Publication details
Significance of microRNAs in predictive oncology: experimental and clinical observations in colorectal cancer, breast cancer and glioblastoma
| Authors | |
|---|---|
| Year of publication | 2009 |
| Type | Article in Proceedings |
| Conference | Abstract Book of the The 5th Symposium & Workshop on Molecular Pathology and Histo(cyto)chemistry |
| MU Faculty or unit | |
| Citation | |
| Field | Oncology and hematology |
| Keywords | microRNA; colorectal cancer; breast cancer; glioblastoma |
| Description | MicroRNAs (miRNAs) are short (18-25 nucleotides in length) noncoding RNA molecules that post-transcriptionally regulate gene expression. Bioinformatic tools predict that miRNAs are able to regulate approximately one-third of mammalian genes, including a significant number of oncogenes, tumor suppressor genes and genes associated with the invasion, dissemination and chemoresistance of tumors. In our colorectal cancer study, we examined by real-time PCR expression levels of miR-21, miR-31, miR-143, miR-145 and let-7a-1 in bioptic samples of 35 colorectal cancer (CRC) patients including 5 cases of IUCC Stage I, 13 of Stage II, 8 of Stage III, 9 of Stage IV. For 6 cases of CRC samples also adjacent non-tumor tissue was analyzed. The expression levels of all tested miRNAs significantly differ in tumor and normal mucosa, miR-21 (p=0,0001) and miR-31 (p=0,0006) were up-regulated and miR-143 (p=0,013) and miR-145 (p=0,018) were down-regulated in tumors. miR-21 was also correlated with CRC stage. High expression of miR-21 was associated with lymph node positivity (p = 0,025), development of distant metastases (p = 0,009) and also with a poor survival (long-rank p=0,043) in CRC patients. Tumors with down-regulated miR-143 and miR-145 were bigger and more frequent (not significantly) in proximal CRC. In the case of glioblastoma, we examined the expression levels of miR-21, miR-221, miR-222, miR-181a-c, miR-125b and miR-128a in 22 primary glioblastomas and six specimens of adult brain tissue by Real-Time PCR method. In addition, we examined the methylation status of MGMT (O6-methylguanine-DNA methyltransferase) promoter by methylation-specific RT-PCR, as this has previously been shown to be a predictive marker in glioblastomas. MGMT status and microRNA expression levels were tested for any association with the patients response to concomitant chemoradiotherapy with temozolomide (RT/TMZ). MGMT methylation status was not correlated with age, gender, performance status, expression level of any microRNA analyzed and, most importantly, with response to RT/TMZ. Patients who responded to RT/TMZ tended to have lower expression levels of microRNA-181 family members than those with progressive disease. MiR-181b and miR-181c were significantly down-regulated in patients with a response to treatment (p=0,016; p=0,047, respectively) in comparison to patients with progressive disease. The "basal-like" mammary carcinomas occur in 15% of breast cancer with higher frequency in patients with altered BRCA1. Typical invasive "basal-like" carcinoma is characterized by triple negative phenotype (ER, PR and HER2 negative) and higher frequency of mutations in tumor suppressor p53. It seems probable, that alterations in the apoptotic p53-signaling pathways are one of the causal events in the pathogenesis of this molecular subtype of breast cancer. In our study of the "basal-like" mammary carcinoma we focused on the significance of miR-34a-c family known to be under direct transcriptional control of p53. Results of this study will be part of our presentation. This work was supported by grant IGA MZ NS 9814-4/2008, NR/9076 - 4 of the Czech Ministry of Health and Project No. MZ0MOU2005 of the Czech Ministry of Health . |