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      The RNA demethylase ALKBH5 promotes the progression and angiogenesis of lung cancer by regulating the stability of the LncRNA PVT1

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          Abstract

          Background

          N6-methyladenosine (m6A) is the most common posttranscriptional modification of RNA and plays critical roles in human cancer progression. However, the biological function of m6A methylation requires further studied in cancer, especially in tumor angiogenesis.

          Methods

          A public database was used to analyze the expression and overall survival of ALKBH5 and PVT1 in lung cancer patients. CCK-8 and colony formation assays were performed to detect cell proliferation, a transwell assay was used to assess cell migration, and a tube formation assay was performed to assess angiogenic potential in vitro. A zebrafish lung cancer xenograft model was used to verify the function of ALKBH5 and PVT1 in vivo. Western blot assays were used to measure the relative protein expression in lung cancer cells. SRAMP predictor analysis and RNA stability experiments were used to examine the potential m6A modification.

          Results

          Bioinformatics analysis showed that the expression levels of m6A-related genes were changed significantly in lung cancer tissues compared with normal lung tissues. We then identified that ALKBH5 was upregulated in lung cancer tissues and associated with poor prognosis of lung cancer patients by analyzing a public database. Knockdown of ALKBH5 inhibited the proliferation and migration of cultured lung cancer cell lines. Zebrafish lung cancer xenografts showed that ALKBH5 silencing also suppressed the growth and metastasis of lung cancer cells. Moreover, knockdown of ALKBH5 inhibited the angiogenesis of lung cancer in vitro and in vivo. Mechanistic studies showed that knockdown of ALKBH5 decreased the expression and stability of PVT1 in lung cancer cells. We next observed that PVT1 promoted the progression of lung cancer cells in vitro and in vivo and regulated the expression of VEGFA and angiogenesis in lung cancer. Finally, rescue experiments revealed that ALKBH5 regulated the proliferation, migration and angiogenesis of lung cancer cells, partially through PVT1.

          Conclusion

          Our results demonstrate that ALKBH5 promotes the progression and angiogenesis of lung cancer by regulating the expression and stability of PVT1, which provides a potential prognostic and therapeutic target for lung cancer patients.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12935-022-02770-0.

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          Hallmarks of Cancer: The Next Generation

          Douglas Hanahan, Robert A. Weinberg (2011)
          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Cancer statistics, 2020

            Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)
            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 population-based cancer occurrence. Incidence data (through 2016) 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 (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.
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              N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

              Guifang Jia, Ye Fu, Xu Zhao … (2011)
              We report here that FTO (fat mass and obesity-associated protein) exhibits efficient oxidative demethylation activity of abundant N 6-methyladenosine (m6A) residues in RNA in vitro. FTO knockdown with siRNA led to an increased level of m6A in mRNA, whereas overexpression of FTO resulted in a decreased level of m6A in human cells. We further show that FTO partially colocalizes with nuclear speckles, supporting m6A in nuclear RNA as a physiological substrate of FTO.
              Article 0 comments Cited 1180 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yangsong Zuo: zys126@njmu.edu.cn
                Journal
                Journal ID (nlm-ta): Cancer Cell Int
                Journal ID (iso-abbrev): Cancer Cell Int
                Title: Cancer Cell International
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1475-2867
                Publication date (Electronic): 15 November 2022
                Publication date PMC-release: 15 November 2022
                Publication date Collection: 2022
                Volume: 22
                Electronic Location Identifier: 353
                Affiliations
                [1 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Respiratory Medicine, Lianshui County People’s Hospital, , Kangda College of Nanjing Medical University, ; Huai’an, China
                [2 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Radiotherapy, Lianshui County People’s Hospital, , Kangda College of Nanjing Medical University, ; Huai’an, China
                [3 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Cardiology, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, China
                Article
                Publisher ID: 2770
                DOI: 10.1186/s12935-022-02770-0
                PMC ID: 9664734
                PubMed ID: 36376862
                SO-VID: b1873d09-f2f7-44bd-8136-806ff3f90141
                Copyright © © The Author(s) 2022
                License:

                Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 3 September 2022
                Date accepted : 30 October 2022
                Funding
                Funded by: The Program of Innovation and Entrepreneurship Doctor of Jiangsu Province
                Award ID: 2021
                Award Recipient :
                Funded by: Research Fund of Lianshui County People's Hospital
                Funded by: Jiangsu Key Laboratory of Noncoding RNA Basic and Clinical Translation
                Award ID: 202107
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: lung cancer,alkbh5,angiogenesis,pvt1,rna stability
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: lung cancer, alkbh5, angiogenesis, pvt1, rna stability

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