Weng Weiwei, Zhang Qiongyan, Xu Midie, Wu Yong, Zhang Meng, Shen Chen, Chen Xiaochen, Wang Yiqin, Sheng Weiqi
Department of Pathology, Fudan University Shanghai Cancer CenterShanghai, 200032, China; Department of Oncology, Fudan University Shanghai Cancer CenterShanghai, 200032, China.
Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University Shanghai, 200011, China.
Am J Transl Res. 2016 May 15;8(5):2234-44. eCollection 2016.
The deubiquitinating enzyme OTUB1 participates in multiple cellular processes. However, its expression and functions in gastric adenocarcinoma remains unknown. The aim of this study was to investigate the expression of OTUB1 and its biological role in gastric adenocarcinoma.
We used immunohistochemistry to analyze OTUB1 expressions levels in 80 paired samples of gastric adenocarcinoma and adjacent normal tissue (ANT) and 30 samples of intraepithelial neoplasia (IN). We also analyzed the correlation between OTUB1 expression and clinicopathological parameters and patient survival status. Moreover, we performed wound-healing, transwell, RT-qPCR and Western blot assays to evaluate the impact of OTUB1 on tumor migration and invasion.
In gastric adenocarcinomas, staining for OTUB1 was localized in the cytoplasm. The proportion of samples that expressed OTUB1 and the intensity of its expression were much higher in gastric adenocarcinoma tissues (61 out of 80, 76.25%) than that in either IN (10 out of 30, 33.33%, p<0.001) or ANT (7 out of 80, 8.75%, p<0.001) samples. In malignant cases, higher expression OTUB1 levels were significantly associated with deeper tumor invasion depths (p=0.02), advanced lymph node status (p=0.008) and TNM stage (p=0.001), lymph duct invasion (p<0.001) and nerve invasion (p=0.013). Univariate and multivariate Cox regression analyses revealed that OTUB1 was an independent risk factor for disease-specific survival but not disease-free survival. In vitro wound-healing and transwell assays showed that OTUB1 overexpression promoted tumor cell migration and invasion in gastric cancer cells.
OTUB1 contributes to gastric cancer development by enhancing tumor invasiveness. Targeting OTUB1 should be considered in future molecular therapies.
去泛素化酶OTUB1参与多种细胞过程。然而，其在胃腺癌中的表达及功能尚不清楚。本研究旨在探讨OTUB1在胃腺癌中的表达及其生物学作用。
我们采用免疫组织化学方法分析80对胃腺癌组织及癌旁正常组织（ANT）样本和30例上皮内瘤变（IN）样本中OTUB1的表达水平。我们还分析了OTUB1表达与临床病理参数及患者生存状态之间的相关性。此外，我们进行了伤口愈合实验、Transwell实验、RT-qPCR和蛋白质免疫印迹分析，以评估OTUB1对肿瘤迁移和侵袭的影响。
在胃腺癌中，OTUB1染色定位于细胞质。OTUB1表达的样本比例及其表达强度在胃腺癌组织（80例中的61例，76.25%）中比IN（30例中的10例，33.33%，p<0.001）或ANT（80例中的7例，8.75%，p<0.001）样本中高得多。在恶性病例中，较高的OTUB1表达水平与更深的肿瘤浸润深度（p=0.02）、晚期淋巴结状态（p=0.008）和TNM分期（p=0.001）、淋巴管浸润（p<0.001）及神经浸润（p=0.013）显著相关。单因素和多因素Cox回归分析显示，OTUB1是疾病特异性生存的独立危险因素，但不是无病生存的独立危险因素。体外伤口愈合实验和Transwell实验表明，OTUB1过表达促进胃癌细胞的肿瘤细胞迁移和侵袭。
OTUB1通过增强肿瘤侵袭性促进胃癌发展。未来的分子治疗应考虑靶向OTUB1。
