Significant overexpression of Hsp110 gene during colorectal cancer progression.

Colorectal cancer (CRC) is one of the most frequent malignant diseases in the world. Metastatic spread of the cancer to the lymph nodes is a crucial factor for progression and therapeutic management of the disease. We analysed gene expression profiles of CRC patiens by low-density cancer-focused oligonucleotide microarrays to identify new predictive markers of the extent of the disease and for better understanding of CRC progression. Relative expression levels of 440 genes known to be involved in cancer biology were obtained by low-density oligonucleotide microarrays from 20 tumor samples. Statistical analysis of gene expression data identified 3 genes (HSP110, HYOU1 and TCTP) significantly up-regulated in primary tumors of patients who developed lymph node metastasis. We have shown, for the first time, that up-regulation HSP110 and HYOU1 expression is associated with lymph node involvement in CRC. We validated the differences in HSP110 expression in an independent group of 30 patients of all clinical stages by real-time PCR. We identified significant up-regulation of HSP110 expression in colorectal tumors compared to adjacent non-tumoral tissue (p<0.0003). We observed significant differences of HSP110 gene expression between metastatic and localized disease (p=0.031) and negative trend of HSP110 gene expression and overall survival of CRC patients. We suggest that HSP110 gene is a promising molecular predictor in CRC.

[Gene expression profiling in prediction of tumor response to neoadjuvant concomitant chemoradiotherapy in patients with locally advanced rectal carcinoma: pilot study]. / Vyuzitie profilov génovej expresie k stanoveniu odpovedi k neoadjuvantnej konkomitantnej chemorádioterapii u pacientov s karcinómom rekta: pilotná stúdia.

BACKGROUND: Neoadjuvant concomitant chemoradiotherapy has become a standard treatment of locally advanced rectal adenocarcinomas (LARA). It can reduce tumor volume, thus increases a feasibility of sphincter-sparing surgery, shows less acute toxicity, improves local control rate. It is based on fluoropyrimidines (5-fluorouracil, capecitabine) with concurrent radiotherapy. The aim of the study was to evaluate the capability of gene expression method to identify nonresponders (NR) pretherapeutically. METHODS AND RESULTS: 17 patients with LARA, clinical stage II, III according to IUCC were enrolled into our pilot study. Response to therapy was determined clinically by transrectal ultrasonography and CT/MRI before and after therapy and histopathologically by TRG (tumor regression grade) according to Mandard. Patients with TRG 1-2 were included to responders group (R) and patients with TRG 4-5 composed NR group. Gene expression levels of 440 genes were obtained by low-density oligonucleotide microarrays. Gene expression data analysis based on SAM (Significance Analysis of Microarrays) and t-test methods identified 8 genes (RB1, RBBP4, HYOUI, JUNB, MDM4, CANX, MMP2, TCF7L2) significantly upregulated in NR. CONCLUSIONS: Validation of identified changes on the mRNA level (Real-Time PCR) and on protein level (immunohistochemistry) is ongoing. We suggest that low-density oligonucleotide microarray technology could contribute to individualize the therapy of patients with LARA.

Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer.

OBJECTIVES: Development and metastases of colorectal cancer (CRC) are characterized by multiple genetic alterations. MicroRNAs (miRNAs) are endogenously expressed regulatory noncoding RNAs. Previous, mainly preclinical studies showed altered expression levels of several miRNAs in CRC. METHODS: In our study, the expression levels of miR-21, miR-31, miR-143 and miR-145 in 29 primary colorectal carcinomas and 6 non-tumor adjacent tissue specimens were examined by real-time polymerase chain reaction. miRNA expression levels were also correlated with commonly used clinicopath-ologic features of CRC. RESULTS: Expression levels of analyzed miRNAs significantly differed among tumors and adjacent non-tumor tissues: miR-21 (p = 0.0001) and miR-31 (p = 0.0006) were upregulated, and miR-143 (p = 0.011) and miR-145 (p = 0.003) were downregulated in tumors. For the first time, a high expression of miR-21 was associated with lymph node positivity (p = 0.025) and the development of distant metastases (p = 0.009) in CRC patients. Thus, expression of miR-21 correlated with CRC clinical stage (p = 0.032). Furthermore, tumors >50 mm in maximal tumor diameter were characterized by lower expression of miR-143 (p = 0.006) and miR-145 (p = 0.003). We found no correlation between analyzed miRNAs and serum levels of carcinoembryonic antigen. CONCLUSION: Our results suggest possible roles of miR-21, miR-31, miR-143 and miR-145 in CRC.