Activation of telomerase by seminal plasma in malignant and normal cervical epithelial cells

Liu, Li; Liu, Cheng; Lou, Fenglan; Zhang, Guiyu; Wang, Xizhi; Fan, Yi‐Ming; Kou, Yan; Wang, Kun; Xu, Zhonghua; Hu, Sanyuan; Björkholm, Magnus; Xu, Dawei

doi:10.1002/path.2914

Cited by 13 publications

(10 citation statements)

References 49 publications

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“…We found that HeLa cell xenografts in mice administered SP grew at an accelerated rate resulting in tumours of approximately twice the size and weight compared with controls. These observations are similar to those of Liu and colleagues, who recently showed that HeLa cells pre-treated with seminal plasma and engrafted into nude mice grew at an accelerated rate compared with control cells [47]. We investigated whether the increase in tumour growth was due to cellular proliferation of the engrafted HeLa cells.…”

Section: Discussionsupporting

confidence: 85%

Seminal Plasma Enhances Cervical Adenocarcinoma Cell Proliferation and Tumour Growth In Vivo

et al. 2012

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Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A(VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.

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Section: Discussionsupporting

confidence: 85%

Seminal Plasma Enhances Cervical Adenocarcinoma Cell Proliferation and Tumour Growth In Vivo

et al. 2012

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“…55 293T cells transfected with different plasmids were cross-linked by incubating them in 1% (vol/vol) formaldehyde-containing medium for 10 mins at 37 1C and then sonicated to make soluble chromatin. The antibodies against flag (Sigma-Aldrich) and GFP (Santa Cruz Biotechnology) were used to precipitate DNA fragments bound by their corresponding elements.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

Telomerase reverse transcriptase promotes epithelial–mesenchymal transition and stem cell-like traits in cancer cells

et al. 2012

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Telomerase activation through induction of telomerase reverse transcriptase (hTERT) contributes to malignant transformation by stabilizing telomeres. Clinical studies demonstrate that higher hTERT expression is associated with cancer progression and poor outcomes, but the underlying mechanism is unclear. Because epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are key factors in cancer metastasis and relapse, and hTERT has been shown to exhibit multiple biological activities independently of its telomere-lengthening function, we address a potential role of hTERT in EMT and CSCs using gastric cancer (GC) as a model. hTERT overexpression promotes, whereas its inhibition suppresses, EMT and stemness of GC cells, respectively. Transforming growth factor (TGF)-β1 and β-catenin-mediated EMT was abolished by small interfering RNA depletion of hTERT expression. hTERT interacts with β-catenin, enhances its nuclear localization and transcriptional activity, and occupies the β-catenin target vimentin promoter. All these hTERT effects were independent of its telomere-lengthening function or telomerase activity. hTERT and EMT marker expression correlates positively in GC samples. Mouse experiments demonstrate the in vivo stimulation of hTERT on cancer cell colonization. Collectively, hTERT stimulates EMT and induces stemness of cancer cells, thereby promoting cancer metastasis and recurrence. Thus, targeting hTERT may prevent cancer progression by inhibiting EMT and CSCs.

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“…COX2 was found to activate hTERT transcription in our previous study (Liu et al , 2011). To see whether hTERT affects COX2 expression, we knocked down hTERT in gastric and cervical cancer cells using siRNA oligos specifically targeting hTERT mRNA.…”

Section: Resultsmentioning

confidence: 61%

“…To address these issues, we sought to explore the potential association or synergistic effects between hTERT and other known oncogenic factors, as seen in its interplay with β -catenin. We have previously shown that cyclooxygenase 2 (COX2), a prostaglandin-producing enzyme involved in the pathogenesis and progression of various types of human cancer (Crawford et al , 2004; Nardone et al , 2004; Wang and Dubois, 2004; Sobolewski et al , 2010; Wu et al , 2010; Adhim et al , 2011; Khan et al , 2011), activates telomerase by upregulating hTERT expression in both normal and cancerous epithelial cells (Liu et al , 2011). Thus, we asked whether hTERT and COX2 affect each other positively in the present study.…”

mentioning

confidence: 99%

Telomerase reverse transcriptase inhibition stimulates cyclooxygenase 2 expression in cancer cells and synergizes with celecoxib to exert anti-cancer effects

Liu

Liang

et al. 2013

Br J Cancer

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Background:Telomerase and telomerase reverse transcriptase (hTERT) confer cancer cells sustained proliferation and survival potentials. Targeting telomerase or hTERT is a novel anti-cancer strategy. However, telomerase/hTERT inhibition alone has minimal clinical efficacy. We explored the relationship between hTERT and cyclooxygenase 2 (COX2) and evaluated synergistic anti-cancer effects of targeting both hTERT and COX2.Methods:hTERT was depleted in gastric and cervical cancer cells using small interfering RNA (siRNA) and analysed for COX2 expression using quantitative PCR and immunoblotting. Viable cells and apoptotic cells in gastric cancer cells treated with hTERT siRNA or/and the COX2 inhibitor celecoxib were measured using Trypen blue exclusion and flow cytometry. The in vivo anti-cancer effect of hTERT depletion or/and celecoxib was evaluated using mouse xenograft models.Results:Knocking down hTERT expression in cancer cells led to robust increases in mRNA and protein levels of COX2. The COX2 promoter activity increased substantially in hTERT-depleted cells. hTERT depletion led to the activation of p38 mitogen-activated protein kinase responsible for the stimulation of COX2 gene transcription. hTERT depletion or celecoxib alone did not affect cancer cell survival, whereas their combination synergistically killed them both in vitro and in vivo.Conclusion:hTERT induces COX2 expression and simultaneously targeting hTERT and COX2 synergistically kills cancer cells.

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Activation of telomerase by seminal plasma in malignant and normal cervical epithelial cells

Cited by 13 publications

References 49 publications

Seminal Plasma Enhances Cervical Adenocarcinoma Cell Proliferation and Tumour Growth In Vivo

Seminal Plasma Enhances Cervical Adenocarcinoma Cell Proliferation and Tumour Growth In Vivo

Telomerase reverse transcriptase promotes epithelial–mesenchymal transition and stem cell-like traits in cancer cells

Telomerase reverse transcriptase inhibition stimulates cyclooxygenase 2 expression in cancer cells and synergizes with celecoxib to exert anti-cancer effects

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