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      The Long Noncoding RNA LINC00665 Facilitates c-Myc Transcriptional Activity via the miR-195-5p MYCBP Axis to Promote Progression of Lung Adenocarcinoma

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          Abstract

          Long noncoding RNAs (lncRNAs) have recently received growing substantial attention in cancer research due to their important roles in various cancer types. However, the underlying mechanisms and functions of lncRNAs, especially in lung adenocarcinoma (LUAD), remain elusive. Based on pan-cancer screening analyses, we identified that the noncoding RNA LINC00665 was up-regulated in lung adenocarcinoma, which was subsequently confirmed in clinical samples and cell lines. Higher expression of LINC00665 was positively associated with poor prognosis and advanced T stage. Next, using gain- and loss- of function approaches, we revealed that LINC00665 promotes cell proliferation, cell migration, invasion, and suppresses cell apoptosis in LUAD through in vitro and in vivo experiments. Additionally, our findings showed that LINC00665 was predominately localized in the cytoplasm so as to interact with Ago2 protein, which could function as miRNA sponges. The results of bioinformatics prediction and RNA pull-down assay indicated that LINC00665 directly interacted with miR-195-5p. This was also confirmed by fluorescence colocalization. Furthermore, luciferase reporter assay demonstrated that Myc binding protein (MYCBP, also called AMY-1), which enhanced c-Myc transcriptional activity, was the target gene of LINC00665 dependent on miR-195-5p. Finally, rescue functional assay results uncovered that the oncogenic capability of LINC00665 was dependent on miR-195-5p and c-Myc transcriptional activity. In summary, this work elucidates that LINC00665 accelerates LUAD progression via the miR-195-5p/MYCBP axis by acting as a competing endogenous RNA (ceRNA), suggesting that LINC00665 may represent a potential therapeutic target for clinical intervention of LUAD.

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          Most cited references43

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            Cancer statistics, 2019

            Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.
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              Functional Classification and Experimental Dissection of Long Noncoding RNAs

              Over the last decade, it has been increasingly demonstrated that the genomes of many species are pervasively transcribed, resulting in the production of numerous long noncoding RNAs (lncRNAs). At the same time, it is now appreciated that many types of DNA regulatory elements, such as enhancers and promoters, regularly initiate bidirectional transcription. Thus, discerning functional noncoding transcripts from a vast transcriptome is a paramount priority, and challenge, for the lncRNA field. In this review, we aim to provide a conceptual and experimental framework for classifying and elucidating lncRNA function. We categorize lncRNA loci into those that regulate gene expression in cis versus those that perform functions in trans , and propose an experimental approach to dissect lncRNA activity based on these classifications. These strategies to further understand lncRNAs promise to reveal new and unanticipated biology, with great potential to advance our understanding of normal physiology and disease.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                01 July 2021
                2021
                : 11
                : 666551
                Affiliations
                [1] 1 Department of Thoracic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University , Nanjing, China
                [2] 2 Department of Geriatric Oncology, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
                [3] 3 Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province , Nanjing, China
                [4] 4 The Fourth Clinical College of Nanjing Medical University , Nanjing, China
                Author notes

                Edited by: Zhi Sheng, Virginia Tech, United States

                Reviewed by: Wei Cao, Shanghai Jiao Tong University, China; Yu Feng, The First Affiliated Hospital of Soochow University, China

                *Correspondence: Feng Jiang, fengjiang_nj@ 123456njmu.edu.cn ; Gaochao Dong, ilsyvm@ 123456njmu.edu.cn

                This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology

                †These authors have contributed equally to this work

                Article
                10.3389/fonc.2021.666551
                8281894
                34277412
                57fa35d7-7163-4ab7-be21-fba8e0db64bc
                Copyright © 2021 Wang, Zhang, Wei, Wang, Zhang, Yang, Xia, Mao, Xu, Jiang and Dong

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 February 2021
                : 15 June 2021
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 43, Pages: 11, Words: 4747
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                lncrna,mir-195-5p,mycbp,luad,linc00665
                Oncology & Radiotherapy
                lncrna, mir-195-5p, mycbp, luad, linc00665

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