Department of Dermatology, University of Regensburg, Regensburg, Germany.
PLoS One. 2012;7(2):e31255. doi: 10.1371/journal.pone.0031255. Epub 2012 Feb 17.
Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.
默克尔细胞癌（Merkel cell carcinoma，MCC）是一种具有高侵袭性的皮肤癌，其发病率呈上升趋势。目前对于 MCC 的分子发病机制的认识仍有限。在此，我们研究了 PI3K/AKT 通路，该通路在人类癌症中被广泛激活。对 41 例肿瘤组织和 9 株 MCC 细胞系进行免疫组织化学分析显示，88%的样本中 AKT 丝氨酸 308 磷酸化水平升高。值得注意的是，AKT 磷酸化与 Merkel 细胞多瘤病毒（MCV）的存在与否无关。相应地，用 shRNA 敲低 MCV 阳性 MCC 细胞中的大 T 抗原和小 T 抗原并不影响 AKT 的磷酸化。我们还分析了 46 例 MCC 样本中的 PIK3CA 和 AKT1 突变。46 例 MCC 中有 2 例（4%）存在致癌性 PIK3CA 突变，而 AKT1 外显子 4 无突变。MCC 细胞系对 PI3K 抑制剂 LY-294002 表现出高度敏感性。这一发现，以及我们观察到 PI3K/AKT 通路在大多数人类 MCC 中被激活，表明 PI3K/AKT 可能成为 MCC 患者的一个新的潜在治疗靶点。
