Epigenetic silencing of HOPX is critically involved in aggressive phenotypes and patient prognosis in papillary thyroid cancer

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.

<p>HOPX Is an Epigenetically Inactivated Tumor Suppressor and Overexpression of HOPX Induce Apoptosis and Cell Cycle Arrest in Breast Cancer</p>

“…25 In addition, Ooizumi et al indicated that HOPX is silenced by promoter DNA hypermethylation in papillary thyroid cancer. 26 Our data verified that promoter region of HOPX in CpG islands exhibited higher methylation in four breast cancer cell lines except SKBR3, which was consistent with previous study. 25 In addition, the expression of HOPX was downregulated in MCF-7 and MDA-MB-468 cells, indicating that the epigenetic silencing is involved in suppression of HOPX expression.…”

HOPX: A Unique Homeodomain Protein in Development and Tumor Suppression

“…Loss of HOPX expression as a result of promoter hypermethylation has clinical significance because in patients with gastric and colorectal cancer, the methylation status has been linked to a worse prognosis [ 55 , 61 ] and patients with strong HOPX expression in lung cancer have a considerably longer survival [ 56 ]. Epigenetic suppression of HOPX by promoter methylation plays a critical role in aggressive phenotypes in papillary thyroid cancer and is correlated with a poor prognosis of patients [ 71 ].…”

The role of HOPX in normal tissues and tumor progression

“…In differentiated thyroid cancer, hypermethylation of HOPX-β was associated with poor survival [58]. Ooizumi et al [59] found that HOPX promoter methylation resulted in aggressive phenotype in Papillary thyroid cancer, while forced HOPX expression suppressed cell proliferation, invasive activities, and anchorage-independent growth in vitro. These evidences suggest that the HOPX plays a role as a tumor suppressor gene in solid tumors.…”