ETS1, nucleolar and non-nucleolar TERT expression in nevus to melanoma progression.

Jaskaren S Kohli,Victoria Akhras,Eduardo Nagore,Afsheen Wasif,Dorothy C Bennett,Rajiv Kumar,Heung Chong,Hira Mir

doi:10.18632/oncotarget.22254

Abstract

TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered TERT promoter mutations create binding sites for ETS-family transcription factors to upregulate TERT. ETS1 is reported to be important for TERT upregulation in melanoma. However it is unclear when in melanoma progression TERT and ETS1 proteins are expressed. To elucidate this question, ETS1 and TERT immunohistochemistry were performed on a panel of benign (n=27) and dysplastic nevi (n=34), radial growth phase (n=29), vertical growth phase (n=25) and metastatic melanomas (n=27). Lesions were scored by percentage of positive cells. ETS1 was readily detectable in all lesions, but not in normal melanocytes. TERT was located in either the nucleolus, the nucleoplasm (non-nucleolar) or both. Non-nucleolar TERT increased in prevalence with progression, from 19% of benign nevi to 78% of metastases. It did not however correlate with cell proliferation (Ki-67 immunostaining), nor differ significantly in prevalence between primary melanomas with or without a TERT promoter mutation. These results demonstrate that ETS1 is expressed very early in melanoma progression, and interestingly only non-nucleolar TERT correlates clearly in prevalence with melanoma progression. It can be acquired at various stages and by mechanisms other than promoter mutations.

Highlights

One of the proposed hallmarks of cancer cells is immortality: the ability to proliferate indefinitely by bypassing cell senescence [1]
Non-nucleolar TERT expression does not associate with TERT promoter mutation status in primary melanomas. Since prevalence of both non-nucleolar TERT and TERT promoter mutations correlate with melanoma progression, we investigated whether non-nucleolar TERT might be a marker for these mutations
This presence of ETS1 could allow TERT expression in a nevus cell acquiring an oncogenic TERT promoter mutation, since these mutations reportedly associate with increased TERT transcription and protein expression, in the presence of ETS-family factors [20, 35]

Summary

Introduction

One of the proposed hallmarks of cancer cells is immortality: the ability to proliferate indefinitely by bypassing cell senescence [1]. Cell senescence is a stable proliferative arrest following extensive cell division and telomere attrition, or other triggers including oncogene overexpression or genotoxic stresses [2]. TERT (telomerase reverse transcriptase), the catalytic component of telomerase, is transcriptionally repressed in normal adult www.impactjournals.com/oncotarget somatic cells, which do senesce; but is reportedly re-expressed in 85-90% of human cancers, permitting immortality [3]. This re-expression seems to play a central role in carcinogenesis, making TERT and telomerase potentially important as drivers and therapeutic targets

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