Rad6 is a Potential Early Marker of Melanoma Development.
Rad6 is a Potential Early Marker of Melanoma Development.
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Rad6 是黑色素瘤发展的潜在早期标志物。
DOI：
10.1016/j.tranon.2014.04.009
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发表时间：
2014
影响因子：
5
通讯作者：
Shekhar,MalathyPV
中科院分区：
文献类型：
--
作者：
Rosner,Karli;Adsule,Shreelekha;Haynes,Brittany;Kirou,Evangelia;Kato,Ikuko;Mehregan,DariusR;Shekhar,MalathyPV
在工业化国家，黑色素瘤是皮肤癌的主要死亡原因。一些与黑色素瘤相关的生物标志物和信号通路已经被确定；然而，它们与黑色素瘤的发生/进展或临床结果的相关性仍有待确定。Wnt/β-Catenin通路的异常激活与包括黑色素瘤在内的多种癌症有关。我们之前已经证明了RAD6，一种泛素结合酶，是乳腺癌细胞中β-连环蛋白稳定性的重要介体。与乳腺癌类似，β-连环蛋白激活突变在黑色素瘤中很少见，由于β-连环蛋白信号与黑色素瘤有关，我们研究了黑色素瘤细胞模型中β-连环蛋白水平/活性与β-连环蛋白转录靶标RAD6和小眼球相关转录因子-M(MITF-M)的表达之间的关系，以及黑色素瘤组织标本中RAD6、β-连环蛋白和Melan-A的表达。我们的数据显示，Rad6只在正常人黑素细胞中弱表达，而在黑色素瘤细胞系中过表达。与MITF-M不同，RAD6在黑色素瘤细胞系中的过度表达与高分子量β-连环蛋白水平和β-连环蛋白转录活性呈正相关。黑色素瘤组织芯片中Rad6和Melan-A的双重免疫荧光染色显示黑色素瘤的组织学诊断与Rad6/Melan-A双阳性显著相关(P=0.0029)。与β-catenin在浅表播散性恶性黑色素瘤正常区域和肿瘤区域的强表达相反，在浅表播散性恶性黑色素瘤的正常区域检测不到RAD6的表达，而在浅表播散性恶性黑色素瘤的转移区，RAD6的表达增加与Melan-A的增加是一致的。这些数据提示RAD6在黑色素瘤发病机制中起作用，RAD6的表达状态可能是黑色素瘤发生的早期标志。
Melanoma is the leading cause of death from skin cancer in industrialized countries. Several melanoma-related biomarkers and signaling pathways have been identified; however, their relevance to melanoma development/progression or to clinical outcome remains to be established. Aberrant activation of Wnt/β-catenin pathway is implicated in various cancers including melanoma. We have previously demonstrated Rad6, an ubiquitin-conjugating enzyme, as an important mediator of β-catenin stability in breast cancer cells. Similar to breast cancer, β-catenin-activating mutations are rare in melanomas, and since β-catenin signaling is implicated in melanoma, we examined the relationship between β-catenin levels/activity and expression of β-catenin transcriptional targets Rad6 and microphthalmia-associated transcription factor-M (Mitf-M) in melanoma cell models, and expression of Rad6, β-catenin, and Melan-A in nevi and cutaneous melanoma tissue specimens. Our data show that Rad6 is only weakly expressed in normal human melanocytes but is overexpressed in melanoma lines. Unlike Mitf-M, Rad6 overexpression in melanoma lines is positively associated with high molecular weight β-catenin protein levels and β-catenin transcriptional activity. Double-immunofluorescence staining of Rad6 and Melan-A in melanoma tissue microarray showed that histological diagnosis of melanoma is significantly associated with Rad6/Melan-A dual positivity in the melanoma group compared to the nevi group (P= .0029). In contrast to strong β-catenin expression in normal and tumor areas of superficial spreading malignant melanoma (SSMM), Rad6 expression is undetectable in normal areas and Rad6 expression increases coincide with increased Melan-A in the transformed regions of SSMM. These data suggest a role for Rad6 in melanoma pathogenesis and that Rad6 expression status may serve as an early marker for melanoma development.
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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