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      ALKBH5 regulates IGF1R expression to promote the Proliferation and Tumorigenicity of Endometrial Cancer

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          Abstract

          N6-methyladenosine (m 6A) messenger RNA methylation play important role in cell proliferation and tumorigenicity of endometrial cancer, but the key mechanism is not fully clear. Here, we found that RNA demethylase ALKBH5 expression was significantly upregulated in endometrial cancer, ALKBH5 was then identified to positively regulate proliferation and invasion of endometrial cancer. Mechanistically, the m 6A eraser ALKBH5 demethylated target transcripts IGF1R and enhanced IGF1R mRNA stability, consequently promoting IGF1R translation and activating IGF1R signaling pathway. Thus, we demonstrated that ALKBH5 promoted proliferation and invasion of endometrial cancer via erasing IGF1R m 6A-modifications, which suggests a potential therapeutic target for endometrial cancer.

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          Most cited references14

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          The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus

          Helicases are vital to the induction of antiviral responses. Cao and colleagues demonstrate that the helicase DDX46 is involved in the epigenetic regulation of select RNA species encoding antiviral molecules, which leads to the retention of the RNAs in the nucleus and thus blockade of their translation and the activity of the proteins encoded.
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            Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group.

            Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting. Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles. In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.
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              Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27.

              Type I interferon (IFN) production plays pivotal roles in host antiviral innate immune responses, but an excessive production of type I IFN leads to the development of immunopathological conditions. Investigations on the regulatory mechanisms underlying host type I IFN production are currently of great interest. Here, we found that the expression of lectin family member Siglec1 was upregulated by viral infection in macrophages, which was dependent on the IFN/JAK/STAT1 signaling pathway. Siglec1 was found to negatively regulate viral infection-triggered type I IFN production. Mechanistically, Siglec1 associates with DAP12 to recruit and activate the scaffolding function of SHP2; SHP2 then recruits E3 ubiquitin ligase TRIM27, which induces TBK1 degradation via K48-linked ubiquitination at Lys251 and Lys372. Therefore, viral infection-induced upregulation of Siglec1 feedback loop inhibits type I IFN production and suppresses antiviral innate immune responses. Our study outlines a novel mechanism of negative regulation of type I IFN production, which may help virus to escape immune elimination.
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                Author and article information

                Journal
                J Cancer
                J Cancer
                jca
                Journal of Cancer
                Ivyspring International Publisher (Sydney )
                1837-9664
                2020
                25 July 2020
                : 11
                : 19
                : 5612-5622
                Affiliations
                [1 ]Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
                [2 ]Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
                Author notes
                ✉ Corresponding author: Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, 2699 West Gaoke Road, Shanghai, 201204, P. R. China. E-mail: gzr008@ 123456163.com .

                #These authors contributed equally to this work.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                jcav11p5612
                10.7150/jca.46097
                7477457
                32913456
                e920b48d-acd0-4ceb-a577-ee94ae20cf15
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 17 March 2020
                : 16 July 2020
                Categories
                Research Paper

                Oncology & Radiotherapy
                alkbh5,igf1r,endometrial cancer,insulin signaling pathway,m6a modification
                Oncology & Radiotherapy
                alkbh5, igf1r, endometrial cancer, insulin signaling pathway, m6a modification

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