway, reversed the suppressive effects of miR-125a-5p/cisplatin in ESCC cells on the activation of the STAT3 signaling pathway. Of note, we found that IL-6 markedly reversed the altered cell phenotype mediated by the combination of miR-125a-5p and cisplatin in ESCC cells. These findings suggest that miR-125a-5p may play a pivotal role in the development and progression of ESCC, which may be achieved via the manipulation of the STAT3 signaling pathway.

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“…Furthermore, Yang et al [10] con rmed that EMT could induce gemcitabine resistance in PC, and that reversing EMT in PC cells enhances the sensitivity of the cells to gemcitabine. These studies provide a new direction for improving the effect of cancer chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of NEAT1 sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis

Deng

Xiao

et al. 2020

Preprint

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BackgroundChemoresistance is a major cause of treatment failure in pancreatic cancer (PC). It has been demonstrated that epithelial-to-mesenchymal transition (EMT) is closely related to drug resistance in PC; however, the underlying mechanisms are not yet fully understood. Recently found evidence has suggested that nuclear-enriched abundant transcript 1 (NEAT1) is involved in the development of chemoresistance. However, the role and mechanism of NEAT1 in PC gemcitabine resistance remain unknown.MethodsTwo independent gemcitabine-resistant (GR) PC cell lines, PANC-1/GR and SW1990/GR, were established. Transwell assays were used to validate whether GR cells acquired EMT. qRT-PCR and western blot were performed to detect the expression levels of NEAT1, miR-506-3p, and ZEB2 in GR cells. MTT and cell apoptosis assays were conducted to evaluate the sensitivity of GR cells to gemcitabine. Rescue experiments were employed to investigate whether NEAT1 mediates drug resistance of GR cells through modulation of the miR-506-3p/ZEB2/EMT axis. Furthermore, a mouse xenograft model was established to confirm these findings.ResultsGR cells displayed markedly enhanced migration and invasion abilities, decreased expression of E-cadherin, and upregulation of N-cadherin, Vimentin, Snail, ZEB1, and ZEB2. Furthermore, elevated expression of NEAT1 was observed in GR cells. Downregulation of NEAT1 sensitized GR cells to gemcitabine. More importantly, we demonstrated that downregulation of NEAT1 enhanced the sensitivity of GR cells to gemcitabine by reversing the EMT process. NEAT1 regulated ZEB2 expression by sponging miR-506-3p, and the function of NEAT1 in GR cells was dependent on miR-506-3p. These findings were further confirmed in a nude mouse xenograft model.ConclusionsTaken together, downregulation of NEAT1 sensitized the GR PC cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis. These results provide a new direction for improving the chemotherapeutic effects in PC.

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miR-3656 expression enhances the chemosensitivity of pancreatic cancer to gemcitabine through modulation of the RHOF/EMT axis

Cited by 37 publications

References 36 publications

Roles of Small GTPases in Acquired Tamoxifen Resistance in MCF-7 Cells Revealed by Targeted, Quantitative Proteomic Analysis

Roles of Small GTPases in Acquired Tamoxifen Resistance in MCF-7 Cells Revealed by Targeted, Quantitative Proteomic Analysis

MicroRNA-125a-5p enhances the sensitivity of esophageal squamous cell carcinoma cells to cisplatin by suppressing the activation of the STAT3 signaling pathway

Downregulation of NEAT1 sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis

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