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The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma

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Abstract
Hepatocellular carcinoma (HCC) represents the second cause of cancer-related mortality worldwide and is associated with poor prognosis, especially in patients not amenable for curative treatments. The multi-kinase inhibitor sorafenib represents the first-line treatment option for advanced HCC; nevertheless, its effectiveness is limited due to tumor heterogeneity as well as innate or acquired drug resistance, raising the need for new therapeutic strategies. MicroRNAs (miRNAs) involvement in treatment response as well as their safety and efficacy in preclinical models and clinical trials have been widely documented in the oncologic field, including HCC. Here, we identified miR-494 upregulation in a subgroup of human and rat HCCs with stem cell-like characteristics, as well as multiple epigenetic mechanisms involved in its aberrant expression in HCC cell lines and patients. Moreover, we identified p27, puma and pten among miR-494 targets, contributing to speed up cell cycle progression, enhance survival potential in stressful conditions and increase invasive and clonogenic capabilities. MiR-494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines and, in line, high miR-494 levels associated with decreased sorafenib response in two HCC animal models. A sorafenib-combined anti-miR-494-based strategy revealed an enhanced anti-tumor potential with respect to sorafenib-only treatment in our HCC rat model. In conclusion, our findings suggested miR-494 as a possible therapeutic target as well as a candidate biomarker for patient stratification in advanced HCC.
Keywords
HUMAN HEPATOCARCINOMA CELLS, LIVER-CANCER, DOXORUBICIN SENSITIVITY, COLORECTAL-CANCER, DOWN-REGULATION, TARGETING PTEN, HCV INFECTION, CYCLIN G1, MICRORNA, INVASION

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Chicago
Pollutri, Daniela, Clarissa Patrizi, Sara Marinelli, Catia Giovannini, Elena Trombetta, Ferdinando A Giannone, Maurizio Baldassarre, et al. 2018. “The Epigenetically Regulated miR-494 Associates with Stem-cell Phenotype and Induces Sorafenib Resistance in Hepatocellular Carcinoma.” Cell Death & Disease 9.
APA
Pollutri, D., Patrizi, C., Marinelli, S., Giovannini, C., Trombetta, E., Giannone, F. A., Baldassarre, M., et al. (2018). The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma. CELL DEATH & DISEASE, 9.
Vancouver
1.
Pollutri D, Patrizi C, Marinelli S, Giovannini C, Trombetta E, Giannone FA, et al. The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma. CELL DEATH & DISEASE. 2018;9.
MLA
Pollutri, Daniela et al. “The Epigenetically Regulated miR-494 Associates with Stem-cell Phenotype and Induces Sorafenib Resistance in Hepatocellular Carcinoma.” CELL DEATH & DISEASE 9 (2018): n. pag. Print.
@article{8558595,
  abstract     = {Hepatocellular carcinoma (HCC) represents the second cause of cancer-related mortality worldwide and is associated with poor prognosis, especially in patients not amenable for curative treatments. The multi-kinase inhibitor sorafenib represents the first-line treatment option for advanced HCC; nevertheless, its effectiveness is limited due to tumor heterogeneity as well as innate or acquired drug resistance, raising the need for new therapeutic strategies. MicroRNAs (miRNAs) involvement in treatment response as well as their safety and efficacy in preclinical models and clinical trials have been widely documented in the oncologic field, including HCC. Here, we identified miR-494 upregulation in a subgroup of human and rat HCCs with stem cell-like characteristics, as well as multiple epigenetic mechanisms involved in its aberrant expression in HCC cell lines and patients. Moreover, we identified p27, puma and pten among miR-494 targets, contributing to speed up cell cycle progression, enhance survival potential in stressful conditions and increase invasive and clonogenic capabilities. MiR-494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines and, in line, high miR-494 levels associated with decreased sorafenib response in two HCC animal models. A sorafenib-combined anti-miR-494-based strategy revealed an enhanced anti-tumor potential with respect to sorafenib-only treatment in our HCC rat model. In conclusion, our findings suggested miR-494 as a possible therapeutic target as well as a candidate biomarker for patient stratification in advanced HCC.},
  articleno    = {4},
  author       = {Pollutri, Daniela and Patrizi, Clarissa and Marinelli, Sara and Giovannini, Catia and Trombetta, Elena and Giannone, Ferdinando A and Baldassarre, Maurizio and Quarta, Santina and Vandewynckel, Yves-Paul and Vandierendonck, Astrid and Van Vlierberghe, Hans and Porretti, Laura and Negrini, Massimo and Bolondi, Luigi and Gramantieri, Laura and Fornari, Francesca},
  issn         = {2041-4889},
  journal      = {CELL DEATH & DISEASE},
  keywords     = {HUMAN HEPATOCARCINOMA CELLS,LIVER-CANCER,DOXORUBICIN SENSITIVITY,COLORECTAL-CANCER,DOWN-REGULATION,TARGETING PTEN,HCV INFECTION,CYCLIN G1,MICRORNA,INVASION},
  language     = {eng},
  pages        = {16},
  title        = {The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma},
  url          = {http://dx.doi.org/10.1038/s41419-017-0076-6},
  volume       = {9},
  year         = {2018},
}

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