Wang Zhaoxia, Li Fengyan, Wei Meiyan, Zhang Sanyuan, Wang Tong
Department of Gynecology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
Cancer Manag Res. 2020 Nov 19;12:11897-11908. doi: 10.2147/CMAR.S278903. eCollection 2020.
The mortality rate of ovarian cancer is the highest among gynecological tumors. The two factors leading to high mortality of ovarian cancer are late clinical stage and chemotherapy resistance. It is very important to reverse or intervene chemotherapy resistance. Abnormal circadian rhythm is related to the occurrence of tumor, and circadian clock protein PERIOD2 (PER2) acts as a tumor suppressor in cancer; however, little is known about its involvement in chemosensitivity.
This study aimed to investigate the role and underlying mechanisms of PER2 in ovarian cancer sensitivity to cisplatin. Overexpression and knockdown of PER2 were performed to explore its role in ovarian cancer cell sensitivity to cisplatin both in vitro and in vivo. The protein levels of PI3K, AKT, caspase 3, E-cadherin, and other drug resistance-related molecules were determined in parental SKOV3 and SKOV3/DDP cells as well as in xenograft tumor tissues.
Compared with parental cells, SKOV3/DDP cells had dramatically decreased PER2 expression, possibly due to hypermethylation in the PER2 promoter. PER2 overexpression significantly inhibited proliferation while promoting cisplatin-induced apoptosis in SKOV3 and SKOV3/DDP cells. In agreement, PER2-overexpressing SKOV3/DPP cells yielded significantly reduced tumor mass in cisplatin-treated mice compared with control cells. Mechanistically, PER2 overexpression remarkably reduced the protein amounts of PI3K, AKT, and MDR1 while increasing those of caspase 3 and E-cadherin in tumor tissues. Knockdown of PER2 exhibited opposite effects. PER2 overexpression also reduced the serum levels of TNF-α and IL-6 in tumor-bearing mice before the initiation of cisplatin treatment.
This study suggests that loss of PER2 contributes to cisplatin resistance in SKOV3 cells, possibly by activating the PI3K/AKT pathway and EMT, inhibiting apoptosis, and promoting drug efflux and inflammatory responses. Overexpression of PER2 could reverse these alterations and sensitize both parental SKOV3 and SKOV3/DDP cells to cisplatin.
卵巢癌死亡率在妇科肿瘤中最高。导致卵巢癌高死亡率的两个因素是临床分期晚和化疗耐药。逆转或干预化疗耐药非常重要。昼夜节律异常与肿瘤发生有关，昼夜节律蛋白周期蛋白2（PER2）在癌症中起肿瘤抑制作用；然而，关于其在化疗敏感性中的作用知之甚少。
本研究旨在探讨PER2在卵巢癌对顺铂敏感性中的作用及潜在机制。通过PER2的过表达和敲低来探究其在体外和体内对卵巢癌细胞顺铂敏感性的作用。在亲本SKOV3和SKOV3/DDP细胞以及异种移植肿瘤组织中测定PI3K、AKT、半胱天冬酶3、E-钙黏蛋白和其他耐药相关分子的蛋白水平。
与亲本细胞相比，SKOV3/DDP细胞中PER2表达显著降低，可能是由于PER2启动子的高甲基化。PER2过表达显著抑制SKOV3和SKOV3/DDP细胞的增殖，同时促进顺铂诱导的凋亡。同样，与对照细胞相比，过表达PER2的SKOV3/DPP细胞在顺铂处理的小鼠中产生的肿瘤体积显著减小。机制上，PER2过表达显著降低肿瘤组织中PI3K、AKT和MDR1的蛋白量，同时增加半胱天冬酶3和E-钙黏蛋白的蛋白量。敲低PER2表现出相反的效果。在开始顺铂治疗前，PER2过表达还降低了荷瘤小鼠血清中TNF-α和IL-6的水平。
本研究表明，PER2的缺失可能通过激活PI3K/AKT途径和上皮-间质转化、抑制凋亡、促进药物外排和炎症反应导致SKOV3细胞对顺铂耐药。PER2的过表达可以逆转这些改变，并使亲本SKOV3和SKOV3/DDP细胞对顺铂敏感。
