Significant overexpression of Hsp110 gene during colorectal cancer progression

Abstract

Abstract. 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 lowdensity 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. IntroductionColorectal cancer (CRC) is one of the most frequent malignant diseases in the world. With the incidence rate ~78 per 100,000 people, the Czech Republic is a country with one of the highest incidence of CRC in the world and the highest in Europe (1). The prognosis of these patients depends largely on the extent of the disease and a possibility of curative surgical intervention which is feasible only in patients with disease limited to the primary tumor and regional lymph nodes. Spread of the cancer to lymph nodes has been considered a crucial factor for progression and further therapeutic management of the disease. While in the case of clinical stage I and IV, the prognostic significance of the TNM classification is evident, for the group of patients diagnosed at stages II (without dissemination to regional lymph nodes) and III (with dissemination to lymph nodes) the prognostic information of clinical stage is much lower. The fact, that 30% of patients with clinical stage II of CRC will progress within five years and only 45% of the patients with clinical stage III will reach a 5-year survival, although undergoing radical surgery, implies that recent staging of CRC based on TNM classification is not optimal and failed for a significant proportion of non-advanced CRC patients. This situation is caused by two factors: firstly, understaging of regional lymph node status for the reason of insufficient number of resected and/or examined lymph nodes, secondly, the TNM classification does not include biological characteristics and predictors of tumor behaviour. Multicentric studies ba...

A Novel Regulatory Mechanism of Pim-3 Kinase Stability and Its Involvement in Pancreatic Cancer Progression

“…TCTP was overexpressed in many human cancer tissues including liver (42), colorectal (43), prostate (44), breast (45), and lung cancer (46). Similarly, TCTP was detected in pancreatic cancer cell lines, and malignant duct epithelial cells and some normal acinar cells but not normal pancreatic duct epithelial cells adjacent to tumor foci.…”

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

“…Only a few previous studies, which were conducted with small colorectal cancer sample sizes, reported that HSP110 overexpression was associated with worse overall survival, advanced stage and nodal metastasis in colorectal cancer. 36,37 In these circumstances, the study by Dorard et al 25 provided important clues about the effect of HSP110 mutations on colorectal cancer. It is reasonable that the increased expression of mutant HSP110 inhibits the normal functions of HSP, which are beneficial to cancer cell survival; therefore, this molecular alteration can result in positive effects on survival in patients with cancer.…”

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

“…TCTP protein levels are upregulated in cancer cells and in human tumours (Tuynder et al, 2004;Kim et al, 2008a;Ma et al, 2009;Slaby et al, 2009). Downregulation of TCTP has been implicated in biological models of tumour reversion (Tuynder et al, 2002(Tuynder et al, , 2004, and the protein is the target of various anticancer drugs (Tuynder et al, 2004;Efferth, 2005), of which one has entered a phase-I/II clinical trial (Telerman and Amson, 2009).…”