Murata Maho, Ito Takamichi, Tanaka Yuka, Yamamura Kazuhiko, Furue Kazuhisa, Furue Masutaka
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan.
J Clin Med. 2020 Feb 25;9(3):618. doi: 10.3390/jcm9030618.
Progression of actinic keratosis (AK) to cutaneous squamous cell carcinoma (cSCC) is rare. Most cases of AK remain as intraepidermal lesions, owing to the suppression of the epithelial-to-mesenchymal transition (EMT). Ovo-like transcriptional repressor 1 (OVOL1) and ovo-like zinc finger 2 (OVOL2) are important modulators of EMT in some tumors, but their roles in skin tumors remain elusive. This study elucidated the roles of OVOL1/2 in AK and cSCC using 30 AK/30 cSCC clinical samples, and an A431 human SCC cell line using immunohistochemistry and molecular biological approaches. Immunohistochemically, OVOL1/2 were upregulated in AK and downregulated in cSCC. Meanwhile, EMT-related factors, vimentin and zinc finger E-box binding homeobox 1 (ZEB1) were downregulated in AK and upregulated in cSCC. Moreover, ZEB1 expression was higher in tumors in which OVOL2 expression was low. Thus, we observed an inverse association between OVOL2 and ZEB1 expression in AK and cSCC. Although knockdown of OVOL1 or OVOL2 increased the mRNA and protein levels of ZEB1, only OVOL2 knockdown increased the invasive ability of A431. In conclusion, OVOL2 inhibits ZEB1 expression and may inhibit the promotion of AK into cSCC. OVOL2/ZEB1 axis may be a potential target for preventing the development of cSCC.
光化性角化病（AK）进展为皮肤鳞状细胞癌（cSCC）的情况较为罕见。由于上皮-间质转化（EMT）受到抑制，大多数AK病例仍为表皮内病变。卵样转录抑制因子1（OVOL1）和卵样锌指蛋白2（OVOL2）在某些肿瘤中是EMT的重要调节因子，但它们在皮肤肿瘤中的作用仍不清楚。本研究使用30例AK/30例cSCC临床样本以及A431人鳞状细胞癌细胞系，采用免疫组织化学和分子生物学方法阐明了OVOL1/2在AK和cSCC中的作用。免疫组织化学结果显示，OVOL1/2在AK中上调，在cSCC中下调。同时，EMT相关因子波形蛋白和锌指E盒结合同源框1（ZEB1）在AK中下调，在cSCC中上调。此外，在OVOL2表达低的肿瘤中ZEB1表达更高。因此，我们观察到在AK和cSCC中OVOL2与ZEB1表达呈负相关。虽然敲低OVOL1或OVOL2会增加ZEB1的mRNA和蛋白水平，但只有敲低OVOL2会增加A431的侵袭能力。总之，OVOL2抑制ZEB1表达，可能抑制AK向cSCC的进展。OVOL2/ZEB1轴可能是预防cSCC发生发展的潜在靶点。
