Telomerase inhibition by an siRNA directed against hTERT leads to telomere attrition in HT29 cells

Nascimento, Patrícia de Souza; Alves, Gilda; Fiedler, Wolfgang

doi:10.3892/or.16.2.423

Cited by 26 publications

(24 citation statements)

References 26 publications

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“…Growth evidence has demonstrated that inhibiting telomerase; especially hTERT, by genetic, antisense RNAi is a highly promising for cancer therapy as already demonstrated in several cancer cell lines (15)(16)(17)(18). Zhang et al transfected a plasmid encoding hTERT-specific shRNAs into human hepatocellular carcinoma cell lines and found that they could stably suppress hTERT expression, which led to the inhibition of cell proliferation and to an attenuated tumorigenic potency (19).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of hTERT by siRNA inhibits cervical cancer cell growth in vitro and in vivo

Shi

Zhao

Zhang

et al. 2014

International Journal of Oncology

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Abstract. Human telomerase reverse transcriptase (hTERT)is the catalytic component of telomerase that facilitates tumor cell invasion and proliferation. It has been reported that telomerase and hTERT are significantly upregulated in majority of cancers including cervical cancer, thus, downregulation of hTERT is a promising target in malignant tumor treatment. We established a short interfering RNA (siRNA) targeting hTERT, and transfected it into HeLa cells (a cervical cancer cell line) to investi gate the effect of cell proliferation, apoptosis, migration and invasion in cervical cancer cells. The results showed that siRNA targeting hTERT could effectively knock down hTERT expression, remarkably suppress telomerase activity, cell proliferation, migration and invasion, and induced cell apoptosis of cervical cancers cells in vitro. In addition, we evaluated whether siRNA targeting hTERT affects tumor growth in nude mice, and found that it dramatically inhibited tumorigenesis and growth of mice injected with siRNA targeting hTERT. Furthermore, we also found that knockdown of hTERT was able to significantly suppress constitutive phosphorylation of Akt, PI3K, which might imply that reduction of hTERT inhibited tumor growth via the PI3K/ Akt signaling pathway to some extent. These results suggest that the suppression of hTERT expression by siRNA inhibits cervical cancer cell growth in vitro and in vivo, and may provide a novel target for anticancer gene therapy. IntroductionCervical cancer is caused by a multistep process that involves transformation of the normal cervical epithelium to a preneoplastic cervical intraepithelial neoplasia that is subsequently transformed to invasive cervical cancer (1,2). The incidence and mortality of invasive cervical cancer have steadily decreased (3), and cervical cancer remains the third most common cancer in women worldwide (4) and the leading malignancy in developing countries, accounting for 83% of all cancer cases (5). Although well organized screening and early therapeutic schedules have been carried out, the occurrence of invasive cervical cancer remains high in developing areas (6). Furthermore, as the understanding of key cellular pathways involved in tumor growth has improved, molecular targeted therapies have been widely exploited. Therefore, the development of new therapeutic strategies bases on molecular targeted therapies is necessary to improve survival in patients with cervical cancer.Telomerase plays a key role in conferring immortality to cancer cells through regulation of telomere length (7,8). It synthesizes the telomeric repeats at the ends of chromosomes and replaces the progressively lost end sequences during each cell cycle, allowing cells to escape mortality and continue to proliferate. The reverse transcriptase telomerase is composed of two core components: a ubiquitously expressed RNA component (hTR), and a catalytic subunit human telomerase reverse transcriptase (hTERT) which expression is limited to the formation of a catalytically active enzyme (9) and ...

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Section: Introductionmentioning

confidence: 99%

Knockdown of hTERT by siRNA inhibits cervical cancer cell growth in vitro and in vivo

Shi

Zhao

Zhang

et al. 2014

International Journal of Oncology

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“…RNA interference (RNAi ) is a novel gene therapy technology (16,17) in which 21-25 nucleotide small interfering RNA (siRNA) duplexes, homologous to the silenced gene, function as sequence-specific RNAi mediators, suppressing the expression of the target gene. siRNA synthesis in vitro is the latest development in RNAi; however, the poor stability and specificity of siRNA in vivo restricts its use (18).…”

Section: Introductionmentioning

confidence: 99%

Chemically modified siRNA directed against the KDR gene inhibits the proliferation of breast cancer cells

