D 2009

Significance of microRNAs in predictive oncology: experimental and clinical observations in colorectal cancer, breast cancer and glioblastoma

SLABÝ, Ondřej, Marek SVOBODA, Pavel FABIAN, Milana ŠACHLOVÁ, Pavel FADRUS et. al.

Základní údaje

Originální název

Significance of microRNAs in predictive oncology: experimental and clinical observations in colorectal cancer, breast cancer and glioblastoma

Název česky

Significance of microRNAs in predictive oncology: experimental and clinical observations in colorectal cancer, breast cancer and glioblastoma

Autoři

Vydání

2009. vyd. Olomouc, Abstract Book of the The 5th Symposium & Workshop on Molecular Pathology and Histo(cyto)chemistry, od s. 22-22, 1 s. 2009

Nakladatel

The Czech Society of Pathologists CLS JEP

Další údaje

Jazyk

angličtina

Typ výsledku

Stať ve sborníku

Obor

30200 3.2 Clinical medicine

Stát vydavatele

Řecko

Utajení

není předmětem státního či obchodního tajemství

Organizační jednotka

Lékařská fakulta

ISBN

978-80-87327-07-4

Klíčová slova anglicky

microRNA; colorectal cancer; breast cancer; glioblastoma

Štítky

Příznaky

Mezinárodní význam
Změněno: 22. 6. 2009 16:14, prof. RNDr. Ondřej Slabý, Ph.D.

Anotace

ORIG CZ

V originále

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 .

Česky

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 .