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      PIWI-interacting RNA-36712 restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA

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          Abstract

          Background

          Breast cancer is one of the most common malignancies and the major cause of cancer-related death in women. Although the importance of PIWI-interacting RNAs (piRNAs) in cancer has been increasingly recognized, few studies have been explored the functional mechanism of piRNAs in breast cancer development and progression.

          Methods

          We examined the top 20 highly expressed piRNAs based on the analysis of TCGA breast cancer data in two patient cohorts to test the roles of piRNAs in breast cancer. The effects of piRNA-36,712 on the malignant phenotypes and chemosensitivity of breast cancer cells were detected in vitro and in vivo. MS2-RIP and reporter gene assays were conducted to identify the interaction and regulation among piRNA-36,712, miRNAs and SEPW1P. Kaplan-Meier estimate with log-rank test was used to compare patient survival by different piRNA-36,712 expression levels.

          Results

          We found piRNA-36,712 level was significantly lower in breast cancer than in normal breast tissues and low level was correlated with poor clinical outcome in patients. Functional studies demonstrated that piRNA-36,712 interacts with RNAs produced by SEPW1P, a retroprocessed pseudogene of SEPW1, and subsequently inhibits SEPW1 expression through competition of SEPW1 mRNA with SEPW1P RNA for microRNA-7 and microRNA-324. We also found that higher SEPW1 expression due to downregulation of piRNA-36,712 in breast cancer may suppress P53, leading to the upregulated Slug but decreased P21 and E-cadherin levels, thus promoting cancer cell proliferation, invasion and migration. Furthermore, we found that piRNA-36,712 had synergistic anticancer effects with the paclitaxel and doxorubicin, two chemotherapeutic agents for breast cancer.

          Conclusions

          These findings suggest that piRNA-36,712 is a novel tumor suppressor and may serve as a potential predictor for the prognosis of breast cancer patients.

          Electronic supplementary material

          The online version of this article (10.1186/s12943-019-0940-3) contains supplementary material, which is available to authorized users.

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          Most cited references46

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          A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

          Laura Poliseno, Leonardo Salmena, JiangWen Zhang … (2010)
          The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs possess a biological role in cancer cells that relies upon their ability to compete for microRNA binding and is independent of their protein-coding function. As a paradigm for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene (PTENP1) and the critical consequences of this interaction. We find that PTENP1 is biologically active as determined by its ability to regulate cellular levels of PTEN, and that it can exert a growth-suppressive role. We also show that PTENP1 locus is selectively lost in human cancer. We extend our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. Further, we demonstrate that the transcripts of protein coding genes such as PTEN are also biologically active. Together, these findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.
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            A germline-specific class of small RNAs binds mammalian Piwi proteins.

            Angélique Girard, Ravi Sachidanandam, Gregory Hannon … (2006)
            Small RNAs associate with Argonaute proteins and serve as sequence-specific guides to regulate messenger RNA stability, protein synthesis, chromatin organization and genome structure. In animals, Argonaute proteins segregate into two subfamilies. The Argonaute subfamily acts in RNA interference and in microRNA-mediated gene regulation using 21-22-nucleotide RNAs as guides. The Piwi subfamily is involved in germline-specific events such as germline stem cell maintenance and meiosis. However, neither the biochemical function of Piwi proteins nor the nature of their small RNA guides is known. Here we show that MIWI, a murine Piwi protein, binds a previously uncharacterized class of approximately 29-30-nucleotide RNAs that are highly abundant in testes. We have therefore named these Piwi-interacting RNAs (piRNAs). piRNAs show distinctive localization patterns in the genome, being predominantly grouped into 20-90-kilobase clusters, wherein long stretches of small RNAs are derived from only one strand. Similar piRNAs are also found in human and rat, with major clusters occurring in syntenic locations. Although their function must still be resolved, the abundance of piRNAs in germline cells and the male sterility of Miwi mutants suggest a role in gametogenesis.
            Article 0 comments Cited 550 times – based on 0 reviews     Review now
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              A distinct small RNA pathway silences selfish genetic elements in the germline.

