Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cancer Med. 2017 Jun;6(6):1453-1464. doi: 10.1002/cam4.1090. Epub 2017 May 23.
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.
染色体不稳定（CIN），其特征为非整倍性，是胃癌的主要分子亚型之一。去泛素化酶 USP44 是纺锤体检验点中 APC 激活的重要调节剂，可导致染色体正确分离，防止非整倍性。USP44 的异常表达会导致细胞中的 CIN；然而，USP44 与胃癌中 DNA 非整倍性之间的相关性在很大程度上尚不清楚。我们通过免疫组织化学分析了 207 例胃癌患者的 USP44 表达情况，发现 USP44 表达的比例在胃癌肿瘤中（平均为 39.6%）高于胃正常黏膜（平均为 14.6%）（P < 0.0001）。在 124 例胃癌病例中观察到 DNA 非整倍性，USP44 在癌症中的高表达与 DNA 非整倍性强烈相关（P = 0.0005）。高 USP44 表达组的总生存率明显低于低 USP44 组（P = 0.033）。值得注意的是，USP44 表达在二倍体亚组中对预后没有影响；然而，在非整倍体亚组中，USP44 高表达是无进展生存期（P = 0.018）和总生存期（P = 0.036）的强烈不良预后因素。我们还证实，与对照组（6.6%）相比，USP44 的稳定过表达可在 hTERT-RPE-1 细胞中诱导体细胞拷贝数异常（50.6%）（P < 0.0001）。综上所述，我们的数据表明 USP44 在 CIN 胃癌亚型中具有诱导 DNA 非整倍性和不良预后的临床影响。