Zhang¹,

Zhang²,

Hou³

et al. 2008

Mol Med Rep

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Abstract. Vascular endothelial growth factor receptor-2 or kinase insert domain-containing receptor (VEGFR2/KDR) is secreted by most solid tumors, including breast cancer, and is an important mediator of angiogenesis. To observe the effects of KDR gene expression on cell proliferation and the cell cycle in MCF-7 cells in vitro and in vivo, we used chemically modified siRNA directed against KDR. The results revealed that chemically modified siRNA transfection of the KDR gene effectively inhibited the proliferation of MCF-7 cells, arrested cells in the G1 phase and down-regulated the expression of KDR. In addition, in the progression of cell cycle arrest induced by siRNA, phosphorylated ERK and CDK1 expression was down-regulated (P<0.01). In vivo, the growth of tumors was visibly suppressed. RT-PCR and the results of immunohistochemistry indicated that KDR mRNA and protein expression was reduced in the excised tumors. In contrast, there were no obvious changes in the control groups. This implies that chemically modified KDR siRNA markedly decreases KDR gene expression and inhibits cellular proliferation in vitro, as well as suppressing tumor growth in a xenograft model. KDR may be a new target for breast cancer treatment. IntroductionAngiogenesis is a complex process that is essential for tumor growth beyond 1 or 2 mm 3 . Kinase insert domain-containing receptor (KDR), commonly known as VEGFR2, is one of the best characterized pro-angiogenic factors, playing a critical role in physiological and pathological angiogenesis (1). Via its interaction with VEGF, KDR mediates many key components of angiogenesis, including endothelial cell proliferation, invasion, migration and survival, as well as vessel permeability.It also plays an important role in the regulation of tumor genesis and development (2-4). In addition to activating KDR on vessels in a paracrine manner, VEGF secreted by tumor cells also activates KDR on itself in an autocrine manner, and directly promotes the growth of tumor cells (5-10). Therefore, by inhibiting the expression of KDR, tumor growth can be suppressed on two levels.With one million new cases presenting each year, breast cancer is the most common cancer among women and the leading cause of death worldwide in those between the ages of 30 and 70 years (11,12). In human breast cancer, levels of KDR have been correlated with tumor progression and invasion (13). KDR and VEGF are co-expressed in primary breast carcinomas, and their expression is increased when tumors shift to an angiogenic phenotype (14,15). Many investigators are beginning to advocate silencing the gene expression of angiogenic factors as an anti-angiogenic strategy.RNA interference (RNAi ) is a novel gene therapy technology (16,17) in which 21-25 nucleotide small interfering RNA (siRNA) duplexes, homologous to the silenced gene, function as sequence-specific RNAi mediators, suppressing the expression of the target gene. siRNA synthesis in vitro is the latest development in RNAi; however, the poor stability and specificity of siRNA...

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“…undergoing deleterious degradation and fusion events (9,10). A great number of studies manifest that cellular radiosensitivity is related to the cellular reproductive ability, so there should be some kind of intrinsic correlation between the telomere length and radiosensitivity (11)(12)(13). Our previous research also indicated that radiosensitivity is negatively correlated with telomere length, the longer the telomere length, the lower the radiosensitivity (8).…”

Section: Discussionmentioning

confidence: 90%

Increased expression of telomere-related proteins correlates with resistance to radiation in human laryngeal cancer cell lines

Tang

Zhou²,

Han³

et al. 2009

Oncol Rep

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Abstract.Telomere-associated proteins function as survival factors in telomere maintenance, which are major contributors to radiosensitivity in human cancers. The aim of this study was to investigate the association of telomere-associated gene expression and radiation resistance in human larynx squamous carcinoma. The changes of telomere-associated gene expressions and bionomical characteristics that occur in two human larynx squamous carcinoma cell lines (Hep-2 and Hep-2R), with different radiosensitivities in vitro were explored in the present study. Based on previous research, elevated POT1 and TPP1 expressions were detected by reverse transcription-PCR and Western blotting in Hep-2R cell lines. Furthermore, Hep-2R cells showed increased recovery ratio accompanied by a reduction of cell arrested in G2/S phase, suggesting that the radioresistance of Hep-2R cells was due to a faster growth in which telomere length had recently been demonstrated to be a powerful prognostic marker. These results manifest that radioresistant Hep-2R cell lines showed certain changes in gene expression and bionomical profiles that are different from the profile changes of the moresensitive Hep-2 cell lines, and that evaluation of telomereassociated genes may be a prognostic marker for response to radiotherapy in larynx squamous cell carcinoma (LSCC).

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Telomerase inhibition by an siRNA directed against hTERT leads to telomere attrition in HT29 cells

Cited by 26 publications

References 26 publications

Knockdown of hTERT by siRNA inhibits cervical cancer cell growth in vitro and in vivo

Knockdown of hTERT by siRNA inhibits cervical cancer cell growth in vitro and in vivo

Chemically modified siRNA directed against the KDR gene inhibits the proliferation of breast cancer cells

Increased expression of telomere-related proteins correlates with resistance to radiation in human laryngeal cancer cell lines

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