A transcriptomic approach reveals selective ribosomal remodelling in the tumour versus the stromal compartment of metastatic colorectal cancer

Because of its high incidence and poor prognosis, colorectal cancer (CRC) represents an important health issue in several countries. As with other carcinomas, the so-called tumour microenvironment (TME) has been shown to play key roles in CRC progression and related therapeutical outcomes, even though a deeper understanding of the underlying molecular mechanisms is needed to devise new treatment strategies. For some years now, omics technologies and consolidated bioinformatics pipelines have allowed scientists to access large amounts of biologically relevant information, even when starting from small tissue samples; thus, in order to shed new light upon the role of the TME in CRC, we compared the gene expression profiles of 6 independent tumour tissues (all progressed towards metastatic disease) to the expression profile of the surrounding stromata. To do this, paraffin-embedded whole tissues were first microdissected to obtain samples enriched with tumour and stromal cells, respectively. Afterwards, RNA was extracted and analysed using a microarray-based approach. A thorough bioinformatics analysis was then carried out to identify transcripts differentially expressed between the two groups and possibly enriched functional terms. Overall, 193 genes were found to be significantly downregulated in tumours compared to the paired stromata. The functional analysis of the downregulated gene list revealed three principal macro areas of interest: the extracellular matrix, cell migration, and angiogenesis. Conversely, among the upregulated genes, the main alterations detected by the functional annotation were related to the ribosomal proteins (rProteins) of both the large (60S) and small (40S) subunits of the cytosolic ribosomes. Subsequent gene set enrichment analysis (GSEA) confirmed the massive overexpression of most cytosolic—but not mitochondrial—ribosome rProteins

Herg1 gene and HERG1 protein are overespressed in colorectal cancers and regulate cell invasion of tumor cells

The acquisition of the capacity to invade surrounding tissues confers a more malignant phenotype to tumor cells and is necessary for the establishment of metastases. The understanding of the molecular mechanisms underlying cell invasion in human solid tumors such as colorectal cancers could provide not only more sensitive prognostic analyses but also novel molecular targets for cancer therapy.We report in this article that K+ ion channels belonging to the HERG family are important determinants for the acquisition of an invasive phenotype in colorectal cancers. The herg1 gene and HERG1 protein are expressed in many colon cancer cell lines, and the activity of HERG channels modulates colon cancer cell invasiveness. Moreover, the amount of HERG1 protein expressed on the plasma membrane is directly related to the invasive phenotype of colon cancer cells.Finally, both the herg1 gene and HERG1 protein were expressed in a high percentage of primary human colorectal cancers, with the highest incidence occurring in metastatic cancers, whereas no expression could be detected either in normal colonic mucosa or in adenomas

hERG1 Potassium Channel Expression in Colorectal Adenomas: Comparison with Other Preneoplastic Lesions of the Gastrointestinal Tract

Preneoplastic lesions represent a useful target for early diagnosis and follow-up of gastrointestinal malignancies. hERG1 channel expression was tested by immunohistochemistry (IHC) in a cohort of colorectal adenoma samples belonging to Italian subjects. Overall, hERG1 was expressed in 56.5% of cases with both high staining intensity and a high percentage of positive cells. Moreover, hERG1 was expressed in a higher percentage of dysplastic adenomas with respect to hyperplastic lesions, and the proportion of positive samples further increased in patients with high-grade dysplasia. Comparing hERG1 expression in other preneoplastic lesions of the GI tract (gastric dysplasia and Barrett’s esophagus), it emerged that in all the conditions, hERG1 was expressed with a diffused pattern, throughout the cell, with variable staining intensity within the samples. The highest expression was detected in gastric dysplasia samples and the lowest in Barrett’s esophagus at similar levels observed in colorectal adenomas. Our results show that hERG1 is aberrantly expressed in human preneoplastic lesions of the gastrointestinal tract and has a different pattern of expression and role in the different sites. Overall, the detection of hERG1 expression in preneoplastic lesions could represent a novel diagnostic or prognostic marker of progression in the gastrointestinal tract

The hERG1 potassium channel behaves as prognostic factor in gastric dysplasia endoscopic samples

Purpose: Gastric cancer (GC) is still a relevant health issue worldwide. The identification of prognostic factors for progression of gastric dysplasia (GD), the main pre-cancerous lesion of the intestinal-type GC, is hence mandatory.Patients and methods: A cohort of 83 GD endoscopic samples belonging to Italian subjects was collected. hERG1 expression was evaluated by immunohistochemistry and scored 0-3, depending on the percentage of stained cells. Expression data were analysed in conjunction with clinico-pathological and survival data.Results: hERG1 turned out to be expressed in 67.47% (56 out of 83) of the GD samples. hERG1 expression was higher in high-grade GD compared to low-grade GD (29 out of 39, 74.36% vs 27 out of 44, 61.36%), although the statistical significance was not reached (P=0.246). No association emerged between hERG1 expression and clinical features of the patients (age, gender, localization, H. pylori infection, gastritis and intestinal metaplasia). In a subset of cases for which sequential samples of gastric lesions (from GD to Early Gastric Cancer and Advanced Gastric Cancer) were available, hERG1 expression was maintained in all the steps of gastric carcinogenesis from GD onwards. A general trend to increased expression in advanced lesions was observed. hERG1 score had a statistically significant impact on both Progression-Free Survival (P=0.018) and Overall Survival (P=0.031). In particular, patients displaying a high hERG1 score have a shorter survival.Conclusion: hERG1 is aberrantly expressed in human GD samples and has an impact on both PFS and OS, hence representing a novel prognostic marker for progression of GD towards GC of the intestinal histotype. Once properly validated, hERG1 detection could be included in the clinical practice, during endoscopic surveillance protocols, for the management of GD at higher risk of progression, as already proposed for Barrett's oesophagus