Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex

Background:Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is a functional long non-coding RNA (lncRNA), which is highly expressed in several tumours, including colorectal cancer (CRC). Its biological function and mechanism in the prognosis of human CRC is still largely under investigation.Methods:This study aimed to investigate the new effect mechanism of MALAT1 on the proliferation and migration of CRC cells in vitro and in vivo, and detect the expression of MALAT1, SFPQ (also known as PSF (PTB-associated splicing factor)), and PTBP2 (also known as PTB (polypyrimidine-tract-binding protein)) in CRC tumour tissues, followed by correlated analysis with clinicopathological parameters.Results:We found that overexpression of MALAT1 could promote cell proliferation and migration in vitro, and promote tumour growth and metastasis in nude mice. The underlying mechanism was associated with tumour suppressor gene SFPQ and proto-oncogene PTBP2. In CRC, MALAT1 could bind to SFPQ, thus releasing PTBP2 from the SFPQ/PTBP2 complex. In turn, the increased SFPQ-detached PTBP2 promoted cell proliferation and migration. SFPQ critically mediated the regulatory effects of MALAT1. Moreover, in CRC tissues, MALAT1 and PTBP2 were overexpressed, both of which were associated closely with the invasion and metastasis of CRC. However, the SFPQ showed unchanged expression either in CRC tissues or adjacent normal tissues.Conclusions:Our findings implied that MALAT1 might be a potential predictor for tumour metastasis and prognosis. Furthermore, the interaction between MALAT1 and SFPQ could be a novel therapeutic target for CRC.

[1]  B. Vogelstein,et al.  A genetic model for colorectal tumorigenesis , 1990, Cell.

[2]  J. G. Patton,et al.  Characterization and molecular cloning of polypyrimidine tract-binding protein: a component of a complex necessary for pre-mRNA splicing. , 1991, Genes & development.

[3]  J. G. Patton,et al.  Cloning and characterization of PSF, a novel pre-mRNA splicing factor. , 1993, Genes & development.

[4]  J. G. Patton,et al.  A novel set of spliceosome‐associated proteins and the essential splicing factor PSF bind stably to pre‐mRNA prior to catalytic step II of the splicing reaction. , 1994, The EMBO journal.

[5]  P. Chomez,et al.  Characterization of the GAGE genes that are expressed in various human cancers and in normal testis. , 1999, Cancer research.

[6]  R. Foisner,et al.  Differential nuclear localization and nuclear matrix association of the splicing factors PSF and PTB , 2000, Journal of cellular biochemistry.

[7]  S. Eddy.  Non–coding RNA genes and the modern RNA world , 2001, Nature Reviews Genetics.

[8]  René Bernards,et al.  A progression puzzle. , 2002, Nature.

[9]  Michael Thomas,et al.  MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer , 2003, Oncogene.

[10]  I. Fidler,et al.  The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited , 2003, Nature Reviews Cancer.

[11]  G. Camenisch,et al.  Integration of Oxygen Signaling at the Consensus HRE , 2005, Science's STKE.

[12]  G. Christofori.  New signals from the invasive front , 2006, Nature.

[13]  T. Takayama,et al.  Colorectal cancer: genetics of development and metastasis , 2006, Journal of Gastroenterology.

[14]  John N. Hutchinson,et al.  A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains , 2007, BMC Genomics.

[15]  M. Karin,et al.  A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas , 2007, Oncogene.

[16]  Jun O. Liu,et al.  RNA-Binding Proteins HuR and PTB Promote the Translation of Hypoxia-Inducible Factor 1α , 2007, Molecular and Cellular Biology.

[17]  J. Coon,et al.  Knockdown of polypyrimidine tract-binding protein suppresses ovarian tumor cell growth and invasiveness in vitro , 2007, Oncogene.

[18]  P. Stadler,et al.  RNA Maps Reveal New RNA Classes and a Possible Function for Pervasive Transcription , 2007, Science.

[19]  David L. Spector,et al.  3′ End Processing of a Long Nuclear-Retained Noncoding RNA Yields a tRNA-like Cytoplasmic RNA , 2008, Cell.

[20]  E. Heard,et al.  Combined immunofluorescence, RNA fluorescent in situ hybridization, and DNA fluorescent in situ hybridization to study chromatin changes, transcriptional activity, nuclear organization, and X-chromosome inactivation. , 2008, Methods in molecular biology.

[21]  G. Calin,et al.  Cancer-associated genomic regions (CAGRs) and noncoding RNAs: bioinformatics and therapeutic implications , 2008, Mammalian Genome.

[22]  Yingying Lian,et al.  Role of human noncoding RNAs in the control of tumorigenesis , 2009, Proceedings of the National Academy of Sciences.

[23]  E. Sontheimer,et al.  Origins and Mechanisms of miRNAs and siRNAs , 2009, Cell.

[24]  M. Daidone,et al.  miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. , 2009, Cancer research.

[25]  S. Hsu,et al.  Metastasis associated lung adenocarcinoma transcript 1 is up-regulated in placenta previa increta/percreta and strongly associated with trophoblast-like cell invasion in vitro. , 2009, Molecular human reproduction.

[26]  Gang Wang,et al.  Regulation of proto-oncogene transcription, cell proliferation, and tumorigenesis in mice by PSF protein and a VL30 noncoding RNA , 2009, Proceedings of the National Academy of Sciences.

[27]  G. Tsongalis,et al.  MicroRNAs: novel biomarkers for human cancer. , 2009, Clinical chemistry.

[28]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[29]  Jiajia Wang,et al.  Inhibition of metastasis-associated lung adenocarcinoma transcript 1 in CaSki human cervical cancer cells suppresses cell proliferation and invasion. , 2010, Acta biochimica et biophysica Sinica.

[30]  Frederick P. Roth,et al.  Identification of Neuronal RNA Targets of TDP-43-containing Ribonucleoprotein Complexes , 2010, The Journal of Biological Chemistry.

[31]  B. Blencowe,et al.  The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. , 2010, Molecular cell.

[32]  Changanamkandath Rajesh,et al.  The splicing-factor related protein SFPQ/PSF interacts with RAD51D and is necessary for homology-directed repair and sister chromatid cohesion , 2010, Nucleic Acids Res..

[33]  Min-hui Yang,et al.  MALAT-1: a long non-coding RNA and its important 3' end functional motif in colorectal cancer metastasis. , 2011, International journal of oncology.

[34]  F. Zhang,et al.  Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation , 2012, Medical Oncology.

[35]  A. Watson,et al.  Colon Cancer: A Civilization Disorder , 2011, Digestive Diseases.

[36]  S. Koschmieder,et al.  The Long Noncoding MALAT-1 RNA Indicates a Poor Prognosis in Non-small Cell Lung Cancer and Induces Migration and Tumor Growth , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[37]  Yiran Huang,et al.  Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition. , 2012, Molecular bioSystems.

[38]  Jianlin Ren,et al.  Resveratrol Inhibits Invasion and Metastasis of Colorectal Cancer Cells via MALAT1 Mediated Wnt/β-Catenin Signal Pathway , 2013, PloS one.

[39]  D. Spector,et al.  The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. , 2013, Cancer research.

[40]  S. Diederichs,et al.  MALAT1 — a paradigm for long noncoding RNA function in cancer , 2013, Journal of Molecular Medicine.