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      N6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis.

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          Abstract

          Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N6-methyladenosine (m6A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N6-methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease.

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          Messenger RNA modifications: Form, distribution, and function.

          Wendy V. Gilbert, Tristan Bell, Cassandra Schaening (2016)
          RNA contains more than 100 distinct modifications that promote the functions of stable noncoding RNAs in translation and splicing. Recent technical advances have revealed widespread and sparse modification of messenger RNAs with N(6)-methyladenosine (m(6)A), 5-methylcytosine (m(5)C), and pseudouridine (Ψ). Here we discuss the rapidly evolving understanding of the location, regulation, and function of these dynamic mRNA marks, collectively termed the epitranscriptome. We highlight differences among modifications and between species that could instruct ongoing efforts to understand how specific mRNA target sites are selected and how their modification is regulated. Diverse molecular consequences of individual m(6)A modifications are beginning to be revealed, but the effects of m(5)C and Ψ remain largely unknown. Future work linking molecular effects to organismal phenotypes will broaden our understanding of mRNA modifications as cell and developmental regulators.
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            MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis.

            Keun Hur, Yuji Toiyama, Masanobu Takahashi … (2013)
            Distant metastasis is the major cause of cancer-related death in patients with colorectal cancer (CRC). Although the microRNA-200 (miR-200) family is a crucial inhibitor of epithelial-to-mesenchymal transition (EMT) in human cancer, the role of miR-200 members in the pathogenesis of metastatic CRC has not been investigated. Fifty-four pairs of primary CRC and corresponding matched liver metastasis tissue specimens were analysed for expression and methylation status of the miR-200 family members. Functional analysis of miR-200c overexpression was investigated in CRC cell lines, and cells were analysed for proliferation, invasion and migration. Expression of several miR-200c target genes (ZEB1, ETS1 and FLT1) and EMT markers (E-cadherin and vimentin) in CRC cell lines and tissue specimens was validated. Liver metastasis tissues showed higher expression of miR-200c (primary CRC = 1.31 vs. liver metastasis = 1.59; p = 0.0014) and miR-141 (primary CRC = 0.14 vs. liver metastasis = 0.17; p = 0.0234) than did primary CRCs, which was significantly associated with hypomethylation of the promoter region of these miRNAs (primary CRC = 61.2% vs. liver metastasis = 46.7%; p < 0.0001). The invasive front in primary CRC tissues revealed low miR-200c expression by in situ hybridization analysis. Transfection of miR-200c precursors resulted in enhanced cell proliferation but reduced invasion and migration behaviours in CRC cell lines. Overexpression of miR-200c in CRC cell lines caused reduced expression of putative gene targets, and resulted in increased E-cadherin and reduced vimentin expression. The associations between miR-200c, target genes and EMT markers were validated in primary CRCs and matching liver metastasis tissues. miR-200c plays an important role in mediating EMT and metastatic behaviour in the colon. Its expression is epigenetically regulated, and miR-200c may serve as a potential diagnostic marker and therapeutic target for patients with CRC.
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              Foxo3 activity promoted by non-coding effects of circular RNA and Foxo3 pseudogene in the inhibition of tumor growth and angiogenesis.

              W. P. Yang, W W Du, X-X Li … (2016)
              It has recently been shown that the upregulation of a pseudogene specific to a protein-coding gene could function as a sponge to bind multiple potential targeting microRNAs (miRNAs), resulting in increased gene expression. Similarly, it was recently demonstrated that circular RNAs can function as sponges for miRNAs, and could upregulate expression of mRNAs containing an identical sequence. Furthermore, some mRNAs are now known to not only translate protein, but also function to sponge miRNA binding, facilitating gene expression. Collectively, these appear to be effective mechanisms to ensure gene expression and protein activity. Here we show that expression of a member of the forkhead family of transcription factors, Foxo3, is regulated by the Foxo3 pseudogene (Foxo3P), and Foxo3 circular RNA, both of which bind to eight miRNAs. We found that the ectopic expression of the Foxo3P, Foxo3 circular RNA and Foxo3 mRNA could all suppress tumor growth and cancer cell proliferation and survival. Our results showed that at least three mechanisms are used to ensure protein translation of Foxo3, which reflects an essential role of Foxo3 and its corresponding non-coding RNAs.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature communications
                Publisher: Springer Science and Business Media LLC
                ISSN (Electronic): 2041-1723
                ISSN (Print): 2041-1723
                Publication date (Electronic): October 16 2019
                Volume: 10
                Issue: 1
                Affiliations
                [1 ] State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510000, China.
                [2 ] Department of Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510000, China.
                [3 ] Departments of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, 510000, China.
                [4 ] XenTech SAS, Evry, 91000, France.
                [5 ] Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510000, China.
                [6 ] Department of Clinical Oncology, the University of Hong Kong, Hong Kong, 999077, China.
                [7 ] State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510000, China. wangfengw@sysucc.org.cn.
                [8 ] State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510000, China. xurh@sysucc.org.cn.
                [9 ] State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510000, China. xiedan@sysucc.org.cn.
                [10 ] Departments of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, 510000, China. xiedan@sysucc.org.cn.
                Article
                Publisher Item ID: 10.1038/s41467-019-12651-2
                DOI: 10.1038/s41467-019-12651-2
                PMC ID: 6795808
                PubMed ID: 31619685
                SO-VID: 4f7b9a26-05e6-495b-aae7-32203f708391
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