Kampilafkos Panagiotis, Melachrinou Maria, Kefalopoulou Zinovia, Lakoumentas John, Sotiropoulou-Bonikou Georgia
Departments of *Anatomy-Histology-Embryology, and †Pathology, School of Medicine, University of Patras, Patras, Rion, Greece; ‡Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen, Square, London; and §Department of Medical Physics, School of Medicine, University of Patras, Rion, Greece.
Am J Dermatopathol. 2015 Feb;37(2):138-44. doi: 10.1097/DAD.0b013e31828a2d54.
Cancer stem cells and the misregulation of epigenetic modifications have been identified to possess a determinative role in carcinogenesis. The purpose of this study was to investigate the expression profile of EZH2 and H3K4me2 and H3K27me3, which constitute stem cell-like "bivalent" domains, in cutaneous malignant melanoma. A comparative analysis of their immunohistochemical expression between the invasion front (IF) and the inner tumor mass was also evaluated. Immunohistochemical methodology was performed on sections of 89 melanoma lesions from 79 patients. The 3 markers studied were identified in the cell nuclei of melanoma cells, nevus cells, and normal epidermal keratinocytes. A specific distribution pattern of H3K4me2 and H3K27me3 was found, as stronger levels were localized at the IF of the tumor (P = 0.034 and P < 0.01, respectively). In general, H3K4me2 and H3K27me3 levels were lower in metastatic with respect to primary melanoma cases (P = 0.0065 and P = 0.027, respectively). Advanced melanoma demonstrated significantly lower H3K4 immunohistochemical expression than did cases of lowest Clark level (I) (P = 0.038) or low Breslow depth (≤1 mm; P < 0.001). Furthermore, EZH2 expression in melanoma cells was higher compared with that in nevus cells (P = 0.02). A positive correlation between EZH2-H3K27me3 (P = 0.03) and H3K4me2-H3K27me3 (P < 0.01) in melanoma cells was also found. Our results suggest the possibility that combined immunohistochemical expression of EZH2, H3K4me2, and H3K27me3 might identify cancer cells with potential stem cell properties, particularly at the IF of this malignancy. This hypothesis should be further investigated, as many of the epigenetic changes are reversible via pharmacologic manipulations and new therapies, overpassing the resistance of advanced melanoma, may be developed.
癌症干细胞和表观遗传修饰的失调已被证实在癌症发生过程中起决定性作用。本研究的目的是调查构成干细胞样“双价”结构域的EZH2、H3K4me2和H3K27me3在皮肤恶性黑色素瘤中的表达谱。还评估了它们在侵袭前沿（IF）和肿瘤内部肿块之间免疫组化表达的比较分析。对79例患者的89个黑色素瘤病变切片进行了免疫组化方法检测。研究的3种标志物在黑色素瘤细胞、痣细胞和正常表皮角质形成细胞的细胞核中均有发现。发现H3K4me2和H3K27me3有特定的分布模式，其较强水平定位于肿瘤的IF处（分别为P = 0.034和P < 0.01）。一般来说，与原发性黑色素瘤病例相比，转移性黑色素瘤中H3K4me2和H3K27me3水平较低（分别为P = 0.0065和P = 0.027）。晚期黑色素瘤的H3K4免疫组化表达明显低于最低Clark分级（I级）病例（P = 0.038）或低Breslow深度（≤1 mm；P < 0.001）病例。此外，黑色素瘤细胞中EZH2的表达高于痣细胞（P = 0.02）。还发现黑色素瘤细胞中EZH2 - H3K27me3（P = 0.03）和H3K4me2 - H3K27me3（P < 0.01）之间呈正相关。我们的结果表明，EZH2、H3K4me2和H3K27me3的联合免疫组化表达可能识别出具有潜在干细胞特性的癌细胞，特别是在这种恶性肿瘤的IF处。这一假设应进一步研究，因为许多表观遗传变化可通过药物操作逆转，并且可能开发出克服晚期黑色素瘤耐药性的新疗法。
