TMEM2 Is a SOX4-Regulated Gene That Mediates Metastatic Migration and Invasion in Breast Cancer.

The developmental transcription factor SOX4 contributes to the metastatic spread of multiple solid cancer types, but its direct target genes that mediate cancer progression are not well defined. Using a systematic molecular and genomic approach, we identified the TMEM2 transmembrane protein gene as a direct transcriptional target of SOX4. TMEM2 was transcriptionally activated by SOX4 in breast cancer cells where, like SOX4, TMEM2 was found to mediate proinvasive and promigratory effects. Similarly, TMEM2 was sufficient to promote metastatic colonization of breast cancer cells and its expression in primary breast tumors associated with a higher likelihood of metastatic relapse. Given earlier evidence that genetic inactivation of SOX4 or TMEM2 yield similar defects in cardiac development, our findings lead us to propose that TMEM2 may not only mediate the pathologic effects of SOX4 on cancer progression but also potentially its contributions to embryonic development. Cancer Res; 76(17); 4994-5005. ©2016 AACR.

[1]  Z. Szallasi,et al.  An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients , 2010, Breast Cancer Research and Treatment.

[2]  M. Carmo-Fonseca,et al.  Design principles of interconnections between chromatin and pre-mRNA splicing. , 2012, Trends in biochemical sciences.

[3]  Qiang Li,et al.  G8: a novel domain associated with polycystic kidney disease and non-syndromic hearing loss , 2006, Bioinform..

[4]  V. Harley,et al.  The DNA-binding specificity of SOX9 and other SOX proteins. , 1999, Nucleic acids research.

[5]  Aaron M. Zorn,et al.  Sox17 and Sox4 Differentially Regulate β-Catenin/T-Cell Factor Activity and Proliferation of Colon Carcinoma Cells , 2007, Molecular and Cellular Biology.

[6]  R. Baserga,et al.  Transcriptional activity of the human thymidine kinase gene determined by a method using the polymerase chain reaction and an intron-specific probe. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Cigudosa,et al.  The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. , 2009, Human molecular genetics.

[8]  R. Boxtel,et al.  The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe? , 2013, Oncogene.

[9]  Paul J. Scotting,et al.  Differential Expression of SOX4 and SOX11 in Medulloblastoma , 2002, Journal of Neuro-Oncology.

[10]  Hsin-Yi Huang,et al.  SOX4 Transcriptionally Regulates Multiple SEMA3/Plexin Family Members and Promotes Tumor Growth in Pancreatic Cancer , 2012, PloS one.

[11]  D. Wotton,et al.  The High Mobility Group Transcription Factor, SOX4, Transactivates the Human CD2 Enhancer (*) , 1995, The Journal of Biological Chemistry.

[12]  S. Tavazoie,et al.  Convergent Multi-miRNA Targeting of ApoE Drives LRP1/LRP8-Dependent Melanoma Metastasis and Angiogenesis , 2012, Cell.

[13]  Thomas M Green,et al.  A public genome-scale lentiviral expression library of human ORFs , 2011, Nature Methods.

[14]  Colleen D. McCabe,et al.  Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells. , 2009, Cancer research.

[15]  C. Suñé,et al.  Functional coupling of transcription and splicing. , 2012, Gene.

[16]  V. Lefebvre,et al.  Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. , 2007, The international journal of biochemistry & cell biology.

[17]  Véronique Lefebvre,et al.  The three SoxC proteins—Sox4, Sox11 and Sox12—exhibit overlapping expression patterns and molecular properties , 2008, Nucleic acids research.

[18]  H. Clevers,et al.  Sox‐4, an Sry‐like HMG box protein, is a transcriptional activator in lymphocytes. , 1993, The EMBO journal.

[19]  Shalini Oberdoerffer,et al.  Co-transcriptional regulation of alternative pre-mRNA splicing. , 2012, Biochimica et biophysica acta.

[20]  C. Moreno,et al.  SOX4 interacts with plakoglobin in a Wnt3a-dependent manner in prostate cancer cells , 2011, BMC Cell Biology.

[21]  Jorng-Tzong Horng,et al.  Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma , 2008, Oncogene.

