Non-coding MicroRNAs hsa-let-7g and hsa-miR-181b are Associated with Chemoresponse to S-1 in Colon Cancer.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs (~22 nucleotides) that regulate gene expression at a post-transcriptional level via imperfect base pairing to the 3'-UTR of their target mRNAs. Previous studies from our group identified a number of deregulated miRNAs due to the loss of p53 tumor suppressor in colon cancer cell lines. To further investigate the in vivo biological significance of these miRNAs, the expressions of hsa-let-7g, hsa-miR-143, hsa-miR-145, hsa-miR-181b and hsa-miR-200c were investigated using formalin-fixed paraffin-embedded (FFPE) colon cancer specimens to evaluate the potential relationship with chemosensitivity and tumorigenesis. PATIENTS AND METHODS: Forty-six patients with recurrent or residual colon cancer lesions were treated with the 5-fluorouracil-based antimetabolite S-1. This includes twenty-one pairs of tumor and normal samples. Total RNAs were isolated and the expression level of each particular miRNA was quantified using real time qRT-PCR analysis. RESULTS: The expression levels of hsa-let-7g, hsa-miR-181b and hsa-miR-200c were over-expressed in tumor tissues compared to normal tissues. The expression levels of hsa-let-7g (p=0.03; Mann-Whitney test) and hsa-miR-181b (p=0.02; Mann-Whitney test) were strongly associated with clinical response to S-1. Although hsa-let-7g and hsa-miR-181b are strongly associated with patient's response to S-1 treatment, they are not significant prognostic factors for predicting survival. CONCLUSION: hsa-let-7g, hsa-miR-181b and hsa-miR-200c may be associated with tumorigenesis in colon cancer. In addition, hsa-let-7g and hsa-miR-181b may be potential indicators for chemoresponse to S-1 based chemotherapy.

[1]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[2]  L. Lim,et al.  An Abundant Class of Tiny RNAs with Probable Regulatory Roles in Caenorhabditis elegans , 2001, Science.

[3]  V. Ambros,et al.  An Extensive Class of Small RNAs in Caenorhabditis elegans , 2001, Science.

[4]  C. Heidelberger,et al.  Fluorinated Pyrimidines, A New Class of Tumour-Inhibitory Compounds , 1957, Nature.

[5]  P. Piedbois.  Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  M. Mann,et al.  miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. , 2002, Genes & development.

[7]  L. Augenlicht,et al.  Oncogenic Ras Promotes Butyrate-induced Apoptosis through Inhibition of Gelsolin Expression* , 2004, Journal of Biological Chemistry.

[8]  Yitzhak Pilpel,et al.  Differentially Regulated Micro-RNAs and Actively Translated Messenger RNA Transcripts by Tumor Suppressor p53 in Colon Cancer , 2006, Clinical Cancer Research.

[9]  Debabrata Banerjee,et al.  Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. , 2002, Biochimica et biophysica acta.

[10]  S. Groshen,et al.  Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  Jian-Fu Chen,et al.  The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation , 2006, Nature Genetics.

[12]  L. Augenlicht,et al.  Oncogenic Ras increases sensitivity of colon cancer cells to 5-FU-induced apoptosis , 2005, Oncogene.

[13]  J. Lindebjerg,et al.  Molecular factors of 5-fluorouracil metabolism in colorectal cancer: analysis of primary tumor and lymph node metastasis. , 2006, International journal of oncology.

[14]  K. McMasters,et al.  E2F-1 Gene Therapy Induces Apoptosis and Increases Chemosensitivity in Human Pancreatic Carcinoma Cells , 2002, Tumor Biology.

[15]  B. Reinhart,et al.  MicroRNAs in plants. , 2002, Genes & development.

[16]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[17]  B. Iacopetta,et al.  p53 Gene Mutation, Microsatellite Instability and Adjuvant Chemotherapy: Impact on Survival of 388 Patients with Dukes’ C Colon Carcinoma , 2000, Oncology.

[18]  K. Hirata,et al.  Phase II study of oral S‐1 for treatment of metastatic colorectal carcinoma , 2004, Cancer.

[19]  J. Uchida,et al.  Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats , 1996, Cancer Chemotherapy and Pharmacology.

[20]  T. Tuschl,et al.  New microRNAs from mouse and human. , 2003, RNA.

[21]  Bruce A. Hay,et al.  The Drosophila MicroRNA Mir-14 Suppresses Cell Death and Is Required for Normal Fat Metabolism , 2003, Current Biology.

[22]  R. Russell,et al.  bantam Encodes a Developmentally Regulated microRNA that Controls Cell Proliferation and Regulates the Proapoptotic Gene hid in Drosophila , 2003, Cell.

[23]  Michael E. Greenberg,et al.  A brain-specific microRNA regulates dendritic spine development , 2006, Nature.

[24]  P. Schöffski.  The modulated oral fluoropyrimidine prodrug S-1, and its use in gastrointestinal cancer and other solid tumors. , 2004, Anti-cancer drugs.

[25]  K. Sugimachi,et al.  Phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with metastatic colorectal carcinoma , 2000, British Journal of Cancer.

[26]  K. Sugimachi,et al.  Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. , 2000, British journal of cancer.

[27]  U. McDermott,et al.  Molecular and biochemical markers in colorectal cancer. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[28]  T. Taguchi,et al.  [New oral anticancer drug, TS-1 (S-1)--from bench to clinic]. , 2001, Gan to kagaku ryoho. Cancer & chemotherapy.

[29]  M. Buyse,et al.  Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  Michael Z Michael,et al.  Reduced accumulation of specific microRNAs in colorectal neoplasia. , 2003, Molecular cancer research : MCR.

[31]  P. Catalano,et al.  c-myc/p53 interaction determines sensitivity of human colon carcinoma cells to 5-fluorouracil in vitro and in vivo. , 2001, Cancer research.

[32]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[33]  M. Dictor,et al.  Cyclin D1 overexpression versus response to induction chemotherapy in squamous cell carcinoma of the head and neck--preliminary report. , 2001, Acta oncologica.

[34]  T. Tuschl,et al.  Identification of Novel Genes Coding for Small Expressed RNAs , 2001, Science.

[35]  J. Wanders,et al.  EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer , 2003, British Journal of Cancer.

[36]  T. Tuschl,et al.  Identification of Tissue-Specific MicroRNAs from Mouse , 2002, Current Biology.

[37]  J. Ajani,et al.  Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  B. Reinhart,et al.  The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans , 2000, Nature.

[39]  M. O’connell.  Current status of adjuvant therapy for colorectal cancer. , 2004, Oncology.