MicroRNA‐125a‐5p Is a Downstream Effector of Sorafenib in Its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells

Potenza, Nicoletta; Mosca, Nicola; Zappavigna, Silvia; Castiello, Filomena; Panella, Marta; Ferri, Carmela; Vanacore, Daniela; Giordano, Antonio; Stiuso, Paola; Caraglia, Michele; Russo, Andrew F.

doi:10.1002/jcp.25744

Cited by 45 publications

(37 citation statements)

References 55 publications

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“…miR-125a overexpression increased the response to paclitaxel in cervical cancer, through STAT3 down-modulation (131). Sorafenib treatment in HCC showed restoration of mir125 levels by sirtuin-7 and p21/p27 signaling blockage inhibiting cell cycle progression (132). In AML cells, via mubritinib, miR125a inhibited the ERBB pathway and cell cycle proliferation and progression, suggesting that miR-125a increased the sensitivity to the drug (133).…”

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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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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“…MicroRNA‐1274a is upregulated in HCC cells treated with sorafenib, and it targets the ADAM9 gene, hence increasing antitumor immunity and sorafenib activity . Sorafenib also increases cellular expression of miR‐125a, inhibiting cell proliferation by suppressing sirtuin‐7, a nicotinamide adenine dinucleotide‐dependent deacetylase …”

Section: Micrornas Influencing Sorafenib Response and Their Mechanismmentioning

confidence: 99%

Sorafenib response in hepatocellular carcinoma: MicroRNAs as tuning forks

Kanthaje

Makol

Chakraborti

2017

Hepatology Research

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Hepatocellular carcinoma (HCC) is the primary liver malignancy that contributes towards the second most common cause of cancer‐related mortality. The targeted chemotherapeutic agent, sorafenib, is known to show a statistically significant but limited overall survival advantage in advanced HCC. However, the individual patient response towards sorafenib varies drastically, with most experiencing stable disease and few with partial response; complete response is very rare. Progressive disease despite the treatment is also evident in many patients, indicating drug resistance. These varied responses have been linked with the modulation of several intracellular signaling pathways. Notably, the regulation of these pathways through diverse operating biomolecules, including microRNAs (miRNAs), is the focus of recent studies. MicroRNAs are tiny, non‐coding RNA molecules that regulate the expression of several target genes. In addition, miRNAs are known to play a role in the progression of HCC carcinogenesis. Interestingly, miRNAs have also been identified to play differential roles in terms of sorafenib response in HCC such as biomarkers and functional modulation of cellular response to sorafenib, hence, they are also being therapeutically evaluated. This review outlines the role of reported miRNAs in different aspects of sorafenib response in HCC.

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“…This activity has recently been confirmed in HepG2 and HuH-7 cells [22]. In HCC, miR-125a is also known to target vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinase-11 (MMP11) [35].…”

Section: Introductionmentioning

confidence: 99%

Lowered expression of microRNA-125a-5p in human hepatocellular carcinoma and up-regulation of its oncogenic targets sirtuin-7, matrix metalloproteinase-11, and c-Raf

Coppola

Stefano

Panella³

et al. 2017

Oncotarget

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Human microRNA-125a-5p (miR-125a) is expressed in most tissues where it downregulates the expression of membrane receptors or intracellular transductors of mitogenic signals, thus limiting cell proliferation. Expression of this miRNA generally increases with cell differentiation whereas it is downregulated in several types of tumors, such as breast, lung, ovarian, gastric, colon, and cervical cancers, neuroblastoma, medulloblastoma, glioblastoma, and retinoblastoma. In this study, we focused on hepatocellular carcinoma and used real-time quantitative PCR to measure miR-125a expression in 55 tumor biopsies and in matched adjacent non-tumor liver tissues. This analysis showed a downregulation of miR-125a in 80 % of patients, with a mean decrease of 4.7-fold. Comparison of miRNA downregulation with clinicopathological parameters of patients didn't yield significant correlations except for serum bilirubin. We then evaluated the expression of known targets of miR-125a and found that sirtuin-7, matrix metalloproteinase-11, and c-Raf were up-regulated in tumor tissue by 2.2-, 3-, and 1.7-fold, respectively. Overall, these data support a tumor suppressor role for miR-125a and encourage further studies aimed at the comprehension of the molecular mechanisms governing its expression, eventually leading to treatments to restore its expression in tumor cells.

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MicroRNA‐125a‐5p Is a Downstream Effector of Sorafenib in Its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells

Cited by 45 publications

References 55 publications

The Network of Non-coding RNAs in Cancer Drug Resistance

The Network of Non-coding RNAs in Cancer Drug Resistance

Sorafenib response in hepatocellular carcinoma: MicroRNAs as tuning forks

Lowered expression of microRNA-125a-5p in human hepatocellular carcinoma and up-regulation of its oncogenic targets sirtuin-7, matrix metalloproteinase-11, and c-Raf

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