Abstract
Metastases cause recurrence and mortality for patients with colorectal carcinomas (CRC). In present study, we evaluated heterogeneity on drug resistance and its underlying mechanism between metastatic and primary CRC. Immunohistochemical results from clinical tissue microarray (TMA) suggested that the expression concordance rates of cancer stem cells (CSCs) and drug resistance relative proteins between lymph-node metastatic and primary CRC foci were low. The apoptotic and proliferation indexes in metastasis CRC specimens were decreased compared with primary. In vitro experimental results indicated that the migration and invasion abilities were upregulated in metastatic cells SW620 compared with primary cells SW480, the cellular efflux ability and WNT/β-catenin activity were also upregulated in SW620 cells. After 5-fluorouracil (5-Fu) treatment, the reduction in the proportion of cell apoptosis, CD133 and TERT expression levels in SW620 were lower than that in SW480 cells. Bioinformatics analysis in whole-genome transcriptional profiling results between metastatic and primary CRC cells suggested that differentially expressed genes were mainly centered on well-characterized signaling pathways including WNT/β-catenin, cell cycle and cell junction. Collectively, heterogeneity of drug resistant was present between metastatic and primary CRC specimens and cell lines, the abnormal activation of WNT/β-catenin signaling pathway could be a potential molecular leading to drug resistant ability enhancing in metastatic CRC cells.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies in the world
We found that the ability of drug resistant in metastatic cells SW620 was greater than primary colorectal cancer cells SW480 owing to cancer stem cells and drug resistance relative proteins activation, which partially reconfirmed by the clinical tissue microarray (TMA) immunohistochemical staining (IHC) assay
The expression level of EpCAM (Membrane), E-cadherin, MRP, CD133 and Cyclin D1 were significantly upregulated in primary CRC foci compared with the corresponding lymph-node metastatic foci, whereas CD44v6 was downregulated in primary CRC foci (Figure 1A and 1B, p < 0.05)
Summary
Colorectal cancer (CRC) is one of the most common malignancies in the world. 25% to 50% of colorectal cancer patients develop metastatic disease [1]. Once metastasis has occurred in CRC, a complete cure of the disease is unlikely. Colorectal liver metastasis (CLM), occurring in about 20% of CRC patients during the course of their treatment, is the most common distant metastasis from CRC [2, 3]. The phenotype of human CRC cells mainly depends on the interaction of genetic and environmental factors. Numerous researches have pointed out that the heterogeneity was formed during and after the process of epithelial-mesenchymal transition (EMT) in CRC cells [3,4,5]. Thiruvengadam and colleagues reported that Zeb-1 and other regulators of EMT maintain drug resistance in human pancreatic cancer cells [6]. The process of EMT leads to great increases in the number of self-renewing cells that can initiate the seeding of mammospheres, which raises the possibility for achieving EMT process, at the same time, may impart selfrenewal and multidrug resistance capabilities to metastatic cancer cells [7]
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