Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Research and Clinical Center for Yusho and Dioxin, Kyushu University, Fukuoka, Japan.
Mod Pathol. 2017 Jul;30(7):919-927. doi: 10.1038/modpathol.2016.169. Epub 2017 Mar 24.
OVOL1 and OVOL2 are ubiquitously conserved genes encoding C2H2 zinc-finger transcription factors in mammals. They promote epithelial cell proliferation, differentiation, and mesenchymal-to-epithelial transition, coordinately mediated via the Wnt signaling pathway. We previously reported that human OVOL1 and OVOL2 were preferentially expressed in the normal epidermis and hair follicles as well as their tumors, and found that OVOL1 is upregulated in Bowen's disease and downregulated in cutaneous squamous cell carcinoma. The aims of this study were to elucidate the potential role of the OVOL1-OVOL2 axis in Bowen's disease and squamous cell carcinoma, and to reveal the relationship between OVOL and c-Myc, a proto-oncogene that plays a pivotal role in the malignancy of epithelial tumors. We investigated 20 Bowen's disease and 20 squamous cell carcinoma clinical samples and a human squamous cell carcinoma cell line (A431) using immunohistochemical staining and molecular biological approaches. Immunohistochemical analysis revealed that OVOL1 was upregulated in Bowen's disease and markedly downregulated in squamous cell carcinoma; conversely, c-Myc was downregulated in Bowen's disease and upregulated in squamous cell carcinoma. OVOL2 was markedly upregulated in the nucleus of Bowen's disease cells, but the distribution of OVOL2 expression in squamous cell carcinoma varied widely; OVOL2 was typically expressed in the cytoplasm, but only sporadically in the nucleus. Furthermore, knockdown of OVOL1 using a specific small interfering RNA increased the mRNA and protein levels of c-Myc and OVOL2. Knockdown of OVOL2 did not significantly affect the mRNA and protein levels of either c-Myc or OVOL1. These results suggest that OVOL1 is an upstream suppressor of c-Myc and OVOL2, and the OVOL1-OVOL2 axis is a modulator of c-Myc, coordinately regulating the invasiveness of cutaneous squamous cell carcinoma. Taken together, this study suggests that the OVOL1-OVOL2 axis is a key modulator of c-Myc expression in the shift from in situ epidermal malignancy (Bowen's disease) to invasive squamous cell carcinoma.
OVOL1 和 OVOL2 是广泛保守的基因，在哺乳动物中编码 C2H2 锌指转录因子。它们通过 Wnt 信号通路促进上皮细胞增殖、分化和间充质-上皮转化。我们之前报道过，人类 OVOL1 和 OVOL2 优先在正常表皮和毛囊及其肿瘤中表达，发现 OVOL1 在 Bowen 病中上调，在皮肤鳞状细胞癌中下调。本研究的目的是阐明 OVOL1-OVOL2 轴在 Bowen 病和鳞状细胞癌中的潜在作用，并揭示 OVOL 与 c-Myc 之间的关系，c-Myc 是一种原癌基因，在上皮肿瘤的恶性转化中起着关键作用。我们使用免疫组织化学染色和分子生物学方法研究了 20 例 Bowen 病和 20 例鳞状细胞癌临床样本和人鳞状细胞癌细胞系（A431）。免疫组织化学分析显示，OVOL1 在 Bowen 病中上调，在鳞状细胞癌中显著下调；相反，c-Myc 在 Bowen 病中下调，在鳞状细胞癌中上调。OVOL2 在 Bowen 病细胞的核中明显上调，但在鳞状细胞癌中的表达分布差异很大；OVOL2 通常在细胞质中表达，但仅偶尔在核中表达。此外，使用特异性小干扰 RNA 敲低 OVOL1 会增加 c-Myc 和 OVOL2 的 mRNA 和蛋白水平。敲低 OVOL2 对 c-Myc 或 OVOL1 的 mRNA 和蛋白水平均无显著影响。这些结果表明，OVOL1 是 c-Myc 和 OVOL2 的上游抑制剂，OVOL1-OVOL2 轴是 c-Myc 的调节剂，协调调节皮肤鳞状细胞癌的侵袭性。综上所述，本研究表明，OVOL1-OVOL2 轴是从原位表皮恶性肿瘤（Bowen 病）向侵袭性鳞状细胞癌转变过程中 c-Myc 表达的关键调节剂。
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