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      RDM1 plays an oncogenic role in human lung adenocarcinoma cells

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          Abstract

          RAD52 motif containing 1 (RDM1) is involved in DNA damage repair pathway and RDM1 −/− cells increase sensitivity to cisplatin, a common chemotherapy drug. Lung cancer is the leading cause of cancer death worldwide. However, the role of RDM1 in lung cancer is unknown. Here, we find that the mRNA and protein expression levels of RDM1 are significantly increased in human lung tumors, especially in lung adenocarcinoma. The lung adenocarcinoma patients with higher mRNA expression of RDM1 show the worse clinical outcomes. Knockdown of RDM1 in lung adenocarcinoma cells reduces cell proliferation and promotes apoptosis, consistent with the role RDM1 in the overexpression experiments. Xenograft mouse model shows stable knockdown of RDM1 significantly inhibits lung adenocarcinoma tumor growth. These in vitro and in vivo results conclude that RDM1 plays an oncogenic role in human lung adenocarcinoma. Interestingly, P53/RAD51/RAD52 can be regulated by RDM1, and the negative regulation of P53 by RDM1 may be one of major mechanisms for RDM1 to accomplish its oncogenic functions in lung adenocarcinoma. Therefore, RDM1 may be a new target for the treatment of lung adenocarcinoma.

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          Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

          The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.
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            Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas.

            Activation of the EGFR, KRAS, and ALK oncogenes defines 3 different pathways of molecular pathogenesis in lung adenocarcinoma. However, many tumors lack activation of any pathway (triple-negative lung adenocarcinomas) posing a challenge for prognosis and treatment. Here, we report an extensive genome-wide expression profiling of 226 primary human stage I-II lung adenocarcinomas that elucidates molecular characteristics of tumors that harbor ALK mutations or that lack EGFR, KRAS, and ALK mutations, that is, triple-negative adenocarcinomas. One hundred and seventy-four genes were selected as being upregulated specifically in 79 lung adenocarcinomas without EGFR and KRAS mutations. Unsupervised clustering using a 174-gene signature, including ALK itself, classified these 2 groups of tumors into ALK-positive cases and 2 distinct groups of triple-negative cases (groups A and B). Notably, group A triple-negative cases had a worse prognosis for relapse and death, compared with cases with EGFR, KRAS, or ALK mutations or group B triple-negative cases. In ALK-positive tumors, 30 genes, including ALK and GRIN2A, were commonly overexpressed, whereas in group A triple-negative cases, 9 genes were commonly overexpressed, including a candidate diagnostic/therapeutic target DEPDC1, that were determined to be critical for predicting a worse prognosis. Our findings are important because they provide a molecular basis of ALK-positive lung adenocarcinomas and triple-negative lung adenocarcinomas and further stratify more or less aggressive subgroups of triple-negative lung ADC, possibly helping identify patients who may gain the most benefit from adjuvant chemotherapy after surgical resection. ©2011 AACR.
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              Molecular views of recombination proteins and their control.

              The efficient repair of double-strand breaks in DNA is critical for the maintenance of genome stability and cell survival. Homologous recombination provides an efficient and faithful pathway of repair, especially in replicating cells, in which it plays a major role in tumour avoidance. Many of the enzymes that are involved in recombination have been isolated, and the details of this pathway are now being unravelled at the molecular level.
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                Author and article information

                Contributors
                gp_niu15@163.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                1 August 2018
                1 August 2018
                2018
                : 8
                : 11525
                Affiliations
                [1 ]ISNI 0000 0004 0369 6365, GRID grid.22069.3f, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, , East China Normal University, ; 500 Dongchuan Road, Shanghai, 200241 China
                [2 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, Reproductive & Developmental Biology Laboratory, , National Institute of Environmental Health Sciences (NIEHS), ; Research Triangle Prk, NC 27709 USA
                [3 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Department of Musculoskeletal Tumor, Shanghai Cancer Center, , Fudan University, ; Shanghai, China
                [4 ]International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, The China Welfare Institute, Shanghai, China
                [5 ]The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, People’s Republic of China
                Article
                30071
                10.1038/s41598-018-30071-y
                6070564
                30069034
                ca3588a1-050e-4e46-a75c-f15795679e11
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 January 2018
                : 23 May 2018
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