Honda Hiroki, Takamura Masaaki, Yamagiwa Satoshi, Genda Takuya, Horigome Ryoko, Kimura Naruhiro, Setsu Toru, Tominaga Kentaro, Kamimura Hiroteru, Matsuda Yasunobu, Wakai Toshifumi, Aoyagi Yutaka, Terai Shuji
Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan.
Sci Rep. 2017 Nov 14;7(1):15485. doi: 10.1038/s41598-017-15800-z.
Cell motility plays an important role in intrahepatic metastasis of hepatocellular carcinoma (HCC), and predicts poor prognosis in patients. The present study investigated the role of a disintegrin and metalloproteinases (ADAMs) in HCC, since these proteins are known to be associated with cell motility. We confirmed the expression of 12 ADAMs with putative metalloproteinase activity in HCC cells, and established a KYN-2 HCC cell line stably expressing short interfering RNA against ADAM21 to investigate the effect of ADAM21 deficiency on HCC cell motility and metastasis in vitro and in vivo. We also examined ADAM21 expression in a cohort of 119 HCC patients by immunohistochemistry. ADAM21 was overexpressed in KYN-2 cells, and its knockdown reduced invasion, migration, proliferation, and metastasis relative to controls. In clinical specimens, ADAM21 positivity was associated with vascular invasion, large tumor size, high histological grade, and lower overall and recurrence-free survival as compared to cases that were negative for ADAM21 expression. A multivariate analysis revealed that ADAM21 positivity was an independent risk factor for overall (P = 0.003) and recurrence-free (P = 0.001) survival. These results suggest that ADAM21 plays a role in HCC metastasis and can serve as a prognostic marker for disease progression.
细胞运动在肝细胞癌（HCC）肝内转移中起重要作用，并预示患者预后不良。本研究调查了去整合素和金属蛋白酶（ADAMs）在HCC中的作用，因为已知这些蛋白与细胞运动有关。我们证实了12种具有假定金属蛋白酶活性的ADAMs在HCC细胞中的表达，并建立了稳定表达针对ADAM21的短发夹RNA的KYN-2 HCC细胞系，以研究ADAM21缺乏对HCC细胞体外和体内运动及转移的影响。我们还通过免疫组织化学检测了119例HCC患者队列中的ADAM21表达。ADAM21在KYN-2细胞中过表达，相对于对照组，其敲低降低了侵袭、迁移、增殖和转移。在临床标本中，与ADAM21表达阴性的病例相比，ADAM21阳性与血管侵犯、肿瘤体积大、组织学分级高以及总体生存率和无复发生存率较低相关。多变量分析显示，ADAM21阳性是总体生存（P = 0.003）和无复发生存（P = 0.001）的独立危险因素。这些结果表明，ADAM21在HCC转移中起作用，可作为疾病进展的预后标志物。
