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      N 6-methyladenosine (m 6A)-mediated lncRNA DLGAP1-AS1enhances breast canceradriamycin resistance through miR-299-3p/WTAP feedback loop

      research-article
      a , b , c , b , b , b
      Bioengineered
      Taylor & Francis
      Adriamycin resistance, N6-methyladenosine, breast cancer, DLGAP1-AS1, WTAP

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          ABSTRACT

          Chemotherapy resistance is identified as an obstacle for breast cancer (BC) therapy, and, besides, increasing evidence indicates that long-noncoding RNAs (lncRNAs) participate in the regulation of BC adriamycin (ADR) resistance. Here, our work shows that lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) is up-regulated in ADR-resistant BC cells (MCF-7/ADR). Clinically, higher DLGAP1-AS1 expression was closely correlated to poorer clinical prognosis. Results showed that DLGAP1-AS1 promoted the ADR IC 50 and proliferation of ADR-resistant cells. Moreover, N 6-methyladenosine (m 6A) methyltransferase WT1 associated protein (WTAP) binds to the m 6A modified site of DLGAP1-AS1 and motivates its stability. Mechanistically, DLGAP1-AS1 sponged miR-299-3p through 3ʹ-untranslated region (3ʹ-UTR) binding, which in turn relieved the repression of WTAP and thus upregulated WTAP expression. In conclusion, above findings conclude that lncRNA DLGAP1-AS1 promotes BC ADR-resistance through WTAP/DLGAP1-AS1/miR-299-3p feedback loop.

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          Most cited references29

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          Triple-negative breast cancer molecular subtyping and treatment progress

          Triple-negative breast cancer (TNBC), a specific subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2), has clinical features that include high invasiveness, high metastatic potential, proneness to relapse, and poor prognosis. Because TNBC tumors lack ER, PR, and HER2 expression, they are not sensitive to endocrine therapy or HER2 treatment, and standardized TNBC treatment regimens are still lacking. Therefore, development of new TNBC treatment strategies has become an urgent clinical need. By summarizing existing treatment regimens, therapeutic drugs, and their efficacy for different TNBC subtypes and reviewing some new preclinical studies and targeted treatment regimens for TNBC, this paper aims to provide new ideas for TNBC treatment.
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            Long Non-Coding RNA in the Pathogenesis of Cancers

            The incidence and mortality rate of cancer has been quickly increasing in the past decades. At present, cancer has become the leading cause of death worldwide. Most of the cancers cannot be effectively diagnosed at the early stage. Although there are multiple therapeutic treatments, including surgery, radiotherapy, chemotherapy, and targeted drugs, their effectiveness is still limited. The overall survival rate of malignant cancers is still low. It is necessary to further study the mechanisms for malignant cancers, and explore new biomarkers and targets that are more sensitive and effective for early diagnosis, treatment, and prognosis of cancers than traditional biomarkers and methods. Long non-coding RNAs (lncRNAs) are a class of RNA transcripts with a length greater than 200 nucleotides. Generally, lncRNAs are not capable of encoding proteins or peptides. LncRNAs exert diverse biological functions by regulating gene expressions and functions at transcriptional, translational, and post-translational levels. In the past decade, it has been demonstrated that the dysregulated lncRNA profile is widely involved in the pathogenesis of many diseases, including cancer, metabolic disorders, and cardiovascular diseases. In particular, lncRNAs have been revealed to play an important role in tumor growth and metastasis. Many lncRNAs have been shown to be potential biomarkers and targets for the diagnosis and treatment of cancers. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis of certain malignant cancers, including lung, breast, liver, and colorectal cancers, as well as hematological malignancies and neuroblastoma.
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              Long noncoding RNA GAS5 inhibits progression of colorectal cancer by interacting with and triggering YAP phosphorylation and degradation and is negatively regulated by the m 6 A reader YTHDF3

              Background YAP activation is crucial for cancer development including colorectal cancer (CRC). Nevertheless, it remains unclear whether N6-Methyladenosine (m6A) modified transcripts of long noncoding RNAs (lncRNAs) can regulate YAP activation in cancer progression. We investigated the functional link between lncRNAs and the m6A modification in YAP signaling and CRC progression. Methods YAP interacting lncRNAs were screened by RIP-sequencing, RNA FISH and immunofluorescence co-staining assays. Interaction between YAP and lncRNA GAS5 was studied by biochemical methods. MeRIP-sequencing combined with lncRNA-sequencing were used to identify the m6A modified targets of YTHDF3 in CRC. Gain-of-function and Loss-of-function analysis were performed to measure the function of GAS5-YAP-YTHDF3 axis in CRC progression in vitro and in vivo. Results GAS5 directly interacts with WW domain of YAP to facilitate translocation of endogenous YAP from the nucleus to the cytoplasm and promotes phosphorylation and subsequently ubiquitin-mediated degradation of YAP to inhibit CRC progression in vitro and in vivo. Notably, we demonstrate the m6A reader YTHDF3 not only a novel target of YAP but also a key player in YAP signaling by facilitating m6A-modified lncRNA GAS5 degradation, which profile a new insight into CRC progression. Clinically, lncRNA GAS5 expressions is negatively correlated with YAP and YTHDF3 protein levels in tumors from CRC patients. Conclusions Our study uncovers a negative functional loop of lncRNA GAS5-YAP-YTHDF3 axis, and identifies a new mechanism for m6A-induced decay of GAS5 on YAP signaling in progression of CRC which may offer a promising approach for CRC treatment.
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                Author and article information

                Journal
                Bioengineered
                Bioengineered
                Bioengineered
                Taylor & Francis
                2165-5979
                2165-5987
                4 December 2021
                2021
                4 December 2021
                : 12
                : 2
                : 10935-10944
                Affiliations
                [a ]Department of General Surgery, Zhangdian District People's Hospital; , Zibo, China
                [b ]Department of Oncology, Zibo Central Hospital; , Zibo, China
                [c ]Department of Infection Disease, Zibo Central Hospital; , Zibo, China
                Author notes
                CONTACT Min Wang xuyanbin.zibo.edu@ 123456aliyun.com ; eizhuan@ 123456163.com Department of Oncology, Zibo Central Hospital; , Zibo 255020, China
                Author information
                https://orcid.org/0000-0003-4188-4079
                Article
                2000198
                10.1080/21655979.2021.2000198
                8809972
                34866525
                302769ff-c971-4b12-b1f7-cf0da2297c30
                © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 5, Tables: 1, References: 29, Pages: 10
                Categories
                Research Article
                Research Paper

                Biomedical engineering
                adriamycin resistance,n6-methyladenosine,breast cancer,dlgap1-as1,wtap
                Biomedical engineering
                adriamycin resistance, n6-methyladenosine, breast cancer, dlgap1-as1, wtap

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