Reversal of Multidrug Resistance in Gastric Cancer Cells by E2F‐1 Downregulation In Vitro and In Vivo

Yan, Lihan; Wang, Xiaotong; Yang, Jie; Kong, Fan‐Biao; Lian, Chao; Wei, Weiyuan; Luo, Wen; Xie, Yubo; Xiao, Qiang

doi:10.1002/jcb.24652

Cited by 28 publications

(25 citation statements)

References 25 publications

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“…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.…”

Section: Discussionsupporting

confidence: 79%

“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Vange

Bruland

Beisvåg

et al. 2015

The Journal of Pathology

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The oxyntic proliferative isthmus zone contains the main stem/progenitor cells that provide for physiological renewal of the distinct mature cell lineages in the oxyntic epithelium of the stomach. These cells are also proposed to be the potential cells‐of‐origin of gastric cancer, although little is known about their molecular characteristics and specific biological markers are lacking. In this study, we developed a method for serial section‐navigated laser microdissection to isolate cells from the proliferative isthmus zone of rat gastric oxyntic mucosa for genome‐wide microarray gene expression analysis. Enrichment analysis showed a distinct gene expression profile for the isthmus zone, with genes regulating intracellular processes such as the cell cycle and ribosomal activity. The profile was also related to stem cell transcriptional networks and stomach neoplasia. Genes expressed uniquely in the isthmus zone were associated with E2F transcription factor 1 (E2F1), which participates in the self‐renewal of stem cells and in gastric carcinogenesis. One of the unique genes was Aspm [Asp (abnormal spindle) homologue, microcephaly‐associated (Drosophila)]. Here we show ASPM in single scattered epithelial cells located in the proliferative isthmus zone of rat, mouse and human oxyntic mucosa, which do not seem to be actively dividing. The ASPM‐expressing cells are mainly mature cell marker‐deficient, except for a limited overlap with cells with neuroendocrine and tuft cell features. Further, both ASPM and E2F1 were expressed in human gastric cancer cell lines and increased and correlated in human gastric adenocarcinomas compared to non‐tumour mucosa, as shown by expression profile analyses and immunohistochemistry. The association between ASPM and the transcription factor E2F1 in gastric tissue is relevant, due to their common involvement in crucial cell fate‐regulatory mechanisms. Our results thus introduce ASPM as a novel possible oxyntic stem/progenitor cell marker that may be involved in both normal gastric physiology and gastric carcinogenesis. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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

Vange

Bruland

Beisvåg

et al. 2015

The Journal of Pathology

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“…Another well-documented mechanism underlying CDDP resistance in cancer cells is the increased efflux of CDDP by the ABC transporter protein family, including MDR1/ABCB1 (P-glycoprotein), MRP1/ABCC1 and BCRP/ABCG2 (20,29). However, we failed to detect the dysregulated expression of these genes in CDDP-resistant cells following pretreatment with ZOL.…”

Section: A B a Bcontrasting

confidence: 60%

“…The expression of several important genes associated with drug resistant was determined by western blotting. Since the mitochondrial apoptotic pathway has previously been associated with the sensitivity of cancer cells to CDDP (20,21), the expression statuses of BCL-2, BAX and caspase-9 were also evaluated in the present study. As shown in Fig.…”

Section: Zol Pretreatment Increases S-phase Arrest and Cell Apoptosismentioning

confidence: 99%

Zoledronic acid reverses cisplatin resistance in nasopharyngeal carcinoma cells by activating the mitochondrial apoptotic pathway

You

Chen

et al. 2017

Oncology Letters

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Abstract. Despite improvements to radiotherapeutic strategies, resistance to adjuvant chemotherapy remains the main problem underlying the low 5-year survival rate in patients with nasopharyngeal carcinoma (NPC). In the present study, the human NPC cell line HNE1 was exposed to gradually increasing concentrations of cisplatin (CDDP) in order to establish a drug-resistant sub-cell line, HNE1/CDDP. HNE1/CDDP cells exhibited multidrug resistance and a prolonged doubling time, as compared with the parent HNE1 cells. Furthermore, pretreatment with zoledronic acid (ZOL) appeared to resensitize the CDDP-resistant cells by inducing S-phase cell cycle arrest and the mitochondrial apoptotic pathway by upregulating the expression of B-cell lymphoma-2 (BCL-2)-associated X protein and caspase-9 and downregulating the expression of BCL-2. The results of the present study suggested that HNE1/CDDP cells are a stable, multidrug-resistant NPC cell line that may serve as an important tool for research in drug resistance. In addition, the application of ZOL may hold clinical therapeutic potential for the treatment of drug resistance in NPC.

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“…A downstream target of EZH2 such as E-cadherin was increased with decrease in EZH2 which was also accompanied by a decrease in E2F-1 (31). E2F-1 has been reported in previous studies to play a role in multidrug resistance and negatively regulating cell proliferation when overexpressed (32). In our studies, we also observe increased expression of other histone marks associated with “active” gene expression regulations, such as H3K4me2 and H3K9me2.…”

Section: Discussionmentioning

confidence: 97%

Sunitinib Dose Escalation Overcomes Transient Resistance in Clear Cell Renal Cell Carcinoma and Is Associated with Epigenetic Modifications

Adelaiye

Ciamporcero

Miles

et al. 2015

Molecular Cancer Therapeutics

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Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib clinical efficacy, eventually patients develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDXs) were treated 5 days/week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected prior to dose increments for immunohistochemistry analyses and drug levels. Selected intra-patient sunitinib dose escalation was safe and several patients had added progression free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro anti-tumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention.

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Reversal of Multidrug Resistance in Gastric Cancer Cells by E2F‐1 Downregulation In Vitro and In Vivo

Abstract: E2F-1 may be involved in regulating multiple signaling pathways in reversing MDR, suggesting that E2F-1 may represent a novel target for gastric cancer therapy.

Cited by 28 publications

References 25 publications

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

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

Zoledronic acid reverses cisplatin resistance in nasopharyngeal carcinoma cells by activating the mitochondrial apoptotic pathway

Sunitinib Dose Escalation Overcomes Transient Resistance in Clear Cell Renal Cell Carcinoma and Is Associated with Epigenetic Modifications

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