High ubiquitin-specific protease 44 expression induces DNA aneuploidy and provides independent prognostic information in gastric cancer.
High ubiquitin-specific protease 44 expression induces DNA aneuploidy and provides independent prognostic information in gastric cancer.
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DOI：
10.1002/cam4.1090
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发表时间：
2017-06
期刊：
影响因子：
4
通讯作者：
Maehara Y
中科院分区：
文献类型：
--
作者：
Nishimura S;Oki E;Ando K;Iimori M;Nakaji Y;Nakashima Y;Saeki H;Oda Y;Maehara Y
染色体不稳定(CIN)是胃癌的主要分子亚型，以非整倍体为特征。脱泛素酶USP44是纺锤体检查点APC激活的重要调节因子，并导致适当的染色体分离以防止非整倍体。USP44在细胞中的异常表达导致CIN；然而，USP44与DNA非整倍体在胃癌中的相关性尚不清楚。应用免疫组织化学方法检测胃癌组织中USP44蛋白的表达，发现胃癌组织中USP44蛋白的表达比例(平均39.6%)高于正常胃粘膜组织(平均14.6%)(P<0.0001)。12 4例胃癌组织中USP44高表达与DNA异倍体呈正相关(P=0.0.0005)。USP44高表达组的总生存率明显低于低表达组(P<0.033)。值得注意的是，USP44在二倍体亚组中的表达对预后没有影响；然而，在非整倍体亚组中，USP44的高表达是无进展生存(P=0.018)和总体生存(P=0.036)的一个很差的预后因素。我们还证实，稳定过表达USP44在hTERT-RPE-1细胞中诱导的体细胞拷贝数异常(50.6%)与对照组(6.6%)相比(P<0.0001)。总之，我们的数据显示，USP44在CIN胃癌亚型中诱导DNA异倍体和不良预后方面具有临床影响。
Chromosomal instability (CIN), characterized by aneuploidy, is a major molecular subtype of gastric cancer. The deubiquitinase USP44 is an important regulator of APC activation in the spindle checkpoint and leads to proper chromosome separation to prevent aneuploidy. Aberrant expression of USP44 leads CIN in cells; however, the correlation between USP44 and DNA aneuploidy in gastric cancer is largely unknown. We analyzed USP44 expression in 207 patients with gastric cancer by immunohistochemistry and found that the proportion of USP44 expression was higher in gastric cancer tumors (mean, 39.6%) than in gastric normal mucosa (mean, 14.6%) (P < 0.0001). DNA aneuploidy was observed in 124 gastric cancer cases and high USP44 expression in cancer strongly correlated with DNA aneuploidy (P = 0.0005). The overall survival was significantly poorer in the high USP44 expression group compared with the low USP44 group (P = 0.033). Notably, USP44 expression had no prognostic impact in the diploid subgroup; however, high USP44 expression was a strong poor prognostic factor for progression‐free survival (P = 0.018) and overall survival (P = 0.036) in the aneuploid subgroup. We also confirmed that stable overexpression of USP44 induced somatic copy‐number aberrations in hTERT‐RPE‐1 cells (50.6%) in comparison with controls (6.6%) (P < 0.0001). Collectively, our data show USP44 has clinical impact on the induction of DNA aneuploidy and poor prognosis in the CIN gastric cancer subtype.