The role of Wnt/β-catenin signaling pathway in melanoma epithelial-to-mesenchymal-like switching: evidences from patients-derived cell lines.
The role of Wnt/β-catenin signaling pathway in melanoma epithelial-to-mesenchymal-like switching: evidences from patients-derived cell lines.
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DOI：
10.18632/oncotarget.9232
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Bellei B
中科院分区：
文献类型：
--
作者：
Kovacs D;Migliano E;Muscardin L;Silipo V;Catricalà C;Picardo M;Bellei B
WNT/β-连环蛋白信号转导的失调或突变与肿瘤形成和进展相关。然而，关于β-连环蛋白在人类黑色素瘤中的作用的矛盾结果解决了关于其致癌性质和在该肿瘤中的预后价值的开放性问题。WNT信号通路的变化与黑色素瘤细胞在高度增殖/非侵袭性和缓慢增殖/转移性条件之间的表型转换有关。我们使用一组从黑素瘤标本中分离的新细胞系，在初始传代时，研究与WNT/β-连环蛋白信号通路的水平和活性相关的表型差异。该体外细胞系统显示出显著的异质性，在某些情况下，其包括两种不同的肿瘤来源的细胞亚群，其呈现不同的β-连环蛋白活化水平和细胞分布。在来源于同一肿瘤的细胞中，我们证明了LEF 1（高β-连环蛋白表达细胞）或TCF 4（低β-连环蛋白表达细胞）作为DNA结合的β-连环蛋白伴侣的流行与两种不同的WNT应答基因的表达相关。有趣的是，表达相对低水平的β-连环蛋白和侵袭性标志物特征的黑素瘤细胞与TNF-α诱导的促炎途径和化疗耐药性相关，表明具有不同生物学特性的黑素瘤亚群的共存可能影响化疗和免疫治疗的影响。
Deregulations or mutations of WNT/β-catenin signaling have been associated to both tumour formation and progression. However, contradictory results concerning the role of β-catenin in human melanoma address an open question on its oncogenic nature and prognostic value in this tumour. Changes in WNT signaling pathways have been linked to phenotype switching of melanoma cells between a highly proliferative/non-invasive and a slow proliferative/metastatic condition. We used a novel panel of cell lines isolated from melanoma specimens, at initial passages, to investigate phenotype differences related to the levels and activity of WNT/β-catenin signaling pathway. This in vitro cell system revealed a marked heterogeneity that comprises, in some cases, two distinct tumour-derived subpopulations of cells presenting a different activation level and cellular distribution of β-catenin. In cells derived from the same tumor, we demonstrated that the prevalence of LEF1 (high β-catenin expressing cells) or TCF4 (low β-catenin expressing cells) as β-catenin partner for DNA binding, is associated to the expression of two distinct profiles of WNT-responsive genes. Interestingly, melanoma cells expressing relative low level of β-catenin and an invasive markers signature were associated to the TNF-α-induced pro-inflammatory pathway and to the chemotherapy resistance, suggesting that the co-existence of melanoma subpopulations with distinct biological properties could influence the impact of chemo- and immunotherapy.
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