G 蛋白偶联雌激素受体在黑色素瘤和妊娠相关性黑色素瘤中的表达。

Expression of G protein-coupled oestrogen receptor in melanoma and in pregnancy-associated melanoma.

机构信息

Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary.

Doctoral School of Clinical Medicine, Semmelweis University, Budapest, Hungary.

出版信息

J Eur Acad Dermatol Venereol. 2017 Sep;31(9):1453-1461. doi: 10.1111/jdv.14304. Epub 2017 Jun 20.

DOI:10.1111/jdv.14304

PMID:28467693

Abstract

BACKGROUND

The hormone sensitivity of melanoma and the role of 'classical' oestrogen receptor (ER) α and β in tumour progression have been intensively studied with rather contradictory results. The presence of 'non-classical' G protein-coupled oestrogen receptor (GPER) has not been investigated on human melanoma tissues.

OBJECTIVE

To analyse the expression of GPER, ERα and ERβ in pregnancy-associated (PAM) and in non-pregnancy-associated (NPAM) melanomas in correlation with traditional prognostic markers and disease-free survival (DFS).

METHODS

Receptor protein levels were tested using immunohistochemistry in 81 formalin-fixed paraffin-embedded melanoma tissues. PAMs (n = 38) were compared with age- and Breslow thickness-matched cases (n = 43) including non-pregnant women (NPAM-W) (n = 22) and men (NPAM-M) (n = 21). The association between receptor expression and DFS was analysed by uni- and multivariate Cox proportional hazards regression.

RESULTS

G protein-coupled oestrogen receptor was detected both in PAMs and NPAMs. In 39 of the 41 (95.1%) GPER-positive melanomas, GPER and ERβ were co-expressed. GPER/ERβ-positive melanomas were significantly more common in PAM compared to NPAM (P = 0.0001) with no significant difference between genders (P = 0.4383). In PAMs, the distribution of GPER and ERβ was similar (78.4% vs. 81.6%; P = 0.8504), while in NPAM, ERβ was the representative ER (60.5% vs. 27.9%; P = 0.0010) without gender difference (59.1% vs. 61.9%). GPER-/ERβ-positive melanomas were associated with lower Breslow thickness, lower mitotic rate and higher presence of peritumoral lymphocyte infiltration (PLI) compared to GPER-/ERβ-negative cases (P = 0.0156, P = 0.0036 and P = 0.0001) predicting a better DFS (HR = 0.785, 95% CI 0.582-1.058). Despite the significantly higher frequency of GPER and ERβ expression in PAM, no significant difference was found in DFS between PAM and NPAM. All but one case failed to show ERα expression.

CONCLUSIONS

The presence of GPER and its simultaneous expression with ERβ can serve as a new prognostic indicator in a significant subpopulation of melanoma patients.

摘要

背景

黑色素瘤的激素敏感性以及“经典”雌激素受体（ER）α和β在肿瘤进展中的作用已得到深入研究，但结果却存在很大的争议。目前尚未在人黑色素瘤组织中研究过“非经典”G 蛋白偶联雌激素受体（GPER）的存在。

目的

分析孕激素相关（PAM）和非孕激素相关（NPAM）黑色素瘤组织中 GPER、ERα 和 ERβ 的表达情况，并与传统的预后标志物和无病生存（DFS）相关联。

方法

采用免疫组织化学法检测 81 例福尔马林固定石蜡包埋的黑色素瘤组织中受体蛋白水平。将 38 例 PAM 与年龄和 Breslow 厚度匹配的病例（NPAM-W，n=22；NPAM-M，n=21）进行比较。采用单变量和多变量 Cox 比例风险回归分析受体表达与 DFS 的相关性。

结果

GPER 在 PAM 和 NPAM 中均有表达。在 41 例 GPER 阳性黑色素瘤中，有 39 例（95.1%）同时表达 GPER 和 ERβ。与 NPAM 相比，PAM 中 GPER/ERβ 阳性黑色素瘤更为常见（P=0.0001），但在性别方面无显著差异（P=0.4383）。在 PAM 中，GPER 和 ERβ 的分布相似（78.4%vs.81.6%；P=0.8504），而在 NPAM 中，ERβ 是代表性的 ER（60.5%vs.27.9%；P=0.0010），且无性别差异（59.1%vs.61.9%）。与 GPER/ERβ 阴性病例相比，GPER/ERβ 阳性黑色素瘤的 Breslow 厚度较低、有丝分裂率较低、肿瘤周围淋巴细胞浸润（PLI）较高（P=0.0156，P=0.0036 和 P=0.0001），DFS 更好（HR=0.785，95%CI 0.582-1.058）。尽管 PAM 中 GPER 和 ERβ 的表达频率明显较高，但 PAM 和 NPAM 之间的 DFS 无显著差异。除了一个病例外，所有病例均未显示 ERα 的表达。