METTL3对皮肤鳞状细胞癌细胞的增殖和分化的影响研究

The Effect of METTL3 on the Proliferation and Differentiation of Cutaneous Squamous Cell Carcinoma

皮肤鳞状细胞癌来源于表皮干细胞的自我更新和分化的平衡失调。近来研究表明,甲基转移酶3(METTL3)介导的m6A修饰在多种癌症研究中成为前沿热点。然而, METTL3在皮肤鳞状细胞癌中的作用尚未报道。该研究目的在于了解METTL3在皮肤鳞状细胞癌发生中的作用。通过构建shRNA敲低皮肤鳞状细胞癌中METTL3,研究其对WTAP、METTL14以及m6A修饰水平的作用。此外,应用免疫组化、免疫印迹、qPCR以及裸鼠荷瘤实验,在体外和体内水平研究敲低METTL3对鳞状细胞癌增殖、分化和自我更新的影响。结果显示, METTL3在鳞状细胞癌细胞中表达上调。敲低METTL3能降低METTL14以及m6A修饰水平。敲低METTL3促进癌细胞的分化,并增加IKKα的表达;同时抑制癌细胞的增殖和自我更新,降低自我更新相关基因的表达。综上,该实验证明了METTL3在调节皮肤鳞状细胞癌细胞分化和自我更新中的关键作用。该研究也为皮肤鳞状细胞癌的治疗提供一个新的靶点。

The cutaneous squamous cell carcinoma(cSCC)originates from epithelial stem cells through the dysregulation of self-renewal and differentiation.Recently,methyltransferase-like 3(METTL3)-mediated N6-methyladenosine(m6 A)modification emerges as a new frontier of research in several cancers.However,little is known about METTL3 in cSCC.This study is aimed to investigate the role of METTL3 in the tumorigenesis of cSCC.We investigated the effect of METTL3 knock down on the WTAP,METTL3 and METTL14 complex and m6 A modification levels in cSCC.And we investigated the cell differentiation,proliferation and self-renewal in c SCC in vitro and in vivo.The results demonstrated that the expression of METTL3 was up-regulated in cSCC cells.METTL3 knock down reduced the METTL14 protein levels and m6 A modification levels.METTL3 knock down promoted cSCC cell differentiation and increased the expression of IKKα.Also,METTL3 knock down inhibited the cell proliferation and self-renewal and decreased the expression of self-renewal associated genes.In conclusion,we demonstrated a crucial function for METTL3 in regulating cell differentiation and self-renewal in cSCC.Thus,a novel target for cSCC treatment could have been provided.