LncRNA SPRY4-IT1 sponges miR-101-3p to promote proliferation and metastasis of bladder cancer cells through up-regulating EZH2.

Emerging evidences have indicated that long non-coding RNAs (LncRNAs) play vital roles in cancer development and progression. Previous studies have suggested that overexpression of SPRY4-IT1 predicates poor prognosis and promotes tumor progress in several cancers. However, the underlying mechanism of SPRY4-IT1 in bladder cancer remains unknown. In this study, we found that SPRY4-IT1 knockdown induced inhibition of cell proliferation, cell migration and invasion ability, and caused promotion of apoptosis in bladder cancer both in vitro and in vivo. Mechanistically, knockdown of SPRY4-IT1 increased the expression of miR-101-3p and subsequently inhibited the expression of EZH2 at posttranscriptional level. Importantly, SPRY4-IT1 could directly interact with miR-101-3p and down-regulation of miR-101-3p efficiently reversed the suppression of EZH2 induced by SPRY4-IT1 shRNA. Thus, SPRY4-IT1 positively regulated the expression of EZH2 through sponging miR-101-3p, and played an oncogenic role in bladder cancer progression. Together, our study elucidates the role of LncRNA SPRY4-IT1 as a miRNA sponge in bladder cancer, and sheds new light on LncRNA-directed diagnostics and therapeutics in bladder cancer.

[1]  David John,et al.  Screening and validation of lncRNAs and circRNAs as miRNA sponges , 2016, Briefings Bioinform..

[2]  M. Aftab,et al.  Long noncoding RNAs as putative biomarkers for prostate cancer detection. , 2014, The Journal of molecular diagnostics : JMD.

[3]  Rajvir Dahiya,et al.  Long Noncoding RNA MALAT1 Promotes Aggressive Renal Cell Carcinoma through Ezh2 and Interacts with miR-205. , 2015, Cancer research.

[4]  J. Rinn,et al.  Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer , 2016, Nature Communications.

[5]  D. Cacchiarelli,et al.  A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA , 2011, Cell.

[6]  E. Hatzimichael,et al.  Non‐coding RNAs and EZH2 interactions in cancer: Long and short tales from the transcriptome , 2013, International journal of cancer.

[7]  A. Jemal,et al.  Cancer statistics, 2013 , 2013, CA: a cancer journal for clinicians.

[8]  Ming Sun,et al.  Long non-coding RNA LINC01133 represses KLF2, P21 and E-cadherin transcription through binding with EZH2, LSD1 in non small cell lung cancer , 2016, Oncotarget.

[9]  S. Majumdar,et al.  Functional inhibition of Hsp70 by Pifithrin-μ switches Gambogic acid induced caspase dependent cell death to caspase independent cell death in human bladder cancer cells. , 2016, Biochimica et biophysica acta.

[10]  Howard Y. Chang,et al.  Genome regulation by long noncoding RNAs. , 2012, Annual review of biochemistry.

[11]  Y. Mo,et al.  The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage , 2012, Cell Research.

[12]  J. Mattick,et al.  The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. , 2011, Cancer research.

[13]  Wei Zhao,et al.  The Functional Characterization of Long Noncoding RNA SPRY4-IT1 in Human Melanoma Cells , 2014, Oncotarget.

[14]  Howard Y. Chang,et al.  Long noncoding RNAs and human disease. , 2011, Trends in cell biology.

[15]  Juan Li,et al.  The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by upregulating ZNF703 expression , 2015, Molecular Cancer.

[16]  Jie Cao,et al.  Long non-coding RNA SPRY4-IT1 pormotes colorectal cancer metastasis by regulate epithelial-mesenchymal transition , 2016, Oncotarget.

[17]  S. Sunkin,et al.  Specific expression of long noncoding RNAs in the mouse brain , 2008, Proceedings of the National Academy of Sciences.

[18]  Zhengyu Zhang,et al.  An emerging understanding of long noncoding RNAs in kidney cancer , 2014, Journal of Cancer Research and Clinical Oncology.

[19]  P. Pandolfi,et al.  A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? , 2011, Cell.

[20]  C. Mathers,et al.  Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 , 2010, International journal of cancer.

[21]  Xuefei Shi,et al.  Long non-coding RNAs: a new frontier in the study of human diseases. , 2013, Cancer letters.

[22]  Fuqing Zeng,et al.  Methyl jasmonate sensitizes human bladder cancer cells to gambogic acid‐induced apoptosis through down‐regulation of EZH2 expression by miR‐101 , 2014, British journal of pharmacology.

[23]  John N. Hutchinson,et al.  An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. , 2009, Molecular cell.

[24]  D. Spector,et al.  Long noncoding RNAs: functional surprises from the RNA world. , 2009, Genes & development.

[25]  Aungkana Krajarng,et al.  Apoptosis induction associated with the ER stress response through up-regulation of JNK in HeLa cells by gambogic acid , 2015, BMC Complementary and Alternative Medicine.

[26]  Zhi‐hua Liu,et al.  Long noncoding RNA SPRY4-IT1 is upregulated in esophageal squamous cell carcinoma and associated with poor prognosis , 2014, Tumor Biology.

[27]  S. Baltacı,et al.  Significance of second transurethral resection on patient outcomes in muscle-invasive bladder cancer patients treated with bladder-preserving multimodal therapy , 2016, World Journal of Urology.

[28]  Min Liu,et al.  Long non-coding RNA Unigene56159 promotes epithelial-mesenchymal transition by acting as a ceRNA of miR-140-5p in hepatocellular carcinoma cells. , 2016, Cancer letters.

[29]  A. Sandelin,et al.  Deep transcriptome profiling of mammalian stem cells supports a regulatory role for retrotransposons in pluripotency maintenance , 2014, Nature Genetics.

[30]  Paulo P. Amaral,et al.  MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. , 2009, Genome research.

[31]  C. Ponting,et al.  Evolution and Functions of Long Noncoding RNAs , 2009, Cell.

[32]  Nadav S. Bar,et al.  Landscape of transcription in human cells , 2012, Nature.

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

[34]  J. Hou,et al.  Increased expression of SPRY4-IT1 predicts poor prognosis and promotes tumor growth and metastasis in bladder cancer. , 2015, International journal of clinical and experimental pathology.

[35]  J. Mattick,et al.  Long non-coding RNAs: insights into functions , 2009, Nature Reviews Genetics.

[36]  Hui Li,et al.  Long non-coding RNA HOTAIR promotes tumor cell invasion and metastasis by recruiting EZH2 and repressing E-cadherin in oral squamous cell carcinoma. , 2015, International journal of oncology.

[37]  G. Luo,et al.  BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer , 2016, Molecular Cancer Therapeutics.

[38]  L. Collette,et al.  EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guérin. , 2016, European urology.

[39]  Subbaya Subramanian,et al.  Competing endogenous RNAs (ceRNAs): new entrants to the intricacies of gene regulation , 2014, Front. Genet..

[40]  George A Calin,et al.  Long noncoding RNA in prostate, bladder, and kidney cancer. , 2014, European urology.

[41]  R. Kong,et al.  EZH2-mediated epigenetic suppression of long noncoding RNA SPRY4-IT1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial–mesenchymal transition , 2014, Cell Death and Disease.

[42]  David G. Knowles,et al.  The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression , 2012, Genome research.