UBE2S 通过 Wnt/β-catenin 信号通路促进卵巢癌细胞的进展和奥拉帕利耐药性。
UBE2S promotes the progression and Olaparib resistance of ovarian cancer through Wnt/β-catenin signaling pathway.
机构信息
Ultrasonic Diagnosis Room, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China.
Ultrasound Department, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, 215000, China.
出版信息
J Ovarian Res. 2021 Sep 17;14(1):121. doi: 10.1186/s13048-021-00877-y.
BACKGROUND
Ovarian cancer is the most lethal gynecologic malignancy worldwide. Olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), is becoming widely used in ovarian cancer treatment. The overall survival of ovarian cancer has not been significantly changed over the past decades and ovarian cancer has become increasingly resistant to the Olaparib. Ubiquitin-conjugating enzyme E2S (UBE2S) has been proved to promote malignant behaviors in many cancers. However, the function of UBE2S in the development and Olaparib resistance of ovarian cancer are unclear.
MATERIALS AND METHODS
In this study, we detected the expression of UBE2S in normal fallopian tube (FT) and HGSOC tissues. A2780 and SKOV3 cells were stably transfected with PCMV-UBE2S, PCMV-UBE2S-C95S, UBE2S shRNAs, and negative controls. The CCK8 assay and clonogenic assay were conducted to analyze ovarian cancer proliferation and Olaparib resistance. The transwell assay was performed to determine the migration and invasion of ovarian cancer cells. The relative protein levels of the Wnt/β-catenin signaling pathway were tested using western blot. The ovarian cancer cells were treated with XAV-939 to investigate the role of Wnt/β-catenin signaling pathway in Olaparib resistance. Moreover, we repeated some above procedures in the xenograft model.
RESULTS
The results demonstrated that UBE2S was highly upregulated in HGSOC and that high UBE2S expression was correlated with poor outcomes in HGSOC. UBE2S promoted ovarian cancer proliferation and drived the migration and invasion of ovarian cancer cells. UBE2S activated the Wnt/β-catenin signaling pathway in ovarian cancer resulting in Olaparib resistance in vitro and in vivo. Furthermore, UBE2S enhanced the proliferation and Olaparib resistance of ovarian cancer in its enzymatic activity dependent manner.
CONCLUSIONS
These data suggest a possible molecular mechanism of proliferation and metastasis of ovarian cancer and highlight the potential role of UBE2S as a therapeutic target in ovarian cancer.
背景
卵巢癌是全球致死率最高的妇科恶性肿瘤。聚（ADP-核糖）聚合酶（PARP）抑制剂奥拉帕利在卵巢癌治疗中得到广泛应用。但在过去几十年中，卵巢癌的总体生存率并没有显著提高，且对奥拉帕利的耐药性也日益增加。泛素连接酶 E2S（UBE2S）已被证明在许多癌症中促进恶性行为。然而，UBE2S 在卵巢癌的发生发展和奥拉帕利耐药中的作用尚不清楚。
材料与方法
本研究检测了 UBE2S 在正常输卵管（FT）和高级别浆液性卵巢癌（HGSOC）组织中的表达。用 PCMV-UBE2S、PCMV-UBE2S-C95S、UBE2S shRNAs 和阴性对照稳定转染 A2780 和 SKOV3 细胞。通过 CCK8 检测和集落形成实验分析卵巢癌细胞的增殖和奥拉帕利耐药性。通过 Transwell 实验检测卵巢癌细胞的迁移和侵袭。Western blot 检测 Wnt/β-catenin 信号通路的相对蛋白水平。用 XAV-939 处理卵巢癌细胞，研究 Wnt/β-catenin 信号通路在奥拉帕利耐药中的作用。此外，我们在异种移植模型中重复了部分上述实验。
结果
结果表明，UBE2S 在 HGSOC 中高度上调，UBE2S 高表达与 HGSOC 患者预后不良相关。UBE2S 促进卵巢癌细胞增殖，并驱动卵巢癌细胞的迁移和侵袭。UBE2S 在卵巢癌细胞中激活 Wnt/β-catenin 信号通路，导致奥拉帕利在体外和体内的耐药性。此外，UBE2S 以其酶活性依赖的方式增强卵巢癌细胞的增殖和奥拉帕利耐药性。
结论
这些数据提示了卵巢癌增殖和转移的一种可能的分子机制，并强调了 UBE2S 作为卵巢癌治疗靶点的潜在作用。
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