Abstract
In molecular-targeted cancer therapy, acquired resistance to gemcitabine is a major clinical problem that reduces its effectiveness, resulting in recurrence and metastasis of cancers. In spite of great efforts to reveal the overall mechanism of acquired gemcitabine resistance, no definitive genetic factors have been identified that are absolutely responsible for the resistance process. Therefore, we performed a cross-platform meta-analysis of three publically available microarray datasets for cancer cell lines with acquired gemcitabine resistance, using the R-based RankProd algorithm, and were able to identify a total of 158 differentially expressed genes (DEGs; 76 up- and 82 down-regulated) that are potentially involved in acquired resistance to gemcitabine. Indeed, the top 20 up- and down-regulated DEGs are largely associated with a common process of carcinogenesis in many cells. For the top 50 up- and down-regulated DEGs, we conducted integrated analyses of a gene regulatory network, a gene co-expression network, and a protein-protein interaction network. The identified DEGs were functionally enriched via Gene Ontology hierarchy and Kyoto Encyclopedia of Genes and Genomes pathway analyses. By systemic combinational analysis of the three molecular networks, we could condense the total number of DEGs to final seven genes. Notably, GJA1, LEF1, and CCND2 were contained within the lists of the top 20 up- or down-regulated DEGs. Our study represents a comprehensive overview of the gene expression patterns associated with acquired gemcitabine resistance and theoretical support for further clinical therapeutic studies.
Highlights
There have been innumerable clinical trials over the last few decades related to the prevention, detection, and treatment of cancer, acquired drug resistance remains an inevitable obstacle to successful chemotherapy in various types of cancer, causing treatment failure in over 90% of patients with metastatic cancer (Szakacs et al, 2006; Saraswathy and Gong, 2013)
According to the most well known reported studies, acquired drug resistance in cancer cells could be caused by three major mechanisms, as follows: (i) decreased uptake of watersoluble drugs which require membrane transporters to enter cancer cells, (ii) various changes in cancer cells that affect the capacity of cytotoxic drugs to kill them, including alterations in the cell cycle, increased repair of DNA damage, reduced apoptosis, and altered metabolism of drugs, and (iii) increased energy-dependent efflux of hydrophobic drugs
Diagnosed without treatment Newly diagnosed with treatment Persistence or recurrence Remission None Chemotherapy Radiotherapy Concurrent chemoradiation the top 20 up- and down-regulated differentially expressed genes (DEGs) was constructed by mapping them into massive database of BIOGRID
Summary
There have been innumerable clinical trials over the last few decades related to the prevention, detection, and treatment of cancer, acquired drug resistance remains an inevitable obstacle to successful chemotherapy in various types of cancer, causing treatment failure in over 90% of patients with metastatic cancer (Szakacs et al, 2006; Saraswathy and Gong, 2013). Several mechanisms of acquired gemcitabine resistance (AGR) in cancers have been reported; these are anatomical (e.g., desmoplasia, epithelial-mesenchymal transition (EMT), and inherent cancer stem cell resistance), pathophysiological (e.g., abnormal tumor growth, tumor angiogenesis, altered cancer cell survival, and anti-apoptosis), or pharmacological (e.g., the necessity of phosphorylation for prodrug activation) (Nakano et al, 2007; Toschi and Cappuzzo, 2009; Tufman and Huber, 2010; Hung et al, 2012; de Sousa Cavalcante and Monteiro, 2014) None of these mechanisms was confirmed as the etiology of AGR, and the fundamental reason for-and exact process of-AGR is still being studied, in many different ways. We are the first to perform a cross-platform meta-analysis of the gene expression profiles associated with AGR in different cancer cell lines
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