title: Stage-dependent differential expression of microRNAs in colorectal cancer: potential role as markers of metastatic disease.
abstract: MicroRNAs (miRs) are short non-coding RNAs that bind complementary sequences in mRNA resulting in translation repression and/or mRNA degradation. We investigated expression of the reported metastasis-associated miRs-335, 206, 135a, 146a, 146b, 10b, 21, let7a and let7b in normal mucosa, non-metastatic and metastatic colorectal cancer (CRC). Expression of target miRs in micro-dissected paraffin embedded tissues was evaluated in 15 primary tumours with adjacent normal tissue from patients that were disease-free at 4 years (cohort A) and 19 paired primary tumours with corresponding liver metastases (cohort B) by quantitative real-time PCR. Increased expression of miR-21, mir-135a and miR-335 was associated with clinical progression of CRC, while miR-206 demonstrated an opposite trend. The levels of mir-21 did not associate with the expression of PTEN, an important tumour suppressor in CRC and one of many putative targets of miR-21, but interestingly was associated with stage of disease in the PTEN expressing tumours. Surprisingly, let7a, a KRAS-targeting miR, showed elevated expression in metastatic disease compared to normal mucosa or non-metastatic disease, and only in KRAS mutation positive tumors. Finally, a prognostic signature of miR 21,135a, 335, 206 and let-7a for detecting the presence of metastases had a specificity of 87% and sensitivity of 76% for the presence of metastases. In summary, we have shown stage-associated differential expression of five out of nine tested metastasis-associated miRs. We have further found that an analysis of these five miRs expression levels in primary tumors significantly correlates with the presence of metastatic disease, making this a potential clinically useful prognostic tool.
authors: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors: Michael M
authors: MM
authors: Vickers
authors: Jair
authors: J
authors: Bar
authors: Ivan
authors: I
authors: Gorn-Hondermann
authors: Nirit
authors: N
authors: Yarom
authors: Manijeh
authors: M
authors: Daneshmand
authors: Jennifer E L
authors: JE
authors: Hanson
authors: Christina L
authors: CL
authors: Addison
authors: Timothy R
authors: TR
authors: Asmis
authors: Derek J
authors: DJ
authors: Jonker
authors: Jean
authors: J
authors: Maroun
authors: Ian A J
authors: IA
authors: Lorimer
authors: Glenwood D
authors: GD
authors: Goss
authors: Jim
authors: J
authors: Dimitroulakos
mesh_terms: D000368:Aged; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D035683:MicroRNAs