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      METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/ β-Catenin Axis


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          Epithelial ovarian cancer (EOC) ranks third in the incidence of gynecological malignancies. m6A methylation as RNA modification plays a crucial role in the evolution, migration, and invasion of various tumors. However, the role of m6A methylation in ovarian cancer (OC) only recently has begun to be appreciated. Therefore, we used various bioinformatic methods to screen the public GEO datasets of epithelial ovarian cancer (EOC) for m6A methylation-related regulators. We identified methyltransferase 16 (METTL16) that was dramatically downregulated in EOC as such a regulator. We also identified metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a known target lncRNA of METTL16, in these five GEO datasets. RT-qPCR and immunohistochemical staining confirmed that compared with the normal ovarian tissues and cells, METTL16 was significantly downregulated, while lncRNA MALAT1 was significantly upregulated, in 30 EOC tissues of our own validation cohorts and EOC cell lines, revealing a negative correlation between METTL16 and lncRNA MALAT1. Moreover, our analysis unveiled a correlation between downregulated METTL16 and the known adverse prognostic factors of EOC patients in our own cohorts. The CCK-8, EdU, scratch wound healing, and transwell invasion assays revealed that METTL16 significantly suppressed the proliferating, migrating, and invading abilities of OC cells. The inhibitory effects of METTL16 on the in vivo tumor growth of EOC cells were measured by subcutaneous tumor formation assay in mice. Furthermore, the RIP, RNA stability assay, western blotting, and cytoimmunofluorescence staining showed that METTL16 hindered the growth of EOC cells through promoting the degradation of MALAT1 by binding that, in turn, upregulates β-catenin protein and promotes nuclear transport of β-catenin protein in EOC cells. This study suggests that METTL16 acts as a tumor suppressor gene of EOC by achieving its inhibitory function on the malignant progression of EOC through the METTL16/MALAT1/ β-catenin axis that are new targets for EOC diagnosis and therapy.

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          Ovarian cancer statistics, 2018

          In 2018, there will be approximately 22,240 new cases of ovarian cancer diagnosed and 14,070 ovarian cancer deaths in the United States. Herein, the American Cancer Society provides an overview of ovarian cancer occurrence based on incidence data from nationwide population-based cancer registries and mortality data from the National Center for Health Statistics. The status of early detection strategies is also reviewed. In the United States, the overall ovarian cancer incidence rate declined from 1985 (16.6 per 100,000) to 2014 (11.8 per 100,000) by 29% and the mortality rate declined between 1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. Ovarian cancer encompasses a heterogenous group of malignancies that vary in etiology, molecular biology, and numerous other characteristics. Ninety percent of ovarian cancers are epithelial, the most common being serous carcinoma, for which incidence is highest in non-Hispanic whites (NHWs) (5.2 per 100,000) and lowest in non-Hispanic blacks (NHBs) and Asians/Pacific Islanders (APIs) (3.4 per 100,000). Notably, however, APIs have the highest incidence of endometrioid and clear cell carcinomas, which occur at younger ages and help explain comparable epithelial cancer incidence for APIs and NHWs younger than 55 years. Most serous carcinomas are diagnosed at stage III (51%) or IV (29%), for which the 5-year cause-specific survival for patients diagnosed during 2007 through 2013 was 42% and 26%, respectively. For all stages of epithelial cancer combined, 5-year survival is highest in APIs (57%) and lowest in NHBs (35%), who have the lowest survival for almost every stage of diagnosis across cancer subtypes. Moreover, survival has plateaued in NHBs for decades despite increasing in NHWs, from 40% for cases diagnosed during 1992 through 1994 to 47% during 2007 through 2013. Progress in reducing ovarian cancer incidence and mortality can be accelerated by reducing racial disparities and furthering knowledge of etiology and tumorigenesis to facilitate strategies for prevention and early detection. CA Cancer J Clin 2018;68:284-296. © 2018 American Cancer Society.
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            m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer.

            N6-Methyladenosine (m6A) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification found not only in messenger RNAs but also in non-coding RNAs, m6A affects the fate of the modified RNA molecules and plays important roles in almost all vital bioprocesses, including cancer development. Here we review the up-to-date knowledge of the pathological roles and underlying molecular mechanism of m6A modifications (in both coding and non-coding RNAs) in cancer pathogenesis and drug response/resistance, and discuss the therapeutic potential of targeting m6A regulators for cancer therapy.
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              METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m 6 A Modification

              N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic messenger RNAs (mRNAs), plays critical roles in many bioprocesses. However, its functions in normal and malignant hematopoiesis remain elusive. Here, we report that METTL14, a key component of the m6A methyltransferase complex, is highly expressed in normal hematopoietic stem/progenitor cells (HSPCs) and acute myeloid leukemia (AML) cells carrying t(11q23), t(15;17), or t(8;21) and is downregulated during myeloid differentiation. Silencing of METTL14 promotes terminal myeloid differentiation of normal HSPCs and AML cells and inhibits AML cell survival/proliferation. METTL14 is required for development and maintenance of AML and self-renewal of leukemia stem/initiation cells (LSCs/LICs). Mechanistically, METTL14 exerts its oncogenic role by regulating its mRNA targets (e.g., MYB and MYC) through m6A modification, while the protein itself is negatively regulated by SPI1. Collectively, our results reveal the SPI1-METTL14-MYB/MYC signaling axis in myelopoiesis and leukemogenesis and highlight the critical roles of METTL14 and m6A modification in normal and malignant hematopoiesis.

                Author and article information

                Anal Cell Pathol (Amst)
                Anal Cell Pathol (Amst)
                Analytical Cellular Pathology (Amsterdam)
                28 October 2023
                : 2023
                : 9952234
                1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu 241001, Anhui, China
                2The Translational Research Institute for Neurological Disorders, Wuhu 241001, Anhui, China
                3Interdisciplinary Research Center of Neuromedicine and Chemical Biology of Wannan Medical College and Anhui Normal University, Wuhu, Anhui 241001, China
                4Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui 241001, China
                Author notes

                Academic Editor: Yun Ping Lim

                Author information
                Copyright © 2023 Changshu Li et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 8 October 2022
                : 2 July 2023
                : 11 July 2023
                Funded by: Wuhu Municipal Science and Technology Bureau
                Award ID: 2021cg26
                Funded by: Anhui Provincial University Teaching Quality and Teaching Reform Project
                Award ID: 2021jyxm1625
                Award ID: 2021kcszsfkc435
                Award ID: 2022szsfkc116
                Funded by: Reform Project of Yijishan Hospital
                Award ID: Z22006
                Funded by: Wannan Medical College
                Award ID: WK2022F25
                Award ID: 2020jyxm69
                Award ID: WK2022XS44
                Funded by: Yijishan Hospital of Wannan Medical College “Pan Feng” Cultivation Program
                Award ID: PF2019012
                Research Article


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