Up-regulation of HDAC6 Results in Poor Prognosis and Chemoresistance in Patients With Advanced Ovarian High-grade Serous Carcinoma
Up-regulation of HDAC6 Results in Poor Prognosis and Chemoresistance in Patients With Advanced Ovarian High-grade Serous Carcinoma
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DOI：
10.21873/anticanres.14927
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发表时间：
2020-07
影响因子：
2
通讯作者：
M. Yano;M. Miyazawa;Naoki Ogane;A. Ogasawara;K. Hasegawa;H. Narahara;M. Yasuda
中科院分区：
文献类型：
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作者：
M. Yano;M. Miyazawa;Naoki Ogane;A. Ogasawara;K. Hasegawa;H. Narahara;M. Yasuda
背景：卵巢高级别浆液性癌(HGSC)复发后逐渐获得化疗耐药。我们先前对卵巢透明细胞癌的研究发现，组蛋白脱乙酰酶6(HDAC6)过表达导致化疗耐药。本研究旨在评价HDAC6作为卵巢HGSC化疗耐药的预测因子和治疗靶点。患者和方法：用免疫组织化学方法评价HDAC6作为预测HGSC预后和化疗耐药的临床意义。此外，对88例卵巢HGSC患者的临床标本进行了程序性细胞死亡配体-1(PD-L1)和缺氧诱导因子-1α(α)的检测，并对其临床病理特征进行了复习。结果：HDAC6高表达2 3例，PD-L1阳性10例，HIF-1α高表达33例。根据实体瘤反应评估标准，HDAC6表达上调与未接受间歇性去髓核手术(p<；0.001)、不完全手术切除(p=0.002)、频繁发生稳定期疾病/进展性疾病(p=0.005)相关。在Kaplan-Meier分析中，HDAC6的高表达与无进展(p=0.001)和总存活率(p=0.008)的降低显著相关。在多因素分析中，高表达HDAC6(危险比=1.65，95%可信区间为1.03-2.66；p=0.039)和手术状况是无进展生存的独立预后因素。PD-L1、HIF1α表达与HDAC6表达呈正相关。结论：HDAC6可能成为卵巢HGSC患者潜在的治疗靶点，因为它的上调被认为与卵巢癌患者的预后不良有关。
Background: Ovarian high-grade serous carcinoma (HGSC) gradually acquires chemoresistance after recurrence. Our previous study on ovarian clear-cell carcinoma found histone deacetylase 6 (HDAC6) overexpression led to chemoresistance. This study aimed to evaluate HDAC6 as a predictor of chemoresistance and a therapeutic target for ovarian HGSC. Patients and Methods: The clinical significance of HDAC6 as a predictor of prognosis and chemoresistance in HGSC was immunohistochemically evaluated. In addition, expression of programmed cell death ligand-1 (PD-L1), and hypoxia-inducible factor-1α (HIF1α) were analyzed using clinical samples from 88 patients with ovarian HGSC, and their clinicopathological characteristics were reviewed. Results: Twenty-three patients had high HDAC6 expression, 10 positive PD-L1 expression, and 33 high HIF-1α expression. HDAC6 up-regulation was correlated with not undergoing interval debulking surgery (p<0.001), incomplete surgical resection (p=0.002), and frequent occurrence of stable disease/progressive disease according to the Response Evaluation Criteria in Solid Tumors (p=0.005) criteria. On Kaplan-Meier analysis, high HDAC6 expression was significantly associated with reduced progression-free (p=0.001) and overall (p=0.008) survival. On multivariate analysis, high HDAC6 expression (hazard ratio=1.65, 95% confidence interval 1.03-2.66; p=0.039) and surgery status were independent prognostic factors of progression-free survival. PD-L1 and HIF1α expression positively correlated with that of HDAC6. Conclusion: HDAC6 may become a potential therapeutic target in patients with ovarian HGSC since its up-regulation is considered to be associated with a poor prognosis in patients with this cancer.