MAPK/ERK-Dependent Translation Factor Hyperactivation and Dysregulated Laminin γ2 Expression in Oral Dysplasia and Squamous Cell Carcinoma
MAPK/ERK-Dependent Translation Factor Hyperactivation and Dysregulated Laminin γ2 Expression in Oral Dysplasia and Squamous Cell Carcinoma
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DOI：
10.1016/j.ajpath.2012.02.028
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发表时间：
2012-06-01
影响因子：
6
通讯作者：
Rheinwald, James G.
中科院分区：
文献类型：
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作者：
Degen, Martin;Natarajan, Easwar;Rheinwald, James G.
在浸润性口腔和表皮鳞状细胞癌（SCC）之前显示各种异型增生的病变;然而，没有确认或分期癌前病变的组织病理学标准。SCC和发育不良经常包含异常表达层粘连蛋白-332的γ 2亚基的细胞。我们开发了细胞培养模型来研究γ 2失调。正常人角质形成细胞显示密度依赖性抑制γ 2，而癌前角质形成细胞和SCC细胞过表达γ 2和分泌层粘连蛋白组装中间体。肿瘤细胞具有过度活跃的EGFR/MAPK（ERK）信号传导与过表达的γ 2协调，并且EGFR和MEK抑制剂使γ 2表达正常化。经工程改造以表达HPV 16 E6或活化的突变型HRAS、cRAF 1或MEK 1的角质形成细胞丧失了对γ 2的密度抑制，并与肿瘤细胞共享ERK下游的信号传导异常，包括S6和eIF 4翻译因子的磷酸化增加。值得注意的是，qPCR结果显示，γ 2过表达不伴随γ 2 mRNA水平的增加，这与肿瘤细胞中γ 2 mRNA的茎环5 '-非翻译区的ERIC依赖性、eIF 4 B介导的翻译起始一致。MEK的抑制剂，但不是TORC 1/2的抑制剂，阻断S6和eIF 4 B磷酸化和γ 2过表达。口腔发育不良的免疫染色确定γ 2过度表达发生在具有升高的p-S6水平的基底细胞的领域内。这些结果揭示了ERIC依赖的翻译因子激活和层粘连蛋白γ 2失调之间的因果关系，并确定了SCC进展过程中浸润前肿瘤变化的新标志物。(Am J Pathol 2012，180：2462-2478 http：//dx.doi.org/10.1016/j.ajpath.2012.02.028）
Lesions displaying a variety of dysplastic changes precede invasive oral and epidermal squamous cell carcinoma (SCC); however, there are no histopathological criteria for either confirming or staging premalignancy. SCCs and dysplasias frequently contain cells that abnormally express the gamma 2 subunit of laminin-332. We developed cell culture models to investigate gamma 2 dysregulation. Normal human keratinocytes displayed density-dependent repression of gamma 2, whereas premalignant keratinocytes and SCC cells overexpressed gamma 2 and secreted laminin assembly intermediates. Neoplastic cells had hyperactive EGFR/MAPK(ERK) signaling coordinate with overexpressed gamma 2, and EGFR and MEK inhibitors normalized gamma 2 expression. Keratinocytes engineered to express HPV16 E6 or activated mutant HRAS, cRAF1, or MEK1 lost density repression of gamma 2 and shared with neoplastic cells signaling abnormalities downstream of ERK, including increased phosphorylation of S6 and eIF4 translation factors. Notably, qPCR results revealed that gamma 2 overexpression was not accompanied by increased gamma 2 mRNA levels, consistent with ERIC-dependent, eIF4B-mediated translation initiation of the stem-looped, 5'-untranslated region of gamma 2 mRNA in neoplastic cells. Inhibitors of MEK, but not of TORC1/2, blocked S6 and eIF4B phosphorylation and gamma 2 overexpression. Immunostaining of oral dysplasias identified gamma 2 overexpression occurring within fields of basal cells that had elevated p-S6 levels. These results reveal a causal relationship between ERIC-dependent translation factor activation and laminin gamma 2 dysregulation and identify new markers of preinvasive neoplastic change during progression to SCC. (Am J Pathol 2012, 180:2462-2478 http://dx.doi.org/10.1016/j.ajpath.2012.02.028)