Downregulation of ABC Transporters in Non-neoplastic Tissues Confers Better Prognosis for Pancreatic and Colorectal Cancer Patients

Abstract

Transport of a wide variety of substrates, including xenobiotics, is one of the main functions attributed to human ATP-binding cassette (ABC) proteins. Overexpression of ABC genes is considered to be an important mechanism facilitating the development of chemoresistance. Relationships between the expression levels of ABC genes in tumor tissues and established clinicopathological features were extensively studied previously. The current study tested our hypothesis that the expression levels of ABC genes in non-neoplastic (control) tissues also provide important information in relation to the relevant tumor progression. Expression levels of all human ABC genes (48 protein coding and one pseudogene), measured by qRT-PCR, were bioinformatically analyzed. The data originated from four independently collected cohorts covering three types of tumors -breast, colorectal and pancreatic carcinomas. ABC gene expression profiles (signatures) in non-neoplastic tissues (matched to tumor samples from three different tumor types) were characteristically clustered into three main types -those with the vast majority of the genes downregulated, upregulated or heterogeneously regulated. The clusters with mostly downregulated and upregulated genes were shown to possess significant relations to good and poor prognostic markers, respectively, in pancreatic and colorectal cancers. The present findings support the theory that the expression of ABC genes in non-neoplastic tissues can significantly contribute to tumor pathogenesis. Suggested multi-gene panels, consisting of the reduced number of ABC genes, have the potential to be implemented as new prognostic markers, which are especially urgent in pancreatic cancer. The results can also stimulate further primary research in carcinogenesis.

Identification and Verification of Core Genes in Colorectal Cancer

“…Eight ABC transporter subfamilies have been identified based on transporter homology and structural similarity [27]. A study suggested that downregulation of ABC transporters in nonneoplastic tissues may be associated with better prognoses for pancreatic cancer and colorectal cancer [28]. The common DEGs identified in our study were shown to be significantly involved in cancer-related functions and signaling pathways.…”

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

“…Biology 2020, 9, x FOR PEER REVIEW 4 of 38 the prognosis of colon cancer patients receiving 5-FU treatment with studies reporting both negative and positive correlations [20][21][22][23]. Nonetheless, incidence of 5-FU resistance is still consistently motivated by elevated levels of ABC transporters, that includes ABCB1 [P-glycoprotein (P-gp) or MDR1] [24,25]; ABCG2 [breast cancer resistance protein (BCRP)] [26,27]; ABCC1 [multidrug resistance-associated protein (MRP1)] [28,29]; ABCC3 [20], and ABCC2 [30].…”

ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward?

“…Following the analysis of 27 non-neoplastic pancreatic tissues and pairing them with 32 PDAC samples, 4 different clusters could be distinguished based on the gene expression profiles in cancer vs normal specimens. PN1 and PN2 clusters were characterized by upregulation of the majority of ABC transporters genes and correlated with significantly shorter patients’ overall survival (OS) than patients grouped into PN3 and PN4 clusters, in which significant downregulation of genes or heterogeneous gene expression has been observed[ 119 ]. Especially, ABCA2, ABCA4, ABCA5, ABCC2 and ABCD4 signatures showed significant difference in patients’ survival when comparison between upregulated and downregulated genes was carried out.…”