Basal cell carcinoma (BCC) is associated with aberrant Hedgehog (HH) signalling through mutational inactivation of PTCH1; however, there is conflicting data regarding MEK/ERK signalling in BCC and the signalling pathway interactions in these carcinomas. To address this, expression of active phospho (p) MEK and ERK was examined in a panel of 15 non-aggressive and 14 aggressive BCCs. Although not uniformly expressed, both phospho-proteins were detected in the nuclei and/or cytoplasm of normal and tumour-associated epidermal cells however, whereas phospho-MEK (pMEK) was present in all non-aggressive BCCs (14/14), phospho-ERK (pERK) was rarely expressed (2/14). In contrast pERK expression was more prevalent in aggressive tumours (11/14). Interestingly, pMEK was only localized to the tumour mass whereas pERK was expressed in tumours and stroma of aggressive BCCs. Similarly, pERK (but not pMEK) was absent in mouse BCC-like tumours derived from X-ray irradiated Ptch1+/- mice with stromal pERK observed in myofibroblasts of the aggressive variant as well as in the tumour mass. RNA sequencing analysis of tumour epithelium and stroma of aggressive and non-aggressive BCC revealed the upregulation of epidermal growth factor receptor- and ERK-related pathways. Angiogenesis and immune response pathways were also upregulated in the stroma compared with the tumour. PTCH1 suppressed NEB1 immortalized keratinocytes (shPTCH1) display upregulated pERK that can be independent of MEK expression. Furthermore, epidermal growth factor pathway inhibitors affect the HH pathway by suppressing GLI1. These studies reveal differential expression of pERK between human BCC subtypes that maybe active by a pathway independent of MEK.

中文翻译：

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磷酸化 MEK 和 ERK 的差异表达与侵袭性 BCC 亚型相关。

基底细胞癌 (BCC) 通过 PTCH1 的突变失活与异常刺猬 (HH) 信号传导有关；然而，关于 BCC 中 MEK/ERK 信号和这些癌中信号通路相互作用的数据存在矛盾。为了解决这个问题，在一组 15 个非侵袭性和 14 个侵袭性 BCC 中检查了活性磷酸 (p) MEK 和 ERK 的表达。尽管表达不一致，但在正常和肿瘤相关表皮细胞的细胞核和/或细胞质中检测到两种磷蛋白，然而，磷酸化 MEK (pMEK) 存在于所有非侵袭性 BCC (14/14) 中，磷酸化-ERK (pERK) 很少表达 (2/14)。相比之下，pERK 表达在侵袭性肿瘤中更为普遍 (11/14)。有趣的是，pMEK 仅定位于肿瘤块，而 pERK 在侵袭性 BCC 的肿瘤和基质中表达。类似地，在源自 X 射线照射的 Ptch1+/- 小鼠的小鼠 BCC 样肿瘤中不存在 pERK（但不是 pMEK），在侵袭性变异的肌成纤维细胞和肿瘤块中观察到基质 pERK。侵袭性和非侵袭性 BCC 的肿瘤上皮和基质的 RNA 测序分析揭示了表皮生长因子受体和 ERK 相关通路的上调。与肿瘤相比，基质中的血管生成和免疫反应途径也上调。PTCH1 抑制 NEB1 永生化角质形成细胞 (shPTCH1) 显示可独立于 MEK 表达的上调 pERK。此外，表皮生长因子通路抑制剂通过抑制 GLI1 影响 HH 通路。