Abstract
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.
Highlights
Human telomerase reverse transcriptase (TERT), a catalytic subunit of telomerase, plays a critical role in the pathology of aging and cancer by maintaining genome integrity and controlling cell proliferation [1]
We examined TERT promoter mutations in 316 cases of primary hepatocellular carcinoma (HCC) that consisted of non-clear cell HCC (NCCHCC) (n = 259) and CCHCC (n = 57)
The multivariate analysis confirmed that older age (P = 0.006), advanced Barcelona Clinic Liver Cancer (BCLC) stage (P = 0.032), and patients without cirrhosis history (P = 0.027) were independent factors associated with TERT promoter mutations (Supplementary Table 3)
Summary
Human telomerase reverse transcriptase (TERT), a catalytic subunit of telomerase, plays a critical role in the pathology of aging and cancer by maintaining genome integrity and controlling cell proliferation [1]. It is reported that in the precancerous liver cirrhosis, telomere shortening concomitant with a weak positive TERT signal in the nucleus is observed. Several studies identify recurrent somatic mutations in TERT promoter in various cancers, including liver cancer [4,5,6,7]. In addition to canonical telomeric-DNA synthesis activity, telomere-independent functions of telomerase can be performed within the nucleus as well as in other cellular compartments [10]. Cytoplasmic TERT is once dismissed as non-specific staining and non-functional protein. Recent studies confirm the non-nuclear locations of TERT, such as the cytoplasm and mitochondria [11].
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