γ-谷氨酰环转移酶通过激活 PI3K/AKT/mTOR 通路调节上皮-间充质转化促进高级别浆液性卵巢癌的进展。

γ-Glutamyl cyclotransferase contributes to tumor progression in high grade serous ovarian cancer by regulating epithelial-mesenchymal transition via activating PI3K/AKT/mTOR pathway.

机构信息

Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.

出版信息

Gynecol Oncol. 2018 Apr;149(1):163-172. doi: 10.1016/j.ygyno.2018.01.023. Epub 2018 Feb 9.

DOI:10.1016/j.ygyno.2018.01.023

PMID:29429592

Abstract

OBJECTIVE

High grade serous ovarian cancer (HGSC) remains one of the most lethal malignancies in females. We previously reported that γ-glutamyl cyclotransferase (GGCT) was significantly upregulated in serous ovarian cancer. The current study was aimed to explore the function and underlying mechanism of GGCT in HGSC.

METHODS

GGCT expression was assessed by immunohistochemistry in 128 HGSC patients. Stable cell lines with GGCT gene overexpression or knockdown were established to investigate the function of GGCT in HGSC in vitro and in vivo.

RESULTS

GGCT is highly upregulated in HGSC tissues and associated with FIGO stage, lymph node metastasis and ascitic fluid volume. High expression of GGCT is associated with poor survival in HGSC patients. The Harrell's c-indexes of the prognostic models for overall survival and progression-free survival prediction were 0.758 and 0.726, respectively. GGCT knockdown suppresses proliferation, clone formation, migration, and invasion of tumor cells in vitro while forced GGCT overexpression presents opposite results. Furthermore, GGCT silencing inhibits tumor growth and spread in vivo. Epithelial-mesenchymal transition (EMT) and PI3K/AKT/mTOR signaling pathway are suppressed in GGCT silenced cells and enhanced in GGCT overexpressed cells. Inactivation of PI3K/AKT/mTOR signaling pathway in GGCT overexpressed cells induces EMT inhibition.

CONCLUSIONS

Our data reveals an important role of GGCT in regulating EMT and progression of HGSC, providing a valuable prognostic marker and potential target for treatment of HGSC patients.

摘要

目的

高级别浆液性卵巢癌（HGSC）仍然是女性中最致命的恶性肿瘤之一。我们之前报道过γ-谷氨酰环转移酶（GGCT）在浆液性卵巢癌中显著上调。本研究旨在探讨 GGCT 在 HGSC 中的功能和潜在机制。

方法

通过免疫组织化学检测 128 例 HGSC 患者的 GGCT 表达。建立 GGCT 基因过表达或敲低的稳定细胞系，以研究 GGCT 在 HGSC 中的体外和体内功能。

结果

GGCT 在 HGSC 组织中高度上调，与 FIGO 分期、淋巴结转移和腹水体积有关。高表达 GGCT 与 HGSC 患者的不良生存相关。总体生存和无进展生存预测的 Harrell's c 指数分别为 0.758 和 0.726。GGCT 敲低抑制肿瘤细胞的增殖、克隆形成、迁移和侵袭，而强制 GGCT 过表达则呈现相反的结果。此外，GGCT 沉默抑制体内肿瘤的生长和扩散。上皮-间充质转化（EMT）和 PI3K/AKT/mTOR 信号通路在 GGCT 沉默的细胞中受到抑制，而在 GGCT 过表达的细胞中增强。PI3K/AKT/mTOR 信号通路在 GGCT 过表达细胞中的失活诱导 EMT 抑制。