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MiR-218 impairs tumor growth and increases chemo-sensitivity to cisplatin in cervical cancer.

ABSTRACT: MicroRNAs are noncoding RNA molecules of 18-25 nucleotides that regulate gene expression at the post-transcriptional levels. Recent data revealed that miR-218 played key roles in tumor metastasis. Here, we described the regulation and function of miR-218 in cervical cancer. Overexpression of miR-218 reduced the proliferation of the human cervical cancer cell line HeLa and induced cell apoptosis through the AKT-mTOR signaling pathway. In addition, it forced expression of miR-218 suppressed tumor growth in the orthotopic mouse model of HeLa cells. Furthermore, miR-218 increased chemosensitivity to cisplatin (CDDP) in vitro. Our results indicated that targeting miR-218 may provide a strategy for blocking the development of cervical cancer.

SUBMITTER: Li J

PROVIDER: S-EPMC3546678 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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MiR-218 impairs tumor growth and increases chemo-sensitivity to cisplatin in cervical cancer.

Li Jiarui J Ping Zhang Z Ning Hui H

International journal of molecular sciences 20121128 12

MicroRNAs are noncoding RNA molecules of 18-25 nucleotides that regulate gene expression at the post-transcriptional levels. Recent data revealed that miR-218 played key roles in tumor metastasis. Here, we described the regulation and function of miR-218 in cervical cancer. Overexpression of miR-218 reduced the proliferation of the human cervical cancer cell line HeLa and induced cell apoptosis through the AKT-mTOR signaling pathway. In addition, it forced expression of miR-218 suppressed tumor ...[more]

PMID: 23443110

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Project description:Previous microRNA (miR) microarray analysis revealed that miR‑218 is downregulated in cervical cancer tissues. The present study aimed to further evaluate the expression of miR‑218 in cervical cancer specimens, determine the association between its expression with disease progression, and investigate the roles of miR‑218 in cervical cancer cells. Tissue specimens were obtained from 80 patients with cervical squamous cell carcinoma, 30 patients with high‑grade cervical intraepithelial neoplasia [(CIN) II/III] and 15 patients with low‑grade CIN (CINI); in addition, 60 plasma samples were obtained from patients with cervical cancer, and 15 normal cervical tissue specimens and 30 plasma samples were obtained from healthy women. These samples were used for analysis of miR‑218 expression via reverse transcription‑-quantitative PCR. In addition, tumor cells were transfected with miR‑218 mimics, human papillomavirus (HPV)16 E6/E7 small interfering RNA, or their respective negative controls to determine the viability, colony formation, migration and invasion of cells using MTT, colony formation, wound healing and Transwell assays, respectively. Target genes of miR‑218 were bioinformatically predicted and analyzed using Gene Ontology (GO) terms. The results revealed that miR‑218 was downregulated in the tumor tissues and plasma of patients with cervical cancer, with expression associated with the advanced clinicopathological characteristics of patients, including HPV positivity, tumor size, blood vessel invasion and lymph node metastasis. Furthermore, miR‑218 overexpression reduced tumor cell viability and xenograft growth, and suppressed tumor cell migration and invasion. HPV was detected in 75% of the 80 patients with cervical cancer, and HPV positivity was inversely associated with miR‑218 expression. In addition, bioinformatics analysis predicted that roundabout guidance receptor 1 (ROBO1) was a target gene of miR‑218; miR‑218 overexpression significantly reduced ROBO1 levels. Furthermore, GO analysis revealed that ROBO1 was involved in regulating cell proliferation, adhesion and migration, and the cell cycle. In conclusion, the findings of the present study suggested that miR‑218 may possess antitumor activities in cervical cancer.

Project description:BackgroundPlatinum resistance is a major challenge in the management of ovarian cancer. Even low levels of acquired resistance at the cellular level lead to impaired response to cisplatin. In ovarian cancer intraperitoneal therapy, nanoparticle formulation can improve the cisplatin's pharmacokinetics and safety profile.PurposeThis work aimed to investigate the chemo-sensitivity of ovarian cancer SKOV3 cells upon short-term (72h) single treatment of cisplatin and cisplatin-loaded biodegradable nanoparticles (Cis-NP). The aim was then to determine the therapeutic properties of Cis-NP in vivo using a SKOV3-luc cells' xenograft model in mice.MethodsCell cytotoxicity was assessed after the exposure of the cell culture to cisplatin or Cis-NP. The effect of treatments on EMT and CSC-like phenotype was studied by analyzing a panel of markers by flow cytometry. Intracellular platinum concentration was determined by inductively coupled plasma mass spectrometry (ICS-MS), and gene expression was evaluated by RNAseq analysis. The efficacy of intraperitoneal chemotherapy was evaluated in a SKOV3-luc cells' xenograft model in mice, through a combination of bioluminescence imaging, histological, and immunohistochemical analyses.ResultsWe observed in vitro that short-term treatment of cisplatin has a critical role in determining the potential induction of chemoresistance, and a nanotechnology-based drug delivery system can modulate it. The RNAseq analysis underlines a protective effect of nanoparticle system according to their ability to down-regulate several genes involved in chemoresistance, cell proliferation, and apoptosis. The highest intracellular platinum concentration obtained with Cis-NP treatment significantly improved the efficacy. Consistent with in vitro results, we found that Cis-NP treatment in vivo can significantly reduce tumor burden and aggressiveness compared to the free drug.ConclusionNanoparticle-mediated cisplatin delivery may serve as an intracellular depot impacting the cisplatin pharmacodynamic performance at cellular levels. These features may contribute to improving the drawbacks of conventional intraperitoneal therapy, and therefore will require further investigations in vivo.

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MiR-218 impairs tumor growth and increases chemo-sensitivity to cisplatin in cervical cancer.

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MiR-218 impairs tumor growth and increases chemo-sensitivity to cisplatin in cervical cancer.

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