siRNA-mediated inhibition of hTERT enhances chemosensitivity of hepatocellular carcinoma

Guo, Xianling; Wang, Weifen; Zhou, Feng; Lu, Zhenghua; Fang, Ruifang; Jia, Fengqi; Bu, Xinxin; Li, Rong; Zhang, Baihe; Wu, Meng-Chao; Wei, Lixin

doi:10.4161/cbt.7.10.6539

Cited by 28 publications

(13 citation statements)

References 12 publications

(15 reference statements)

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“…Importantly, hepatocytes have been reported to tolerate telomere dysfunctions [37], reinforcing the tumorigenic impact of alcohol-, HBV-, and HCV-associated telomere damage in exposed individuals. Targeting telomerase is becoming a promising approach for the treatment of HCC [38-40] and our present results also support such an approach for treating the main causes of this disease. In contrast, our results suggest that targeting the cause-specific deregulation of telomere protective factors might be of interest in the prevention or the treatment of cirrhosis and HCC.…”

Section: Resultssupporting

confidence: 81%

Cause-specific telomere factors deregulation in hepatocellular carcinoma

Idrissi

Hervieu

Merle

et al. 2013

J Exp Clin Cancer Res

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BackgroundAmong the numerous genetic defects associated with hepatocarcinogenesis, telomere abnormalities appear to play a role both in tumor promotion and maintenance. Telomeres, the chromosome extremities, are protected by specific proteins, the shelterin complex and by additional factors. Besides telomerase dysregulation, expression changes of these telomere factors have been observed in cancers.MethodsHere, we tested the hypothesis that such dysregulation might occur in hepatocellular carcinoma (HCC) with specific patterns depending on the cause of HCC. We compared telomere length, telomerase activity (TA), hTERT and telomere genes expression using PCR and Western-blot analyses between non-cirrhotic liver, peritumoral cirrhotic tissue (40 samples) and cancerous tissue (40 samples) derived from 40 patients with HBV-, HCV-, or alcohol-related HCC.ResultsAlterations in TA, hTERT expression and telomere length between non-cirrhotic, cirrhotic, and tumor samples were not significantly influenced by the cause of HCC. In contrast, the expression pattern of hTR, shelterin, and non-shelterin telomere protective factors clearly distinguished the 3 causes of cirrhosis and HCC. For patients with HBV diseased liver, when compared with non-cirrhotic liver, the cirrhotic tissue underexpressed all shelterin and all but HMRE11A and RAD50 non-shelterin telomere factors. For HCV the expression level of POT1, RAP1, Ku80, and RAD50 was higher in cirrhotic than in non-cirrhotic liver samples without evidence for significant transcriptional change for the remaining genes. For alcohol-related liver diseases, the expression level of POT1, RAP1, TIN2, hMRE11A, hMRE11B, Ku70, Ku80, RAD50, TANK1, and PINX1 was higher in cirrhotic than in non-cirrhotic liver samples. For the 3 causes of HCC, there was no significant change in shelterin and non-shelterin gene expression between cirrhosis and HCC samples.ConclusionsThese results validate our hypotheses and demonstrate that cirrhosis and HCC add-up numerous telomere dysfunctions including numerous cause-specific changes that appear to occur early during the course of the disease.

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Section: Resultssupporting

confidence: 81%

Cause-specific telomere factors deregulation in hepatocellular carcinoma

Idrissi

Hervieu

Merle

et al. 2013

J Exp Clin Cancer Res

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“…Previous work supporting this research showed that downregulating hTERT using siRNA-mediated inhibition enhanced chemosensitivity in hepatocellular carcinoma cells in vitro (Guo et al, 2008). Furthermore, Kanzawa et al (2003) have demonstrated that knockdown of hTERT chemosensitized U87-MG cells toward TMZ.…”

