Promoter mutations and cellular distribution of telomerase in non-clear cell and clear cell hepatocellular carcinoma
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Wan Huang1,*, Weiping Zhou2,*, Can Li1,*, Yuan Yang2, Yu-Kui Shang1, Changsheng Chen3, Jing Zhang4, Rui Yao1, Pei Wang1, Wen Wen1, Han-Qiang Liu5, Ling Wang3, Xia Li4, Huijie Bian1, Zhi-Nan Chen1
1National Translational Science Center for Molecular Medicine, Department of Cell Biology, Fourth Military Medical University, Xi'an, China
2The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
3Department of Health Statistics, Fourth Military Medical University, Xi'an, China
4Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
5Department of Nutrition and Food Hygiene, Fourth Military Medical University, Xi'an, China
*Shared first authors
Zhi-Nan Chen, email: firstname.lastname@example.org
Huijie Bian, email: email@example.com
Keywords: telomerase, subcellular localization, mutation, non-clear cell hepatocellular carcinoma, clear cell hepatocellular carcinoma
Received: July 20, 2016 Accepted: February 07, 2017 Published: February 17, 2017
Reactivation of telomerase is a critical step in the development of hepatocellular carcinoma (HCC). Here we identified the frequency of mutations in telomerase reverse transcriptase (TERT) promoter was 34% in non-clear cell HCC (NCCHCC, n = 259) and 26.3% in clear cell HCC (CCHCC, n = 57). The mutations were independently associated with poor recurrence-free survival of HCCs. Interestingly immunohistochemical analysis demonstrated a higher positive rate of TERT cytoplasmic localization (95%) than nuclear localization (64%) in HCCs. In NCCHCCs, the mutations correlated with higher TERT nuclear expression and increased telomere-dependent telomerase activity. Higher cytoplasmic expression was found in adjacent tissues compared to tumor tissues, and was associated with tumor well-differentiation and lower level of α-fetoprotein. NCCHCCs with low nuclear as well as high cytoplasmic expression correlated with better prognosis. In CCHCCs, elevated TERT cytoplasmic expression was observed in CCHCCs harboring mutations. Higher TERT cytoplasmic expression was found in tumor tissues compared to adjacent tissues, and was associated with multiple numbers of tumors and poor prognosis of CCHCCs. In conclusion, mutations in TERT promoter disclose the significance of both nuclear and cytoplasmic TERT in HCC. Cytoplasmic TERT should also be considered when determining prognosis and treatment of HCCs.
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