Song Joon Seon, Yi Joo Mi, Cho Hanbyoul, Choi Chel Hun, Park Yoonho, Chung Eun Joo, Song Jaewhan, Chung Joon-Yong, Hong Seung-Mo
1 Department of Pathology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea.
2 Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, Republic of Korea.
Tumour Biol. 2018 Oct;40(10):1010428318808678. doi: 10.1177/1010428318808678.
Oncogene-induced senescence occurs following oncogene activation in normal cells and is considered as a critical tumor-suppressing mechanism. Ubiquitin-specific protease 10 (USP10) has been reported to play a vital role in oncogene-induced senescence via the deubiquitination-dependent stabilization of p14ARF. However, knowledge of the clinical significance of USP10 and p14ARF expression in patients with small intestinal adenocarcinoma is limited. To study the clinical significance of USP10 and p14ARF expression, we performed immunohistochemistry for USP10 and p14ARF on 195 surgically resected small intestinal adenocarcinoma specimens. Furthermore, we performed methylation analysis on five small intestinal adenocarcinoma samples and matched adjacent normal intestinal tissue samples. UPS10 ( p = 0.023) and p14ARF ( p = 0.007) expression were significantly decreased in adenocarcinoma in comparison with normal tissue. The loss of USP10 was observed in 124/194 (63.9%) of small intestinal adenocarcinoma samples and was correlated with a higher pT stage ( p = 0.044), lymphatic invasion ( p = 0.033), and the absence of sporadic adenoma ( p = 0.024) and peritumoral dysplasia ( p = 0.019). p14ARF expression was downregulated in 75/195 (38.5%) of small intestinal adenocarcinoma samples and was associated with vascular ( p = 0.011) and lymphatic ( p = 0.013) invasions. The loss of USP10 expression was associated with the loss of p14ARF expression ( r = 0.342, p < 0.001). Multivariate survival analysis revealed that the combined loss of USP10 and p14ARF expression could be an independent prognostic factor for overall survival in small intestinal adenocarcinoma. Furthermore, the aberrant hypermethylation of the USP10 and p14ARF promoter could be a key mechanism for the downregulation of USP10 and p14ARF proteins in small intestinal adenocarcinoma. These findings suggest that the dual loss of USP10 and p14ARF could be used as a prognostic indicator of small intestinal adenocarcinoma.
在正常细胞中，癌基因激活后会发生癌基因诱导的衰老，这被认为是一种关键的肿瘤抑制机制。据报道，泛素特异性蛋白酶10（USP10）通过依赖去泛素化的p14ARF稳定化在癌基因诱导的衰老中发挥重要作用。然而，关于USP10和p14ARF表达在小肠腺癌患者中的临床意义的了解有限。为了研究USP10和p14ARF表达的临床意义，我们对195例手术切除的小肠腺癌标本进行了USP10和p14ARF的免疫组织化学检测。此外，我们对5例小肠腺癌样本及其匹配的相邻正常肠组织样本进行了甲基化分析。与正常组织相比，腺癌中USP10（p = 0.023）和p14ARF（p = 0.007）的表达显著降低。在194例小肠腺癌样本中的124例（63.9%）中观察到USP10缺失，且与较高的pT分期（p = 0.044）、淋巴管侵犯（p = 0.033）以及无散发性腺瘤（p = 0.024）和瘤旁发育异常（p = 0.019）相关。在195例小肠腺癌样本中的75例（38.5%）中p14ARF表达下调，且与血管侵犯（p = 0.011）和淋巴管侵犯（p = 0.013）相关。USP10表达缺失与p14ARF表达缺失相关（r = 0.342，p < 0.001）。多因素生存分析显示，USP10和p14ARF表达的联合缺失可能是小肠腺癌总体生存的独立预后因素。此外，USP10和p14ARF启动子的异常高甲基化可能是小肠腺癌中USP10和p14ARF蛋白下调的关键机制。这些发现表明，USP10和p14ARF的双重缺失可作为小肠腺癌的预后指标。
