Yes-Associated Protein Contributes to the Development of Human Cutaneous Squamous Cell Carcinoma via Activation of RAS
Yes-Associated Protein Contributes to the Development of Human Cutaneous Squamous Cell Carcinoma via Activation of RAS
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Yes 相关蛋白通过 RAS 激活促进人类皮肤鳞状细胞癌的发展
DOI：
10.1016/j.jid.2016.02.005
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发表时间：
2016-06-01
影响因子：
6.5
通讯作者：
Zheng, Yan
中科院分区：
文献类型：
--
作者：
Jia, Jinjing;Li, Changji;Zheng, Yan
皮肤鳞状细胞癌（Cutaneous squamous cell carcinoma，cSCC）是最常见的皮肤恶性肿瘤之一，发病率逐年上升。研究表明，Yes相关蛋白（雅普）作为一种癌基因参与多种肿瘤的发生发展，但其在cSCC中的作用尚未见报道。在这项研究中，我们使用免疫组化显示，雅普的表达在不同阶段的cSCC样本中与正常皮肤相比升高，并且与疾病的进展密切相关。体外实验表明，下调雅普基因表达可抑制CSCC细胞株A431和SCL-1的增殖，诱导细胞在G1/S期发生生长停滞，促进细胞凋亡，降低细胞的侵袭和迁移能力。相反，雅普的过表达促进细胞增殖并保护细胞免受基础和化疗诱导的细胞凋亡。雅普的这些致癌作用与RAS蛋白及其下游AKT和ERK的激活有关。使用小鼠异种移植物模型，我们进一步表明雅普消耗抑制体内cSCC肿瘤生长。我们的结果表明，雅普参与了cSCC的致癌和发展，并且它可能作为这种疾病的生物标志物或治疗靶点。
Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin malignant tumors with an increasing incidence. Studies have shown that Yes-associated protein (YAP) participates in the development of a variety of tumors as an oncogene, but to our knowledge its role in cSCC has not been reported. In this study, we used immunohistochemistry to show that YAP expression was elevated in cSCC samples of different stages versus in normal skin and that it was well correlated with the progression of the disease. Down-regulation of YAP in cSCC cell lines A431 and SCL-1 inhibited cell proliferation by inducing growth arrest during the G1/S phase transition, promoted apoptosis, and reduced invasion and migration abilities in vitro. Conversely, overexpression of YAP promoted cell proliferation and protected cells against basal and chemotherapy-induced apoptosis. These oncogenic effects of YAP were associated with activation of the RAS protein and its downstream AKT and ERK. Using a mouse xenograft model, we further showed that YAP depletion inhibited cSCC tumor growth in vivo. Our results suggested that YAP is involved in the carcinogenesis and development of cSCC and that it may serve as a biomarker or therapeutic target of this disease.