Overexpression of E2F1 in human gastric carcinoma is involved in anti-cancer drug resistance

Abstract

BackgroundRoutine chemotherapy often cannot achieve good therapeutic effects because of multidrug resistance (MDR). MDR is frequently caused by the elevated expression of the MDR1 gene encoding P-glycoprotein (P-gp). E2F1 is a frequently overexpressed protein in human tumor cells that increases the activity of the MDR1 promoter, resulting in higher P-gp levels. The upregulation of P-gp might contribute to the survival of tumor cells during chemotherapy. E2F1 confers anticancer drug resistance; however, we speculate whether E2F1 affects MDR through other pathways. This study investigated the possible involvement of E2F1 in anticancer drug resistance of gastric carcinoma in vitro and in vivo.MethodsA cisplatin-resistant SGC7901/DDP gastric cancer cell line with stable overexpression of E2F1 was established. Protein expression levels of E2F1, MDR1, MRP, TAp73, GAX, ZEB1, and ZEB2 were detected by western blotting. The influence of overexpression of E2F1 on anticancer drug resistance was assessed by measuring IC50 of SGC7901/DDP cells to cisplatin, doxorubicin, and 5-fluorouracil, as well as the rate of doxorubicin efflux, apoptosis, and cell cycle progression detected by flow cytometry. We determined the in vivo effects of E2F1-overexpression on tumor size in nude mice, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining.ResultsThe SGC7901/DDP gastric cancer cell line stably overexpressing E2F1 exhibited significantly inhibited sensitivity to cisplatin, doxorubicin, and 5-fluorouracil. Flow cytometry confirmed that the percentage of apoptotic cells decreased after E2F1 upregulation, and that upregulation of E2F1 potentiated S phase arrest of the cell cycle. Furthermore, upregulation of E2F1 significantly decreased intracellular accumulation of doxorubicin. Western blot revealed that E2F1 upregulation suppressed expression of GAX, and increased the expression of MDR1, MRP, ZEB1, TAp73, and ZEB2.ConclusionsOverexpression of E2F1 promotes the development of MDR in gastric carcinoma, suggesting that E2F1 may represent an efficacious target for gastric cancer therapy.

Genome‐wide analysis of the oxyntic proliferative isthmus zone reveals ASPM as a possible gastric stem/progenitor cell marker over‐expressed in cancer

“…The partial overlap with proliferating cells could reflect distinct characteristics, fitting with the dynamic and heterogenic nature of the cancer stem cells pool within and between tumours . Additionally, aberrant expression of E2F1 is also relevant for gastric cancer, and we are the first to show increased E2F1 mRNA in GAs by genome‐wide analysis, together with increased E2F1 protein by IHC, as previously reported . Our results could imply an association between ASPM and the transcription factor E2F1 in gastric tissue, which is particularly relevant due to their common involvement in crucial cell fate‐regulatory mechanisms.…”

“…Of particular interest are the unique isthmus zone target genes in the top-scored E2F1 transcription factor network, which was also top-scored for the genes associated with stomach neoplasia. The relation of the E2F1 network to both stem cells [26,27] and gastric cancer [53][54][55][56] is relatively novel, and the network plays dichotomous roles in controlling counteracting functions, such as cell-cycle progression versus arrest, apoptosis versus survival and stemness versus differentiation, depending on context [26,44,45,53]. One of the genes in the E2F1 network, Aspm, was particularly intriguing, being a mitotic spindle pole component and already associated with controlling self-renewal and symmetrical cell division in neural stem/progenitor cells [35][36][37][38]40].…”

Direct interaction between miR-203 and ZEB2 suppresses epithelial–mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance

“…Knockdown of ZEB2 significantly increased lung adenocarcinoma cell sensitivity to DDP by suppressing Snail and N-cadherin, while inducing E-cadherin expression. This result was similar to a previous report that ZEB2 could promote gastric cancer resistance to DDP [33]. Taken together, these findings imply that miR-203 sensitizes lung cancer cells to DDP by directly targeting ZEB2-induced EMT signaling.…”

Deregulated E2F5/p38/SMAD3 Circuitry Reinforces the Pro-Tumorigenic Switch of TGFβ Signaling in Prostate Cancer

“…To explore the functional underpinning of E2F5 in prostate cancer, gene expression pattern of other E2F members, and close working partners was monitored. E2F1 and E2F3a did not show any remarkable differences in their expression pattern between benign hyperplastic and prostate cancer tissues though upregulated expressions of E2F1 and E2F3a in cancer have been reported (Li et al, ; Reimer et al, ; Yan et al, ; Zhang et al, ). On the other hand, E2F4 showed an anomalous pattern of expression in transcription and translation.…”