OCT4 accelerates tumorigenesis through activating JAK/STAT signaling in ovarian cancer side population cells
OCT4 accelerates tumorigenesis through activating JAK/STAT signaling in ovarian cancer side population cells
复制标题
OCT4 通过激活卵巢癌侧群细胞中的 JAK/STAT 信号传导加速肿瘤发生
DOI：
10.2147/cmar.s180418
复制
发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Cheng, Weiwei
中科院分区：
文献类型：
--
作者：
Ruan, Zhengyi;Yang, Xingyu;Cheng, Weiwei
背景资料：虽然手术、化疗和放疗可以消除临床上明显的卵巢肿瘤，但5年生存率不超过45%。肿瘤干细胞（cancer stem cells，CSCs）在包括卵巢癌在内的多种肿瘤中具有预防肿瘤转移和复发的作用，本研究旨在探讨肿瘤干细胞标志物OCT 4在卵巢癌发生发展中的作用及其机制。应用Hoechst SP技术从人卵巢癌SKOV 3和A2780细胞中分离出CSC样SP细胞。利用靶向人OCT 4基因的shRNA和慢病毒，在SP细胞中稳定敲低OCT 4，在非SP细胞（NSP）中稳定上调OCT 4。Peficitinib用于抑制JAK/STAT信号传导。采用细胞计数试剂盒-8、流式细胞术和体内移植瘤模型评价OCT 4/JAK/STAT对SP细胞活力、耐药性、凋亡、周期和成瘤性的影响。结果：与NSP细胞相比，SKOV 3和A2780细胞SP中的OCT 4表达上调。OCT 4的下调抑制SP细胞活力、肿瘤发生、降低细胞耐药性并诱导G2/M期阻滞，而OCT 4的上调赋予NSP细胞恶性特征。此外，OCT 4在NSP细胞中的上调增加了JAK和STAT家族蛋白的磷酸化水平，尤其是JAK 1和STAT 6。结论：OCT 4通过激活JAK/STAT信号通路促进卵巢癌细胞的增殖和转移，促进卵巢癌细胞的侵袭和生长。
Background: Although surgery, chemotherapy, and radiotherapy eliminate clinically apparent ovarian tumor, the 5-year survival rate is no more than 45%. Cancer stem cells (CSCs) have been identified for precaution of tumor metastasis and recurrence in many kinds of cancers including ovarian cancer.Aim: This study aims to explore the function of OCT4, a CSC marker, in ovarian cancer progression and to investigate its underlying mechanism.Materials and methods: By Hoechst side population (SP) technique, CSC-like SP cells from human ovarian cancer SKOV3 and A2780 cells were isolated and used for this study. shRNA and lentivirus targeting human OCT4 gene were used to knock down OCT4 in SP cells and upregulate OCT4 in non-SP (NSP) cells stably. Peficitinib was used to inhibit JAK/STAT signaling. Cell counting kit-8, flow cytometry, and in vivo xenograft model were used to evaluate the effects of OCT4/JAK/STAT on the viability, drug resistance, apoptosis, cycle, and tumorigenesis of the SP cells. Immunofluorescence staining was used to detect the location of STAT6.Results: Results showed that OCT4 was upregulated in the SP of SKOV3 and A2780 cells when compared with the NSP cells. Downregulation of OCT4 inhibited SP cell viability, tumorigenesis, and reduced cell drug resistance and induced a G2/M phase arrest, while upregulation of OCT4 conferred NSP cell malignant features. Besides, OCT4 upregulation in NSP cells increased the phosphorylated levels of proteins in JAK and STAT families, especially in JAK1 and STAT6. Furthermore, the roles of apoptosis inhibition and viability, invasion, and tumorigenesis promotions induced by OCT4 in NSP cells were all abolished when adding peficitinib.Conclusion: Our study demonstrated that OCT4 accelerated ovarian cancer progression through activating JAK/STAT signaling pathway.