[22]  K. Miyazono,et al.  Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. , 2009, Cell stem cell.

[23]  Long Yu,et al.  GG: A domain involved in phage LTF apparatus and implicated in human MEB and non‐syndromic hearing loss diseases , 2006, FEBS letters.

[24]  Andy J. Minn,et al.  Genes that mediate breast cancer metastasis to lung , 2005, Nature.

[25]  W. Gerald,et al.  Endogenous human microRNAs that suppress breast cancer metastasis , 2008, Nature.

[26]  Johan Staaf,et al.  GOBO: Gene Expression-Based Outcome for Breast Cancer Online , 2011, PloS one.

[27]  T. Perlmann,et al.  The establishment of neuronal properties is controlled by Sox4 and Sox11. , 2006, Genes & development.

[28]  J. Massagué,et al.  Cancer Metastasis: Building a Framework , 2006, Cell.

[29]  S. Tavazoie,et al.  Extracellular Metabolic Energetics Can Promote Cancer Progression , 2015, Cell.

[30]  S. Tavazoie,et al.  A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells , 2011, Nature.

[31]  P. Goodfellow,et al.  Definition of a consensus DNA binding site for SRY. , 1994, Nucleic acids research.

[32]  Yu Zhang,et al.  SOX4 induces epithelial-mesenchymal transition and contributes to breast cancer progression. , 2012, Cancer research.

[33]  D. Tenen,et al.  Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia. , 2013, Cancer cell.

[34]  V. Lefebvre,et al.  SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. , 2013, Blood.

[35]  V. Lefebvre,et al.  Generation of mice harboring a Sox4 conditional null allele , 2006, Genesis.

[36]  Juan M. Vaquerizas,et al.  DNA-Binding Specificities of Human Transcription Factors , 2013, Cell.

[37]  I. Fidler,et al.  Selection of successive tumour lines for metastasis. , 1973, Nature: New biology.

[38]  R. F. Luco,et al.  More than a splicing code: integrating the role of RNA, chromatin and non-coding RNA in alternative splicing regulation. , 2011, Current opinion in genetics & development.

[39]  A. Cumano,et al.  Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4 , 1996, Nature.

[40]  V. Seshan,et al.  A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis , 2012, Cell.

[41]  M. Affolter,et al.  The novel transmembrane protein Tmem2 is essential for coordination of myocardial and endocardial morphogenesis , 2011, Development.

[42]  Pengbo Liu,et al.  Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. , 2006, Cancer research.

[43]  O. Elemento,et al.  Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival , 2015, Nature Cell Biology.

[44]  M. D. Den Boer,et al.  Differential expression and prognostic significance of SOX genes in pediatric medulloblastoma and ependymoma identified by microarray analysis. , 2008, Neuro-oncology.

[45]  Andrew I Su,et al.  Large scale molecular analysis identifies genes with altered expression in salivary adenoid cystic carcinoma. , 2002, The American journal of pathology.

[46]  W. Gerald,et al.  Identifying site-specific metastasis genes and functions. , 2005, Cold Spring Harbor symposia on quantitative biology.

[47]  H Clevers,et al.  Sox4-deficiency syndrome in mice is an animal model for common trunk. , 1998, Circulation research.

[48]  Piotr J. Balwierz,et al.  Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. , 2013, Cancer cell.

[49]  R. Lovell-Badge,et al.  Novel transcriptional targets of the SRY-HMG box transcription factor SOX4 link its expression to the development of small cell lung cancer. , 2012, Cancer research.

[50]  J. Bakkers,et al.  Transmembrane protein 2 (Tmem2) is required to regionally restrict atrioventricular canal boundary and endocardial cushion development , 2011, Development.

[51]  L. Hood,et al.  Massively Parallel Signature Sequencing and Bioinformatics Analysis Identifies Up-Regulation of TGFBI and SOX4 in Human Glioblastoma , 2010, PloS one.

[52]  William Stafford Noble,et al.  Matrix2png: a utility for visualizing matrix data , 2003, Bioinform..

[53]  T. Barrette,et al.  ONCOMINE: a cancer microarray database and integrated data-mining platform. , 2004, Neoplasia.