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      MicroRNA-29a Functions as a Tumor Suppressor and Increases Cisplatin Sensitivity by Targeting NRAS in Lung Cancer

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          Abstract

          MicroRNAs have been reported to play an important role in diverse biological processes and progression of various cancers. MicroRNA-29a has been observed to be downregulated in human lung cancer tissues, but the function of microRNA-29a in lung cancer has not been well investigated. In this study, we demonstrated that the expression levels of microRNA-29a were significantly downregulated in 38 pairs of lung cancer tissues when compared to adjacent normal tissues. Overexpression of microRNA-29a inhibited the activity of cell proliferation and colony formation of lung cancer cells, H1299 and A549. Furthermore, microRNA-29a targeted NRAS proto-oncogene in lung cancer cells. In human clinical specimens, NRAS proto-oncogene was highly expressed in human lung cancer tissues compared to normal tissues. More interestingly, microRNA-29a also sensitizes lung cancer cells to cisplatin (CDDP[Please replace “CDDP” with its expansion in the abstract and also provide expansion for the same in its first occurrence in text, if appropriate.]) via its target, NRAS proto-oncogene. Thus, our results in this study demonstrated that microRNA-29a acted as a tumor suppressor microRNA, which indicated potential application of microRNAs for the treatment of human lung cancer in the future.

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          A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes.

          The known classes of genes that function as tumor suppressors and oncogenes have recently been expanded to include the microRNA (miRNA) family of regulatory molecules. miRNAs negatively regulate the stability and translation of target messenger RNAs (mRNA) and have been implicated in diverse processes such as cellular differentiation, cell-cycle control and apoptosis. Examination of tumor-specific miRNA expression profiles has revealed widespread dysregulation of these molecules in diverse cancers. Although studies addressing their role in cancer pathogenesis are at an early stage, it is apparent that loss- or gain-of-function of specific miRNAs contributes to cellular transformation and tumorigenesis. The available evidence clearly demonstrates that these molecules are intertwined with cellular pathways regulated by classical oncogenes and tumor suppressors such as MYC, RAS and p53. Incorporation of miRNA regulation into current models of molecular cancer pathogenesis will be essential to achieve a complete understanding of this group of diseases.
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            Downregulation of miR-218 contributes to epithelial–mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling

            Epithelial–mesenchymal transition (EMT) has been recognized as a key element of cell migration and invasion in lung cancer; however, the underlying mechanisms are not fully elucidated. Recently, emerging evidence suggest that miRNAs have crucial roles in control of EMT and EMT-associated traits such as migration, invasion and chemoresistance. Here, we found that miR-218 expression levels were significantly downregulated in lung cancer tissues compared with adjacent non-cancerous tissues, and the levels of miR-218 were significantly associated with histological grades and lymph node metastasis. Overexpression of miR-218 inhibited cell migration and invasion as well as the EMT process. Of particular importance, miR-218 was involved in the metastatic process of lung cancer cells in vivo by suppressing local invasion and distant colonization. We identified Slug and ZEB2 as direct functional targets of miR-218. Inverse correlations were observed between miR-218 levels and Slug/ZEB2 levels in cancer tissue samples. In addition, overexpression of miR-218 in H1299 increased chemosensitivity of cells to cisplatin treatment through suppression of Slug and ZEB2. These findings highlight an important role of miR-218 in the regulation of EMT-related traits and metastasis of lung cancer in part by modulation of Slug/ZEB2 signaling, and provide a potential therapeutic strategy by targeting miR-218 in NSCLC.
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              Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo.

              Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.
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                Author and article information

                Journal
                Technol Cancer Res Treat
                Technol. Cancer Res. Treat
                TCT
                sptct
                Technology in Cancer Research & Treatment
                SAGE Publications (Sage CA: Los Angeles, CA )
                1533-0346
                1533-0338
                1 March 2018
                2018
                : 17
                : 1533033818758905
                Affiliations
                [1 ]Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
                [2 ]Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
                Author notes
                [*]Qingxia Fan, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China. Email: fqx2243@ 123456126.com
                Article
                10.1177_1533033818758905
                10.1177/1533033818758905
                5843100
                29495918
                3892e41a-5752-4b72-97e2-c4f27eb40ee6
                © The Author(s) 2018

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 05 July 2017
                : 15 November 2017
                : 28 December 2017
                Categories
                Original Article
                Custom metadata
                corrected-proof

                mir-29a,nras,cisplatin,lung cancer,tumor suppressor
                mir-29a, nras, cisplatin, lung cancer, tumor suppressor

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