Ovarian cancer is the most lethal cancer in the female reproductive system. It has been shown that "time chemotherapy" of ovarian cancer has an important impact on the chemotherapy effect and prognosis of patients, but the specific mechanism is not known. Methods: We designed a case-control study in strict accordance with epidemiological principles. We collected resection samples of ovarian-cancer patients who worked night-shifts and those who did not, and analyzed the differences in protein expression. Through construction of a normal/circadian-rhythm disorder model of ovarian cancer in nude mice, we explored the molecular mechanism of a "biological clock" rhythm on treatment of ovarian cancer. Results: Expression of interleukin-6, programmed cell death receptor-1 and programmed death ligand 1 increased, and expression of tumor necrosis factor-α, Period 1 (Per1) and Per2 decreased in the night-shift group. Methylation of CpG islands in the promoter of Per2 could result in its decreased expression in SKOV3/DDP（Cisplatin） cells. Dysrhythmia of the circadian clock: (i) had a negative effect on the chemotherapy effect against ovarian cancer; (ii) affected expression of immune factors and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Conclusion: The Per2 gene can affect the drug resistance of ovarian cancer by inhibiting the PI3K/Akt signaling pathway and then acting on its downstream drug-resistance factors, thereby providing a new target for ovarian-cancer treatment.

中文翻译：

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昼夜节律和Period2通过PI3K信号通路调节卵巢癌的化疗效果和多药耐药性。

卵巢癌是女性生殖系统中最致命的癌症。已经显示，卵巢癌的“定时化学疗法”对化学疗法的效果和患者的预后有重要影响，但是具体机制尚不清楚。方法：我们严格按照流行病学原理设计了病例对照研究。我们收集了夜班和不夜班的卵巢癌患者的切除样本，并分析了蛋白质表达的差异。通过建立正常/昼夜节律性卵巢癌裸鼠模型，我们探索了“生物钟”节律治疗卵巢癌的分子机制。结果：白细胞介素6，程序性细胞死亡受体1和程序性死亡配体1的表达增加，夜班组肿瘤坏死因子-α，Period 1（Per1）和Per2的表达下降。Per2启动子中CpG岛的甲基化可能导致其在SKOV3 / DDP（顺铂）细胞中的表达降低。昼夜节律不齐：（i）对卵巢癌的化学疗法产生负面影响；（ii）影响免疫因子和磷酸肌醇3-激酶/蛋白激酶B（PI3K / Akt）信号通路的表达。结论：Per2基因可通过抑制PI3K / Akt信号通路进而作用于其下游耐药因子而影响卵巢癌的耐药性，从而为卵巢癌的治疗提供新的靶点。Per2启动子中CpG岛的甲基化可能导致其在SKOV3 / DDP（顺铂）细胞中的表达降低。昼夜节律不齐：（i）对卵巢癌的化学疗法产生负面影响；（ii）影响免疫因子和磷酸肌醇3-激酶/蛋白激酶B（PI3K / Akt）信号通路的表达。结论：Per2基因可通过抑制PI3K / Akt信号通路进而作用于其下游耐药因子而影响卵巢癌的耐药性，从而为卵巢癌的治疗提供新的靶点。Per2启动子中CpG岛的甲基化可能导致其在SKOV3 / DDP（顺铂）细胞中的表达降低。昼夜节律不齐：（i）对卵巢癌的化学疗法产生负面影响；（ii）影响免疫因子和磷酸肌醇3-激酶/蛋白激酶B（PI3K / Akt）信号通路的表达。结论：Per2基因可通过抑制PI3K / Akt信号通路进而作用于其下游耐药因子而影响卵巢癌的耐药性，从而为卵巢癌的治疗提供新的靶点。（ii）影响免疫因子和磷酸肌醇3-激酶/蛋白激酶B（PI3K / Akt）信号通路的表达。结论：Per2基因可通过抑制PI3K / Akt信号通路进而作用于其下游耐药因子而影响卵巢癌的耐药性，从而为卵巢癌的治疗提供新的靶点。（ii）影响免疫因子和磷酸肌醇3-激酶/蛋白激酶B（PI3K / Akt）信号通路的表达。结论：Per2基因可通过抑制PI3K / Akt信号通路进而作用于其下游耐药因子而影响卵巢癌的耐药性，从而为卵巢癌的治疗提供新的靶点。