              Vasily Vagin, Alla A. Sigova, Chengjian Li … (2006)
              In the Drosophila germline, repeat-associated small interfering RNAs (rasiRNAs) ensure genomic stability by silencing endogenous selfish genetic elements such as retrotransposons and repetitive sequences. Whereas small interfering RNAs (siRNAs) derive from both the sense and antisense strands of their double-stranded RNA precursors, rasiRNAs arise mainly from the antisense strand. rasiRNA production appears not to require Dicer-1, which makes microRNAs (miRNAs), or Dicer-2, which makes siRNAs, and rasiRNAs lack the 2',3' hydroxy termini characteristic of animal siRNA and miRNA. Unlike siRNAs and miRNAs, rasiRNAs function through the Piwi, rather than the Ago, Argonaute protein subfamily. Our data suggest that rasiRNAs protect the fly germline through a silencing mechanism distinct from both the miRNA and RNA interference pathways.
              Article 0 comments Cited 407 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Liping Tan: 988tan@163.com
                Dongmei Mai: maidm@sysucc.org.cn
                Bailin Zhang: bailin_zhang@cicams.ac.cn
                Xiaobing Jiang: jiangxiaob1@sysucc.org.cn
                Jialiang Zhang: zhangjial@sysucc.org.cn
                Ruihong Bai: bairh@sysucc.org.cn
                Ying Ye: yeying1@sysucc.org.cn
                Mei Li: limei@sysucc.org.cn
                Ling Pan: panling@sysucc.org.cn
                Jiachun Su: sujc@sysucc.org.cn
                Yanfen Zheng: zhengyf@sysucc.org.cn
                Zexian Liu: liuzx@sysucc.org.cn
                Zhixiang Zuo: zuozhx@sysucc.org.cn
                Qi Zhao: zhaoqi@sysucc.org.cn
                Xiaoxing Li: lixiaox@sysucc.org.cn
                Xudong Huang: huangxd@sysucc.org.cn
                Jie Yang: yangjie2103@163.com
                Wen Tan: tanwen68@hotmail.com
                Jian Zheng: zhengjian@sysucc.org.cn
                Dongxin Lin: lindx@sysucc.org.cn
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 12 January 2019
                Publication date PMC-release: 12 January 2019
                Publication date Collection: 2019
                Volume: 18
                Electronic Location Identifier: 9
                Affiliations
                [1 ]ISNI 0000 0004 1803 6191, GRID grid.488530.2, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, , Sun Yat-sen University Cancer Center, ; Guangzhou, China
                [2 ]ISNI 0000 0000 9889 6335, GRID grid.413106.1, Department of Breast Surgery, , National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ; Beijing, China
                [3 ]ISNI 0000 0004 1803 6191, GRID grid.488530.2, Department of Surgical Oncology, , Sun Yat-sen University Cancer Center, ; Guangzhou, China
                [4 ]ISNI 0000 0004 1803 6191, GRID grid.488530.2, Department of Pathology, , Sun Yat-sen University Cancer Center, ; Guangzhou, China
                [5 ]ISNI 0000 0000 9889 6335, GRID grid.413106.1, Department of Etiology and Carcinogenesis, , National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ; Beijing, China
                Article
                Publisher ID: 940
                DOI: 10.1186/s12943-019-0940-3
                PMC ID: 6330501
                PubMed ID: 30636640
                SO-VID: 8e2fe978-56a9-4e87-b526-0088433dc2dd
                Copyright © © The Author(s). 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 4 August 2018
                Date accepted : 1 January 2019
                Funding
                Funded by: Young Elite Scientists Sponsorship Program by CAST
                Award ID: 2017QNRC001
                Award Recipient :
                Funded by: National Young Top-notch Talent Support Program
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pirna,breast cancer,p53,drug sensitivity,sepw1
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pirna, breast cancer, p53, drug sensitivity, sepw1

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