Dataset Information

MicroRNA-215-5p Treatment Suppresses Mesothelioma Progression via the MDM2-p53-Signaling Axis.

ABSTRACT: Malignant pleural mesothelioma (MPM) is an incurable, aggressive neoplasm with distinctive features, including preservation of wild-type p53, irrespective of histologic subtype. We posited that this consistent molecular characteristic represents an underexploited therapeutic target that can be approached by leveraging biologic effects of microRNA (miRNA). The Cancer Genome Atlas was surveyed to identify p53-responsive prognostic miRNA(s) in MPM. Using patient samples, in vitro MPM cell lines, and murine tumor xenograft models, we verified specific gene pathways targeted by these miRNAs, and we examined their therapeutic effects. miR-215-5p is a poor prognosis miRNA downregulated in MPM tissues, which has not been recognized previously. When miR-215-5p was ectopically re-expressed in MPM cells and delivered in vivo to tumor xenografts, it exerted significant cell killing by activating p53 function and inducing apoptosis. The mechanistic basis for this effect is due to combinatorial effects of a positive feedback loop of miR-215-MDM2-p53 signaling, additional mouse double minute 2 (MDM2)-p53 positive feedback loop(s) with other miRNAs such as miR-145-5p, and suppression of diverse gene targets associated with cell cycle dynamics not previously drug treatable in MPM clinical studies. Our results suggest a potential pathophysiologic role for and therapeutic significance of miR-215-5p in MPM.

SUBMITTER: Singh A

PROVIDER: S-EPMC6731470 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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MicroRNA-215-5p Treatment Suppresses Mesothelioma Progression via the MDM2-p53-Signaling Axis.

Singh Anand A Bhattacharyya Nisan N Srivastava Abhishek A Pruett Nathanael N Ripley R Taylor RT Schrump David S DS Hoang Chuong D CD

Molecular therapy : the journal of the American Society of Gene Therapy 20190604 9

Malignant pleural mesothelioma (MPM) is an incurable, aggressive neoplasm with distinctive features, including preservation of wild-type p53, irrespective of histologic subtype. We posited that this consistent molecular characteristic represents an underexploited therapeutic target that can be approached by leveraging biologic effects of microRNA (miRNA). The Cancer Genome Atlas was surveyed to identify p53-responsive prognostic miRNA(s) in MPM. Using patient samples, in vitro MPM cell lines, an ...[more]

PMID: 31227395

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Project description:Long non‑coding RNAs (lncRNAs) have been implicated in the development and progression of tumors. However, the roles and underlying mechanisms of long intergenic non‑protein coding RNA 1116 (LINC01116), a member of the lncRNA family, in glioma progression are largely unclear. The expression of LINC01116 and microRNA (miR)‑744‑5p in glioma tissues and cells was detected by reverse transcription‑quantitative PCR. The influences of LINC01116 or miR‑744‑5p on cell proliferation and invasion were evaluated by Cell Counting Kit‑8, colony formation and Transwell assays, and western blotting was used to detect the expression of p53 pathway proteins. A dual‑luciferase reporter system was used to locate common binding sites between miR‑744‑5p and LINC01116 or the 3' untranslated region of E3 ubiquitin‑protein ligase Mdm2 (MDM2). RNA immunoprecipitation was used to determine the interactions between RNAs and proteins. Moreover, a xenograft mouse model was constructed to investigate the effects of LINC01116 in vivo, followed by a TdT‑mediated dUTP nick end labeling assay to determine the degree of apoptosis in nude mouse tumors. LINC01116 was found to be highly expressed in glioma tissues, which was associated with a malignant phenotype. LINC01116 promoted the proliferation and invasiveness of glioma cells, and inhibited the p53 pathway by preserving the expression of MDM2 mRNA via miR‑744‑5p sponging. Furthermore, a low degree of miR‑744‑5p expression was observed in glioma tissues, which was negatively associated with the expression of LINC01116. Overexpression of miR‑744‑5p inhibited the proliferation and invasiveness of glioma cells, which was rescued by LINC01116. Finally, LINC01116 knockdown inhibited tumor growth in nude mice. In conclusion, LINC01116 is aberrantly expressed and promotes the progression of glioma by regulating the miR‑744‑5p‑MDM2‑p53 pathway. In future, targeting LINC01116 may therefore be a potential therapeutic approach for patients with glioma.

Dataset Information

MicroRNA-215-5p Treatment Suppresses Mesothelioma Progression via the MDM2-p53-Signaling Axis.

Publications

MicroRNA-215-5p Treatment Suppresses Mesothelioma Progression via the MDM2-p53-Signaling Axis.

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