Section: Discussionmentioning

confidence: 72%

Silencing DNA Methyltransferase (DNMT) Enhances Glioma Chemosensitivity

Shervington

Patel

2008

Oligonucleotides

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Previously, we demonstrated that demethylation with 5-Aza-2'-deoxycytidine (5azadC) resulted in reduced levels of telomerase that led to telomere shortening, enhanced MGMT expression and enhanced chemosensitivity. Although the results were encouraging, the fact that 5azadC is highly toxic and nonspecific, thus is not favored as a therapeutic molecule. The aim of this research is to downregulate the DNA methyltransferase (DNMT1) gene using three sets of double-stranded RNA oligos designed to align different regions of DNMT1 sequence. Results showed the small-interfering RNA (siRNA) 1 and 3 demonstrated significant levels of silencing DNMT1 and hTERT transcription after 24-hour treatment (p = 0.01) and approximately 90% and 70% transcriptional downregulation of DNMT1 and hTERT, respectively after 48 hours. However, siRNA 2 downregulated DNMT1, hTERT, and MGMT in GOS-3 and U87-MG cells that was attributed to sequence homology between oligo 2 and MGMT complementary DNA. The siRNA-treated glioma cell lines GOS-3 and U87-MG were subjected to two chemotherapeutic agents; taxol and Temozolomide (TMZ). Results suggest that either a combination of siRNA 1 or 3 followed by taxol (2-6 muM) after 48 hours or a combination of siRNA 1 or 3 followed by TMZ (600-1000 microM) after 24 hours would be novel and effective glioma therapies.

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“…2 and Table 2). The role of telomerase in tumorigenesis is well-established in many types of cancer, and high telomerase activity is linked to high tumor malignancy [18] and chemo-resistence [19], [20], [21]. The activation of telomerase is tightly regulated at the transcriptional level, with several studies indicating that TERT transcription is the rate-limiting step in telomerase expression [22].…”

Section: Discussionmentioning

confidence: 99%

TERT Promoter Mutations Lead to High Transcriptional Activity under Hypoxia and Temozolomide Treatment and Predict Poor Prognosis in Gliomas

et al. 2014

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ObjectiveThis study explored the effects of telomerase reverse transcriptase (TERT) promoter mutations on transcriptional activity of the TERT gene under hypoxic and temozolomide (TMZ) treatment conditions, and investigated the status and prognostic value of these mutations in gliomas.MethodsThe effect of TERT promoter mutations on the transcriptional activity of the TERT gene under hypoxic and TMZ treatment conditions was investigated in glioma cells using the luciferase assay. TERT promoter mutations were detected in 101 glioma samples (grades I–IV) and 49 other brain tumors by sequencing. TERT mRNA expression in gliomas was examined by real-time PCR. Hazard ratios from survival analysis of glioma patients were determined relative to the presence of TERT promoter mutations.ResultsMutations in the TERT promoter enhanced gene transcription even under hypoxic and TMZ treatment conditions, inducing upregulation of TERT mRNA expression. Mutations were detected in gliomas, but not in meningiomas, pituitary adenomas, cavernomas, intracranial metastases, normal brain tissues, or peripheral blood of glioma patients. Patients with TERT promoter mutations had lower survival rates, even after adjusting for other known or potential risk factors, and the incidence of mutation was correlated with patient age.Conclusion TERT promoter mutations were specific to gliomas. TERT promoter mutations maintained its ability of inducing high transcriptional activity even under hypoxic and TMZ treatment conditions, and the presence of mutations was associated with poor prognosis in glioma patients. These findings demonstrate that TERT promoter mutations are novel prognostic markers for gliomas that can inform prospective therapeutic strategies.

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siRNA-mediated inhibition of hTERT enhances chemosensitivity of hepatocellular carcinoma

Cited by 28 publications

References 12 publications

Cause-specific telomere factors deregulation in hepatocellular carcinoma

Cause-specific telomere factors deregulation in hepatocellular carcinoma

Silencing DNA Methyltransferase (DNMT) Enhances Glioma Chemosensitivity

TERT Promoter Mutations Lead to High Transcriptional Activity under Hypoxia and Temozolomide Treatment and Predict Poor Prognosis in Gliomas

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