Clinicopathological correlation of ARID1A status with HDAC6 and its related factors in ovarian clear cell carcinoma
Clinicopathological correlation of ARID1A status with HDAC6 and its related factors in ovarian clear cell carcinoma
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DOI：
10.1038/s41598-019-38653-0
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发表时间：
2019-02
影响因子：
4.6
通讯作者：
M. Yano;T. Katoh;M. Miyazawa;Masaki Miyazawa;Naoki Ogane;M. Miwa;K. Hasegawa;H. Narahara;M. Yasuda
中科院分区：
文献类型：
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作者：
M. Yano;T. Katoh;M. Miyazawa;Masaki Miyazawa;Naoki Ogane;M. Miwa;K. Hasegawa;H. Narahara;M. Yasuda
卵巢透明细胞癌（OCCC）与ARID 1A功能的频繁丧失相关。据报道，ARID 1A直接抑制OCCC中的组蛋白脱乙酰酶（HDAC）6。在此，我们评估HDAC 6表达及其相关因素在ARID 1A状态方面的临床意义。对106例OCCC患者的HDAC 6、缺氧诱导因子-1 α（HIF-1α）、程序性死亡-1配体（PD-L1）、CD 44（癌症干细胞标志物）和ARID 1A的免疫组织化学表达进行了分析。高核HDAC 6表达与患者死亡相关（p= 0.038）。在总生存率的多变量分析中，手术状态（完全或不完全切除）（风险比（HR）= 17.5;p= <0.001）、HDAC 6核表达（HR = 1.68;p= 0.034）和PD-L1表达（HR = 1.95;p= 0.022）是独立的预后因素。HDAC 6上调和ARID 1A丢失不一定同时发生。HDAC 6高表达与ARID 1A缺失的OCCC预后不良相关;在ARID 1A缺失的情况下未观察到这一点。HDAC 6表达与HIF-1α、PD-L1和CD 44呈显著正相关。在OCCC中，HDAC 6参与预后取决于ARID 1A状态。HDAC 6还导致免疫耐受和缺氧耐受以及癌症干细胞表型。HDAC 6是ARID 1A缺失的OCCC的有希望的治疗靶点。
Ovarian clear cell carcinoma (OCCC) is associated with a frequent loss in ARID1A function. ARID1A reportedly suppresses histone deacetylase (HDAC)6 in OCCC directly. Here, we evaluated the clinical significance of HDAC6 expression and its related factors in terms of ARID1A status. Immunohistochemical expression of HDAC6, hypoxia inducible factors-1α (HIF-1α), programmed death-1 ligand (PD-L1), CD44 (cancer stem cell marker), and ARID1A was analysed for 106 OCCC patients. High nuclear HDAC6 expression correlated with patient death (p= 0.038). In the multivariate analysis of overall survival, surgical status (complete or incomplete resection) (hazard ratio (HR) = 17.5;p= <0.001), HDAC6 nuclear expression (HR = 1.68;p= 0.034), and PD-L1 expression (HR = 1.95;p= 0.022) were the independent prognostic factors. HDAC6 upregulation and ARID1A loss did not necessarily occur simultaneously. High HDAC6 expression was associated with poor prognosis in OCCC with ARID1A loss; this was not observed without ARID1A loss. HDAC6 expression showed a significant positive correlation with HIF-1α, PD-L1, and CD44. In OCCC, HDAC6 involvement in prognosis depended on ARID1A status. HDAC6 also led to immuno- and hypoxia- tolerance and cancer stem cell phenotype. HDAC6 is a promising therapeutic target for OCCC with loss of ARID1A.