LincRNA-p21 enhances the sensitivity of radiotherapy for human colorectal cancer by targeting the Wnt/β-catenin signaling pathway.

Recent studies show that long intergenic noncoding RNA-p21 (lincRNA-p21) is aberrantly expressed in several types of cancer, including colorectal cancer (CRC), one of the most common cancers in the world. Radiotherapy is considered as a standard preoperative treatment approach to reduce local recurrence for local advanced rectal cancer. However, a considerable number of rectal cancers are resistant to radiotherapy. In the present study, we evaluated the role of lincRNA‑p21 in radiotherapy for CRC and detected the possible molecular mechanism. By expression profile analysis, we demonstrated that lincRNA-p21 decreases in CRC cell lines and tissue samples, which contributes to the elevation of β-catenin in CRC. We further showed that lincRNA‑p21 increases following X-ray treatment, and enforced expression of the lincRNA enhances the sensitivity of radiotherapy for CRC by promoting cell apoptosis. Suppression of the β-catenin signaling pathway and elevation of the pro-apoptosis gene Noxa expression may help explain the role of lincRNA-p21 in CRC radiotherapy. The present study not only deepens our understanding of the mechanism of radiotherapy for CRC, but it also provides a potential target for CRC radiotherapy.

[1]  S. Akira,et al.  Integral role of Noxa in p53-mediated apoptotic response. , 2003, Genes & development.

[2]  Rainer Fietkau,et al.  Preoperative versus postoperative chemoradiotherapy for rectal cancer. , 2004, The New England journal of medicine.

[3]  Shuhan Sun,et al.  Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients' poor recurrence‐free survival after hepatectomy , 2012, Hepatology.

[4]  John S. Mattick,et al.  lncRNAdb: a reference database for long noncoding RNAs , 2010, Nucleic Acids Res..

[5]  A. Harris,et al.  Phase I/II Trial of Bevacizumab and Radiotherapy for Locally Advanced Inoperable Colorectal Cancer: Vasculature-Independent Radiosensitizing Effect of Bevacizumab , 2009, Clinical Cancer Research.

[6]  Thomas D. Schmittgen,et al.  Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. , 2007, Cancer cell.

[7]  P. Casali,et al.  Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  M. K. Doeberitz,et al.  Reduction of β-Catenin/T-Cell Transcription Factor Signaling by Aspirin and Indomethacin Is Caused by an Increased Stabilization of Phosphorylated β-Catenin , 2003 .

[9]  Jiayi Wang,et al.  CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer , 2010, Nucleic acids research.

[10]  N. Tran,et al.  Regulation of apoptosis by a prostate-specific and prostate cancer-associated noncoding gene, PCGEM1. , 2006, DNA and cell biology.

[11]  Y. Samuels,et al.  Oncogenic mutations of PIK3CA in human cancers. , 2004, Current topics in microbiology and immunology.

[12]  Xiang Du,et al.  The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine , 2013, Modern Pathology.

[13]  M. Tretiakova,et al.  The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. , 2006, Cancer research.

[14]  S. Meltzer,et al.  Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma. , 2013, Gastroenterology.

[15]  Kazuhiko Hayashi,et al.  Systematic analysis of microRNA expression of RNA extracted from fresh frozen and formalin-fixed paraffin-embedded samples. , 2007, RNA.

[16]  J. Rinn,et al.  A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response , 2010, Cell.

[17]  C. Croce,et al.  Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma , 2010, Proceedings of the National Academy of Sciences.

[18]  S T Pals,et al.  Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines , 2004, British Journal of Cancer.

[19]  J. Merchant Inflammation, atrophy, gastric cancer: connecting the molecular dots. , 2005, Gastroenterology.

[20]  O. Kranenburg,et al.  Synergistic killing of colorectal cancer cells by oxaliplatin and ABT-737 , 2011, Cellular Oncology.

[21]  Y. Shimada,et al.  Unique Characteristics of Radiation-Induced Apoptosis in the Postnatally Developing Small Intestine and Colon of Mice , 2009, Radiation research.

[22]  Carolyn J. Brown,et al.  The functional role of long non-coding RNA in human carcinomas , 2011, Molecular Cancer.

[23]  O. Fodstad,et al.  Clinical significance of long intergenic noncoding RNA-p21 in colorectal cancer. , 2013, Clinical colorectal cancer.

[24]  B. He,et al.  Berberine inhibits the proliferation of colon cancer cells by inactivating Wnt/β-catenin signaling. , 2012, International journal of oncology.

[25]  M. Bordonaro Crosstalk between Wnt Signaling and RNA Processing in Colorectal Cancer , 2013, Journal of Cancer.

[26]  H. Dinh,et al.  Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth. , 2011, Cancer research.

[27]  P. Calabresi,et al.  The Brain Cytoplasmic RNA BC1 Regulates Dopamine D2 Receptor-Mediated Transmission in the Striatum , 2007, The Journal of Neuroscience.

[28]  J. Goodrich,et al.  Non-coding-RNA regulators of RNA polymerase II transcription , 2006, Nature Reviews Molecular Cell Biology.

[29]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[30]  B. Mao,et al.  Henryin, an ent-kaurane Diterpenoid, Inhibits Wnt Signaling through Interference with β-Catenin/TCF4 Interaction in Colorectal Cancer Cells , 2013, PloS one.

[31]  F. Pauler,et al.  The Air noncoding RNA: an imprinted cis-silencing transcript. , 2004, Cold Spring Harbor symposia on quantitative biology.

[32]  R. Costa,et al.  Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. , 2006, Cancer research.

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

[34]  R. Bright-Thomas,et al.  APC, β-Catenin and hTCF-4; an unholy trinity in the genesis of colorectal cancer , 2003 .

[35]  T. Hsia,et al.  Gallic acid induces apoptosis via caspase-3 and mitochondrion-dependent pathways in vitro and suppresses lung xenograft tumor growth in vivo. , 2009, Journal of agricultural and food chemistry.

[36]  A. G. de Herreros,et al.  A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. , 2008, Genes & development.

[37]  Sergio Verjovski-Almeida,et al.  Long noncoding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer , 2011, Molecular Cancer.

[38]  Qizhi Yao,et al.  Expression and Function of a Large Non-coding RNA Gene XIST in Human Cancer , 2011, World Journal of Surgery.

[39]  Feng Yang,et al.  Long noncoding RNA CCAT1, which could be activated by c-Myc, promotes the progression of gastric carcinoma , 2013, Journal of Cancer Research and Clinical Oncology.

[40]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

[41]  Kotb Abdelmohsen,et al.  LincRNA-p21 suppresses target mRNA translation. , 2012, Molecular cell.

[42]  T. Beißbarth,et al.  Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy. , 2011, Carcinogenesis.

[43]  T. Khor,et al.  A comparative study of the expression of Wnt-1, WISP-1, survivin and cyclin-D1 in colorectal carcinoma , 2006, International Journal of Colorectal Disease.

[44]  Jisheng Han,et al.  Electroacupuncture frequency‐related transcriptional response in rat arcuate nucleus revealed region‐distinctive changes in response to low‐ and high‐frequency electroacupuncture , 2012, Journal of neuroscience research.

[45]  U. Gezer,et al.  Differential expression of long non-coding RNAs during genotoxic stress-induced apoptosis in HeLa and MCF-7 cells , 2013, Clinical and Experimental Medicine.

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

[47]  S. Batalov,et al.  Antisense Transcription in the Mammalian Transcriptome , 2005, Science.