MicroRNA Expression in KRAS- and BRAF-mutated Colorectal Cancers.

BACKGROUND/AIM KRAS and BRAF are two genes commonly mutated in colorectal cancer (CRC). Even though BRAF is a downstream target of KRAS in the MAPK signalling pathway, KRAS- and BRAF-mutated CRCs are found to display several different clinical and histopathological features. We investigated whether a differential expression of microRNAs (miRNAs) could explain the clinicopathological differences seen between KRAS- and BRAF-mutated CRCs. MATERIALS AND METHODS Using a PCR array, we analyzed the expression of 84 different miRNAs in CRC cell lines wild-type in KRAS and BRAF, or mutated in KRAS or BRAF. RESULTS Ten miRNAs were selected for further analyses in tumor tissue specimens (let-7a, let-7i, miR-10a, miR-10b, miR-31, miR-100, miR-181a, miR-181b, miR-372, and miR-373). BRAF-mutated tumors were found to express significantly higher levels of miR-31 as well as significantly lower levels of miR-373, compared to wild-type tumors. CONCLUSION Our results suggest that KRAS- and BRAF-mutated CRCs may have different miRNA signatures compared to CRC tumors wild-type in KRAS and BRAF. However, no difference in expression levels between KRAS- and BRAF-mutated tumors was evident for the miRNAs analyzed in this study.

[1]  Jingyuan Fang,et al.  The Structure and Clinical Roles of MicroRNA in Colorectal Cancer , 2016, Gastroenterology research and practice.

[2]  Shung-Haur Yang,et al.  Mutation spectra of RAS gene family in colorectal cancer. , 2016, American journal of surgery.

[3]  F. Sinicrope,et al.  Molecular Biomarkers in the Personalized Treatment of Colorectal Cancer. , 2016, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[4]  Y. Choi,et al.  MicroRNA Expression Signatures Associated With BRAF-Mutated Versus KRAS-Mutated Colorectal Cancers , 2016, Medicine.

[5]  R. Wolff,et al.  Colorectal tumor molecular phenotype and miRNA: expression profiles and prognosis , 2016, Modern Pathology.

[6]  G. Storm,et al.  MicroRNA Targeting to Modulate Tumor Microenvironment , 2016, Front. Oncol..

[7]  T. Hu,et al.  Association of a let-7 KRAS rs712 polymorphism with the risk of breast cancer. , 2015, Genetics and molecular research : GMR.

[8]  J. Chen,et al.  Multiple Roles of MicroRNA-100 in Human Cancer and its Therapeutic Potential , 2015, Cellular Physiology and Biochemistry.

[9]  R. Palmqvist,et al.  The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer , 2015, The journal of pathology. Clinical research.

[10]  Chuanhua Cao,et al.  Diverse functions of miR-373 in cancer , 2015, Journal of Translational Medicine.

[11]  Xiao-jun Liu,et al.  MicroRNA-100 functions as a tumor suppressor by inhibiting Lgr5 expression in colon cancer cells. , 2015, Molecular medicine reports.

[12]  Zhaoxia Wang,et al.  Potential role of miR-100 in cancer diagnosis, prognosis, and therapy , 2015, Tumor Biology.

[13]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[14]  Tao Xi,et al.  miR-31 promotes proliferation of colon cancer cells by targeting E2F2 , 2015, Biotechnology Letters.

[15]  Hiromu Suzuki,et al.  MicroRNA‐31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions , 2014, International journal of cancer.

[16]  F. Kisseljov MicroRNAs and cancer , 2014, Molecular Biology.

[17]  Hiromu Suzuki,et al.  Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway. , 2014, Carcinogenesis.

[18]  Shuang Wang,et al.  Elevated MicroRNA-31 Expression Regulates Colorectal Cancer Progression by Repressing Its Target Gene SATB2 , 2013, PloS one.

[19]  Reiko Nishihara,et al.  Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. , 2013, Journal of the National Cancer Institute.

[20]  R. Palmqvist,et al.  The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer , 2013, British Journal of Cancer.

[21]  Aung Ko Win,et al.  KRAS-mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers , 2013, British Journal of Cancer.

[22]  Albert C. Koong,et al.  BRAF-mutated, Microsatellite-stable Adenocarcinoma of the Proximal Colon: An Aggressive Adenocarcinoma With Poor Survival, Mucinous Differentiation, and Adverse Morphologic Features , 2012, The American journal of surgical pathology.

[23]  A. Duval,et al.  MiRNA Genes Constitute New Targets for Microsatellite Instability in Colorectal Cancer , 2012, PloS one.

[24]  O. Yokosuka,et al.  Epigenetic silencing of microRNA-373 plays an important role in regulating cell proliferation in colon cancer. , 2011, Oncology reports.

[25]  E. Van Cutsem,et al.  Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  R. Palmqvist,et al.  Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor , 2011, Modern Pathology.

[27]  R. Wolff,et al.  MicroRNAs and colon and rectal cancer: Differential expression by tumor location and subtype , 2011, Genes, chromosomes & cancer.

[28]  A. Krasinskas EGFR Signaling in Colorectal Carcinoma , 2011, Pathology research international.

[29]  R. Palmqvist,et al.  The Role of the CpG Island Methylator Phenotype in Colorectal Cancer Prognosis Depends on Microsatellite Instability Screening Status , 2010, Clinical Cancer Research.

[30]  J. Neumann,et al.  Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. , 2009, Pathology, research and practice.

[31]  J. Barrett,et al.  KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  Jian-ming Li,et al.  Down‐regulated expression of SATB2 is associated with metastasis and poor prognosis in colorectal cancer , 2009, The Journal of pathology.

[33]  C. Croce,et al.  Pathogenetic and clinical relevance of microRNAs in colorectal cancer. , 2009, Cancer genomics & proteomics.

[34]  V. Heinemann,et al.  Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. , 2009, Cancer treatment reviews.

[35]  M. Loda,et al.  CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. , 2006, The Journal of molecular diagnostics : JMD.

[36]  P. Laird,et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer , 2006, Nature Genetics.

[37]  S. Kakar,et al.  BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non‐mucinous colorectal cancer , 2006, International journal of cancer.

[38]  Y. Akao,et al.  let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. , 2006, Biological & pharmaceutical bulletin.

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

[40]  V. Ambros The functions of animal microRNAs , 2004, Nature.

[41]  Armando Santoro,et al.  Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. , 2004, The New England journal of medicine.

[42]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

[43]  R. Palmqvist,et al.  SOX 2 Expression Is Regulated by BRAF and Contributes to Poor Patient Prognosis in Colorectal Cancer , 2017 .

[44]  M. Kretz,et al.  Non-coding RNAs: Classification, Biology and Functioning. , 2016, Advances in experimental medicine and biology.

[45]  A. Adjei,et al.  The Ras/Raf/MAPK pathway. , 2006, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[46]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[47]  B. Vogelstein,et al.  Prevalence of ras gene mutations in human colorectal cancers , 1987, Nature.