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* Corresponding author 1 LBMC - Laboratoire de Biologie Moléculaire de la Cellule 2 Service Central d-Anatomie et Cytologie Pathologiques 3 Service d-Hépatologie et de Gastroentérologie 4 CRCL - Centre de Recherche en Cancérologie de Lyon 5 Service d-Hématologie

Abstract : BACKGROUND: Among 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. METHODS: Here, 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. RESULTS: Alterations 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. CONCLUSIONS: These 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.

Keywords : Liver Hepatocellular carcinoma Telomere Telomerase Shelterin Hepatitis B virus Hepatitis C virus Alcohol Cirrhosis





Autor: Manale El Idrissi - Valérie Hervieu - Philippe Merle - Franck Mortreux - Eric Wattel -

Fuente: https://hal.archives-ouvertes.fr/



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