Ito Takamichi, Tsuji Gaku, Ohno Fumitaka, Uchi Hiroshi, Nakahara Takeshi, Hashimoto-Hachiya Akiko, Yoshida Yuichi, Yamamoto Osamu, Oda Yoshinao, Furue Masutaka
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Am J Pathol. 2016 Apr;186(4):1036-43. doi: 10.1016/j.ajpath.2015.12.013. Epub 2016 Feb 9.
OVOL1 and OVOL2, ubiquitously conserved genes encoding C2H2 zinc finger transcription factors in mammals, control epithelial cell proliferation, and differentiation, including those in skin. OVOL1 and OVOL2 expression is coordinately mediated via the Wnt signaling pathway, and OVOL1 negatively regulates OVOL2 expression in a transcriptional manner. Our previous study of OVOL1 expression in human skin revealed that OVOL1 is preferentially expressed in the inner root sheath of the hair follicle. Therefore, we hypothesized that the OVOL1-OVOL2 axis is involved in normal and neoplastic follicular differentiation. Immunohistochemical analysis showed that OVOL1 and OVOL2 were strongly expressed in a mutually exclusive manner in the cytoplasm of inner root sheath cells and matrix cells, respectively, in normal follicles. OVOL2 was also expressed in pilomatricoma, with only partial expression of OVOL1. Cultured human keratinocytes expressed OVOL1 and OVOL2 on both the mRNA and protein levels. The expression of OVOL2 was higher in keratinocytes transfected with siRNA of OVOL1. Ketoconazole, a hair growth stimulant, up-regulated the expression of OVOL1 but did not affect OVOL2 expression. These results indicated that the OVOL1-OVOL2 axis may actively contribute to cell differentiation and proliferation in the hair bulb, suggesting that the OVOL1 and OVOL2 may be therapeutic targets of hair disorders, including alopecia, and play important roles in the tumorigenesis of pilomatricoma.
OVOL1和OVOL2是哺乳动物中普遍保守的基因，编码C2H2锌指转录因子，可控制上皮细胞的增殖和分化，包括皮肤中的上皮细胞。OVOL1和OVOL2的表达通过Wnt信号通路协同介导，且OVOL1以转录方式负调控OVOL2的表达。我们之前对人皮肤中OVOL1表达的研究表明，OVOL1优先在毛囊的内根鞘中表达。因此，我们推测OVOL1 - OVOL2轴参与正常和肿瘤性毛囊分化。免疫组织化学分析显示，在正常毛囊中，OVOL1和OVOL2分别在内根鞘细胞和基质细胞的细胞质中以相互排斥的方式强烈表达。OVOL2也在毛母质瘤中表达，而OVOL1仅部分表达。培养的人角质形成细胞在mRNA和蛋白质水平上均表达OVOL1和OVOL2。用OVOL1的siRNA转染的角质形成细胞中OVOL2的表达更高。酮康唑是一种毛发生长刺激剂，可上调OVOL1的表达，但不影响OVOL2的表达。这些结果表明，OVOL1 - OVOL2轴可能积极促进毛球中的细胞分化和增殖，提示OVOL1和OVOL2可能是包括脱发在内的毛发疾病的治疗靶点，并在毛母质瘤的肿瘤发生中起重要作用。
