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Published OnlineFirst October 1, 2014. Mol Cancer Res    Zhi-xiang Lu, Qin Huang, Juw Won Park, et al.   Splicing Associated with Metastatic Colonization Transcriptome-wide Landscape of Pre-mRNA Alternative   Updated version   10.1158/1541-7786.MCR-14-0366 doi: Access the most recent version of this article at:   Material Supplementary   http://mcr.aacrjournals.org/content/suppl/2014/10/02/1541-7786.MCR-14-0366.DC1.html Access the most recent supplemental material at:   Manuscript
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   Published OnlineFirst October 1, 2014. Mol Cancer Res Zhi-xiang Lu, Qin Huang, Juw Won Park, et al. Splicing Associated with Metastatic ColonizationTranscriptome-wide Landscape of Pre-mRNA Alternative   Updated version   10.1158/1541-7786.MCR-14-0366doi:Access the most recent version of this article at:   MaterialSupplementary   http://mcr.aacrjournals.org/content/suppl/2014/10/02/1541-7786.MCR-14-0366.DC1.html Access the most recent supplemental material at:   ManuscriptAuthor edited. Author manuscripts have been peer reviewed and accepted for publication but have not yet been   E-mail alerts  related to this article or journal.Sign up to receive free email-alerts   SubscriptionsReprints and .pubs@aacr.orgDepartment atTo order reprints of this article or to subscribe to the journal, contact the AACR Publications   Permissions  .permissions@aacr.orgDepartment atTo request permission to re-use all or part of this article, contact the AACR Publications on October 6, 2014. © 2014 American Association for Cancer Research. mcr.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 1, 2014; DOI: 10.1158/1541-7786.MCR-14-0366 on October 6, 2014. © 2014 American Association for Cancer Research. mcr.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 1, 2014; DOI: 10.1158/1541-7786.MCR-14-0366  1   Transcriptome-wide Landscape of Pre-mRNA Alternative Splicing Associated with Metastatic Colonization Zhi-xiang Lu 1,4 , Qin Huang 2,3,4 , Juw Won Park  1,4 , Shihao Shen 1 , Lan Lin 1 , Collin J. Tokheim 1 , Michael D. Henry 2,3,* , Yi Xing 1,*   1 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA 2 Department of Molecular Physiology and Biophysics, 3 Department of Pathology, University of Iowa, Iowa City, IA 52242, USA 4 These authors contributed equally. Present Address: Collin J. Tokheim, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA Running title:  Alternative Splicing Associated with Metastatic Colonization Keyword:  alternative splicing, splicing factor, cancer, metastasis, RNA-seq The work was supported by the National Institutes of Health [CA130916 to MDH and GM105431 to YX]. YX is supported by an Alfred Sloan Research Fellowship. * To whom correspondence should be addressed. Tel: +1 310-825-6806; Fax: +1 310-206-3663; Email: yxing@ucla.edu. Correspondence may also be addressed to MDH (Tel: +1 319-335-7886; Fax: +1 319-335-7330; Email: Michael-henry@uiowa.edu). In the manuscript: 8110 words, six figures and one table. Conflict of Interest: The authors declare no conflict of interest. on October 6, 2014. © 2014 American Association for Cancer Research. mcr.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 1, 2014; DOI: 10.1158/1541-7786.MCR-14-0366  2   Abstract Metastatic colonization is an ominous feature of cancer progression. Recent studies have established the importance of pre-mRNA alternative splicing (AS) in cancer biology. However, little is known about the transcriptome-wide landscape of AS associated with metastatic colonization. Both in vitro  and in vivo  models of metastatic colonization were utilized to study AS regulation associated with cancer metastasis. Transcriptome profiling of prostate cancer cells and derivatives crossing in vitro  or in vivo  barriers of metastasis revealed splicing factors with significant gene expression changes associated with metastatic colonization. These include splicing factors known to be differentially regulated in epithelial-mesenchymal transition (ESRP1, ESRP2, RBFOX2), a cellular process critical for cancer metastasis, as well as novel findings (NOVA1, MBNL3). Finally, RNA-seq indicated a large network of AS events regulated  by multiple splicing factors with altered gene expression or protein activity. These AS events are enriched for pathways important for cell motility and signaling, and affect key regulators of the invasive phenotype such as CD44 and GRHL1.  Implications Transcriptome-wide remodeling of AS is an integral regulatory process underlying metastatic colonization and AS events impact the metastatic behavior of cancer cells.   on October 6, 2014. © 2014 American Association for Cancer Research. mcr.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 1, 2014; DOI: 10.1158/1541-7786.MCR-14-0366  3   Introduction A central goal of cancer research is to elucidate molecular events that contribute to the life-threatening metastasis of cancer cells. Hematogenous dissemination and metastatic colonization of distant organs is a salient feature of malignant cancers (1). An emerging theme in our understanding of this critical process of cancer progression is that epithelial-to-mesenchymal transition (EMT) may facilitate metastasis (2). EMT is a normal process in development whereby cells phenotypically switch from an epithelial state to a mesenchymal state enabling, among other things, invasive and migratory cell behavior (2). It is also considered as a key process by which epithelial tumors acquire the capability to metastasize (3). This phenotypically plastic EMT-like state is driven by global changes of the gene regulatory program at both the transcriptional and post-transcriptional levels (4-7). Transcriptome profiling studies have identified the core transcriptional regulatory network of EMT involving key transcription factors and their upstream regulators and downstream targets (4). Recent studies have also begun to reveal widespread changes in mRNA isoforms during EMT arising from pre-mRNA alternative splicing (AS) (6-8). AS is an important mechanism of generating regulatory complexity in higher eukaryotes (9). Through alternative choices of exons and splice sites during splicing, a single gene can generate functionally distinct mRNA and protein isoforms. Many genes are differentially spliced during development or among different tissues and cell types (10). Cell-type-specific AS patterns are largely controlled by a small number of master splicing regulators (“splicing factors”) with cell-type-specific gene expression or protein activity (11-13). Pioneering work by Carstens and colleagues identified the epithelial-specific splicing factors ESRP1 and ESRP2 as the master splicing regulators in epithelial cells (14). During EMT, the expression levels of ESRPs are on October 6, 2014. © 2014 American Association for Cancer Research. mcr.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 1, 2014; DOI: 10.1158/1541-7786.MCR-14-0366
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