Overexpression of KDM5B/JARID1B is associated with poor prognosis in hepatocellular carcinoma.
Overexpression of KDM5B/JARID1B is associated with poor prognosis in hepatocellular carcinoma.
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DOI：
10.18632/oncotarget.26144
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发表时间：
2018-09-28
期刊：
影响因子：
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通讯作者：
Yamaue H
中科院分区：
文献类型：
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作者：
Shigekawa Y;Hayami S;Ueno M;Miyamoto A;Suzaki N;Kawai M;Hirono S;Okada KI;Hamamoto R;Yamaue H
肝细胞癌有很高的复发潜力，即使是在根治性手术病例中也是如此。尽管已有几种分子靶向药物应用于复发性肝癌，但其疗效有限。因此，这项研究旨在通过蛋白质甲基化来开发新型抗癌药物。我们研究了JmjC组蛋白去甲基酶成员KDM5B/JARID1B在肝细胞癌中的作用。应用免疫组织化学方法检测105例肝细胞癌临床标本中KDM5B的表达情况。为了利用肝癌细胞株检测KDM5B的功能效应，我们进行了KDM5B特异性小干扰RNA(SiKDM5B)处理的功能丧失分析。将所有病例分为KDM5B阳性表达组(n=54)和阴性表达组(n=51)。在5年总生存率中，KDM5B阳性组预后较KDM5B阴性组差(61%比77%，P=0.047)。KDM5B阳性组预后明显差于阴性组，尤其是慢性乙型或丙型肝炎持续感染者(54%vs78%，P=0.015)。多因素分析显示，KDM5B是预后不良的最强危险因素，尤其是在由乙肝病毒/丙型肝炎衍生的肝癌中。抑制KDM5B可通过促进NO从G1期进入S期而显著抑制肝癌细胞的增殖。实时定量聚合酶链式反应和Western blotting结果表明，E2F1/E2F2是KDM5B的下游基因。KDM5B的过度表达导致肝细胞癌预后不良，尤其是来源于乙肝病毒/丙型肝炎的肝细胞癌。KDM5B似乎是抗癌药物开发的理想靶点。
Hepatocellular carcinoma (HCC) has high potential for recurrence, even in curative operative cases. Although several molecular-targeting drugs have been applied to recurrent HCC, their effectiveness has been limited. This study therefore aims to develop novel cancer drugs through protein methylation. We investigated the role of KDM5B/JARID1B, a member of JmjC histone demethylase, in HCC. Expression profiles of KDM5B were examined by immunohistochemical analysis in 105 HCC clinical tissue samples. To examine functional effects of KDM5B using HCC cell lines, we performed loss-of-function analysis treated with KDM5B-specific small interfering RNAs (siKDM5B). All HCC cases were divided into KDM5B-positive expression group (n=54) and negative expression group (n=51). In five-year overall survival, KDM5B-positive group had poorer prognosis than KDM5B-negative (61% vs 77%, p=0.047). KDM5B-positive group had much poorer prognosis than that of the negative group, especially in HCC derived from persistent infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) (54% vs 78%, p=0.015). Multivariate analysis indicated that KDM5B was the strongest risk factor for poor prognosis, especially in HCC derived from HBV/HCV. Inhibition of KDM5B could significantly suppress HCC cell proliferation through no promotion from G1 to S phase. Real-time PCR and Western blotting demonstrated that E2F1/E2F2 were downstream genes of KDM5B. Overexpression of KDM5B results in poor prognosis in HCC that especially derived from HBV/HCV. KDM5B appears to be an ideal target for the development of anti-cancer drugs.