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      New insights into the interplay between long non‐coding RNAs and RNA‐binding proteins in cancer

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          Abstract

          With the development of proteomics and epigenetics, a large number of RNA‐binding proteins (RBPs) have been discovered in recent years, and the interaction between long non‐coding RNAs (lncRNAs) and RBPs has also received increasing attention. It is extremely important to conduct in‐depth research on the lncRNA‐RBP interaction network, especially in the context of its role in the occurrence and development of cancer. Increasing evidence has demonstrated that lncRNA‐RBP interactions play a vital role in cancer progression; therefore, targeting these interactions could provide new insights for cancer drug discovery. In this review, we discussed how lncRNAs can interact with RBPs to regulate their localization, modification, stability, and activity and discussed the effects of RBPs on the stability, transport, transcription, and localization of lncRNAs. Moreover, we explored the regulation and influence of these interactions on lncRNAs, RBPs, and downstream pathways that are related to cancer development, such as N6‐methyladenosine (m6A) modification of lncRNAs. In addition, we discussed how the lncRNA‐RBP interaction network regulates cancer cell phenotypes, such as proliferation, apoptosis, metastasis, drug resistance, immunity, tumor environment, and metabolism. Furthermore, we summarized the therapeutic strategies that target the lncRNA‐RBP interaction network. Although these treatments are still in the experimental stage and various theories and processes are still being studied, we believe that these strategies may provide new ideas for cancer treatment.

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          Most cited references165

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          Microenvironmental regulation of tumor progression and metastasis.

          Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
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            Apoptosis: a review of programmed cell death.

            The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.
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              m6A-dependent regulation of messenger RNA stability

              N6 -methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA (mRNA) of all higher eukaryotes 1,2 . Although essential to cell viability and development 3–5 , the exact role of m6A modification remains to be determined. The recent discovery of two m6A demethylases in mammalian cells highlighted the importance of m6A in basic biological functions and disease 6–8 . Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m6A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies 9 . The C-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA whereas the N-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m6A modification is recognized by selective-binding proteins to affect the translation status and lifetime of mRNA.
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                Author and article information

                Contributors
                chenksh2002@163.com
                lib2128@163.com
                Journal
                Cancer Commun (Lond)
                Cancer Commun (Lond)
                10.1002/(ISSN)2523-3548
                CAC2
                Cancer Communications
                John Wiley and Sons Inc. (Hoboken )
                2523-3548
                12 January 2022
                February 2022
                : 42
                : 2 ( doiID: 10.1002/cac2.v42.2 )
                : 117-140
                Affiliations
                [ 1 ] Ministry of Education Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes Institute of Life and Health Engineering Jinan University Guangzhou Guangdong 510632 P. R. China
                [ 2 ] Department of Pathology Henan Key Laboratory of Tumor Pathology the First Affiliated Hospital of Zhengzhou University Zhengzhou Henan 450001 P. R. China
                [ 3 ] Ministry of Education Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine National Engineering Research Center of Genetic Medicine Institute of Biomedicine College of Life Science and Technology Jinan University Guangzhou Guangdong 510632 P. R. China
                [ 4 ] Key Laboratory of Biological Targeting Diagnosis Therapy and Rehabilitation of Guangdong Higher Education Institutes the Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510700 P. R. China
                Author notes
                [*] [* ] Correspondence

                Bin Li, Ministry of Education Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou 510632, Guangdong, P. R. China.

                E‐mail: lib2128@ 123456163.com

                Kui‐Sheng Chen, Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Tumor Pathology, Zhengzhou 450006, Henan, P. R. China.

                E‐mail: chenksh2002@ 123456163.com

                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-8979-610X
                Article
                CAC212254
                10.1002/cac2.12254
                8822594
                35019235
                64a9155c-c885-4f9c-9a4d-93f53d8a76ac
                © 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 07 October 2021
                : 30 December 2021
                Page count
                Figures: 3, Tables: 2, Pages: 24, Words: 16962
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                February 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.1 mode:remove_FC converted:08.02.2022

                cancer epigenetics,cancer,interaction network,lncrna‐rbp,long non‐coding rna,rna‐binding protein,treatment strategy

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