Abstract
HOPX is involved in multiple organ development and acts as a tumor suppressor in various cancers. Epigenetic silencing of HOPX via its promoter methylation has been shown frequent and cancer-specific in human cancers. The proliferation of thyroid cancer cells and cancer progression are strongly influenced by epigenetic alterations as well as genetic changes. Papillary thyroid cancer (PTC) comprises the vast majority of thyroid cancers and exhibits slow progression. However, ~10% of patients still show disease recurrence and refractoriness to treatment. Accordingly, it is important approach to research epigenetic mechanisms in PTC progression to find useful biomarkers. Here, we aimed to seek into the roles and clinical impact of epigenetic silencing of HOPX in PTC.The promoter methylation of HOPX was observed in five of six human thyroid cancer cell lines. Down-regulation of HOPX was seen in three cell lines including PTC line K1, and demethylating agents restored HOPX expression. The promoter methylation was observed with high sensitivity and specificity in human PTC tissues. HOPX promoter methylation independently predicted disease recurrence in PTC patients. Epigenetic silencing of HOPX was associated with Ki-67 expression. Of note, HOPX promoter methylation was dramatically associated with worse prognosis especially in patients with stage I PTC. Forced HOPX expression suppressed cell proliferation, invasive activities, and anchorage-independent growth in vitro. HOPX promoter methylation is frequent and cancer-specific event, leading to aggressive phenotype in PTC. Epigenetic silencing of HOPX may be a clue to tackle cancer progression and have clinical impact as a novel biomarker in PTC.
Highlights
Papillary thyroid cancer (PTC) is one of the most prevalent malignancies and comprises the majority of all thyroid cancers [1]
HOPX expression was initially examined in 6 human thyroid cancer cell lines
HOPX-γ expression was not observed in all 6 thyroid cancer cell lines tested
Summary
Papillary thyroid cancer (PTC) is one of the most prevalent malignancies and comprises the majority of all thyroid cancers [1]. Accumulation of genetic alterations and epigenetic gene modifications are one of the hallmarks of cancer [3]. Cancer emerges as a result of such epigenetic changes or genetic abnormalities [4]. Several genetic alterations such as BRAFV600E mutation, RET/PTC or PAX8/PPARγ translocation and www.oncotarget.com. RAS mutation are thought involved in carcinogenesis in thyroid follicular cells, and further genetic change drives stepwise dedifferentiation of cancer cells [5]. A growing body of evidences have demonstrated that complicated mechanisms of carcinogenesis and cancer progression cannot be solved by genetic alterations alone, and involve epigenetic modifications such as DNA methylation, histone modifications, and microRNA expression [6]. The differentiation and proliferation of thyroid cancer cells are strongly affected by epigenetic alterations, results in cancer progression [7]. It is important approach to seek into epigenetic mechanisms in thyroid cancer progression in order to identify a clinically available biomarker
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