circRNA circ-MYBL2 is a novel tumor suppressor and potential biomarker in multiple myeloma
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RESEARCH ARTICLE
circRNA circ‑MYBL2 is a novel tumor suppressor and potential biomarker in multiple myeloma Shanshan Yu1 · Limei Ai1 · Wei Wei1 · Jing Pan1 Received: 24 July 2020 / Accepted: 19 September 2020 © Japan Human Cell Society 2020
Abstract Currently, multiple myeloma (MM) is still an incurable disease. Deciphering its pathogenesis will bring new targets for clinical diagnosis and treatment. In the present study, we identified a MM-associated circular RNA (circRNA), circ-MYBL2, which was dramatically decreased in MM tissue and serum samples in comparison to normal samples. Low circ-MYBL2 level was closely correlated with high clinical stage and unfavorable outcome, and serum circ-MYBL2 had excellent accuracy in diagnosing MM. Exogenous circ-MYBL2 expression notably repressed MM cell viability, DNA synthesis and cell cycle progression. Further exploration revealed that circ-MYBL2 exerted the tumor-inhibiting effect by affecting the phosphorylation level of its linear isoform, in which circ-MYBL2 facilitated the binding of Cyclin F to MYBL2, dampening MYBL2 phosphorylation and activation, thereby inhibiting the transcription of a number of well-known proliferation-related oncogenes. Importantly, overexpression of circ-MYBL2 significantly reduced the tumor size of subcutaneous xenografts in nude mice. Taken together, our data unveil a regulatory mechanism linking circ-MYBL2 and its host gene mediated by Cyclin F, providing a potential diagnostic, prognostic and therapeutic target for MM patients. Keywords Multiple myeloma · Circular RNA · MYBL2 · Biomarker
Introduction Multiple myeloma (MM, also known as plasma cell tumor) is a malignant tumor originating from plasma cells in the bone marrow [1]. A large number of monoclonal malignant plasmacytosis may cause soft tissue involvement and extensive metastasis in late stage [2]. Despite advances in the diagnosis, prediction and treatment of MM in recent years, it is still incurable [3]; thus, it is necessary to identify novel MM-related targets via exploring its underlying pathogenesis. Human gene group plan shows that only about 2% of the genes in the human genome can be translated into proteins, and the rest are non-coding RNAs. Circular RNA (circRNA) is a special class of non-coding RNA that is characterized by a covalently closed ring structure [4, 5]. It is derived from the head–tail splicing of pre-mRNA, one gene can produce * Limei Ai [email protected] 1
Department of Hematology, The First Affiliated Hospital of Jinzhou Medical University, No.2, Section 5, Renmin Street, Guta District, Jinzhou 121000, Liaoning, China
multiple circRNAs, most of which consist of exons [6, 7]. Compared to conventional linear RNA, circRNA is highly stable; thus, it is abundant in tissues and body fluids [8]. The expression abundance of some circRNAs is more than 20 times that of their linear parent genes [9]. Emerging evidence shows that circRNA acts as a key player in human disease progression, including in blood malignancies [10]. It serves as a tumor suppresso
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