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  • Pathology Research and Practice xxx xxxx xxxx br Contents

    2022-09-02

     Pathology - Research and Practice xxx (xxxx) xxxx
    Contents lists available at ScienceDirect
    Biomedicine & Pharmacotherapy
    journal homepage: www.elsevier.com/locate/biopha
    circMTO1 promotes tumorigenesis and chemoresistance of cervical cancer T via regulating miR-6893
    Mengmeng Chena,1, Guihai Aia,1, Jianhong Zhoua, Weipu Maob, Huan Lic, Jing Guoa,
    a Gynaecology and Obstetrics Department, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, PR China
    b Urology Surgery Department, Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, PR China
    c Clinical Medicine Department, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
    Keywords:
    Cervical cancer
    Tumorigenesis
    Chemoresistance
    circMTO1
    Autophagy 
    Background: Cervical cancer has been one of the most common cancer in women worldwide. However, the detailed mechanism underlying circMTO1-regulated cervical cancer remains unclear.
    Methods: RT-qPCR and westernblot were used to examine genes Y-27632 levels. Wound healing assay and transwell invasion assay were utilized to probe migration and invasion abilities of cervical cancer cells. In addition, cell viability and apoptosis were measured by MTT and TUNEL assay, respectively. Finally, we em-ployed bioinformatic approach to analyze gene expression levels in clinical cervical cancer tissues.
    Results: circMTO1 was shown to be greatly upregulated in cervical cancer cell lines and tumors. circMTO1 directly interacts with miR-6893. miR-6893 could restore circMTO1-regulated migration, invasion and che-moresistance of cervical cancer cells. Furthermore, we identified S100A1 as downstream effector for circMTO1/ miR-6893-induced tumorigenesis of cervical cancer cells. Besides, westernblot analyses demonstrated that circMTO1 and miR-6893 inhibitor enhanced Beclin1 expression and downregulated p62 level. We found that autophagy inhibitor 3-MA could revert cell viability and apoptosis of HeLa regulated by circMTO1 and miR-6893 inhibitor. More importantly, the bioinformatic results showed the dysregulated expression patterns of circMTO1, miR-6893 and S100A1 in human clinical cervical cancer tissues.
    Conclusions: In summary, we reveal, for the first time, a novel mechanism of circMTO1/miR-6893 in tumor-igenesis and chemoresistance of cervical cancer. Our findings support the notion of developing the new therapies and biomarkers by targeting circMTO1 for cervical cancer.
    1. Introduction
    Cervical cancer is the most common cancer, Therefore, it is neces-sary to improve our understanding of cervical cancer pathogenesis and identify new targets for development of diagnostic and therapeutic approaches.
    CircRNAs (circRNAs) is a new form of endogenous non-coding RNAs [1]. They were generated by covalently closed loop structures without 5′ to 3′ polarity or poly A tail [2]. According to previous studies, cir-cRNAs are implicated in a variety of cell biologies (such as transcrip-tional regulation, cell proliferation, differentiation and cancer pro-gression) [3]. CircMTO1 (mitochondrial translation optimization 1 homologue, circRNA ID: hsa_circRNA_0007874) is downregulated in hepatocellular carcinoma, bladder cancer, breast cancer and colorectal cancer [4–7]. However, there is no study reporting the role of circMTO1
    in cervical cancer till now.
    miRNAs are a class of non-coding RNAs with ˜22 nucleotides length, regulating gene expression by complementary binding or complex mechanisms [8,9]. Many studies show miRNAs function both as tumor suppressors or ocogenes in the progression of various cancers [10]. Recently, it has been reported that several miRNAs (such as miR-16, miR-375, miR-106) could inhibit tumorigenesis and chemoresistance of cervical cancer [11,12]. To date, we have not found any evidence of showing the role of miR-6893 in cancer, even cervical cancer.