Yamashita Taro, Koshikawa Naohiko, Shimakami Tetsuro, Terashima Takeshi, Nakagawa Masatoshi, Nio Kouki, Horii Rika, Iida Noriho, Kawaguchi Kazunori, Arai Kuniaki, Sakai Yoshio, Yamashita Tatsuya, Mizukoshi Eishiro, Honda Masao, Kitao Azusa, Kobayashi Satoshi, Takahara Shizuko, Imai Yasuhito, Yoshimura Kenichi, Murayama Toshinori, Nakamoto Yasunari, Yoshida Eisaku, Yoshimura Toru, Seiki Motoharu, Kaneko Shuichi
Department of General MedicineKanazawa University HospitalKanazawaJapan.
Department of GastroenterologyKanazawa University HospitalKanazawaJapan.
Hepatology. 2021 Aug;74(2):760-775. doi: 10.1002/hep.31758. Epub 2021 Apr 28.
Structural dynamics of basement membrane components are still to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of HCC expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined whether elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC).
In HCC cell lines, LG2m was expressed in alpha-fetoprotein (AFP)-negative, CD90-positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida's S1/Boyault's G3 molecular subclasses with poor prognosis, which could not be recognized by AFP. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease patients, and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff, 30 pg/mL). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m-high HCC showed poor prognosis with later development of distant organ metastasis (cutoff, 60 pg/mL). LG2m was slightly elevated in a subset of CHC patients, and Kaplan-Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter, prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR (P < 0.0001).
LG2m is a predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is an HCC risk in CHC patients who have achieved SVR.
在肝癌发生过程中，基底膜成分的结构动力学仍有待阐明。我们评估了表达层粘连蛋白γ2单体（LG2m）的肝癌特征，LG2m是一种在正常组织中未检测到的基底膜成分，用于肝癌诊断。我们进一步确定血清LG2m升高是否是慢性丙型肝炎（CHC）患者发生肝癌的危险因素。
在肝癌细胞系中，LG2m在甲胎蛋白（AFP）阴性、CD90阳性且具有高转移特性的细胞中表达。利用14个细胞系和258份肝癌微阵列数据，我们确定LG2m基因特征与预后不良的Hoshida S1/Boyault G3分子亚类相关，而AFP无法识别该亚类。对24名健康供体、133名慢性肝病患者和142名肝癌患者的血清LG2m进行了评估，LG2m检测对肝癌诊断的敏感性和特异性分别为62.9%和70.5%（临界值为30 pg/mL）。我们在两个独立的肝癌队列（n = 47和n = 81）中评估了LG2m升高的后果，LG2m高表达的肝癌预后较差，远处器官转移出现较晚（临界值为60 pg/mL）。一部分CHC患者的LG2m略有升高，Kaplan-Meier分析显示肝癌发病率较高（n = 70）。为进行验证，我们招募了399名获得持续病毒学应答（SVR）的CHC患者进行一项多中心前瞻性研究，血清LG2m升高与SVR的CHC患者中肝癌的高发病率相关（P < 0.0001）。
LG2m是转移性肝癌发生的预测生物标志物。血清LG2m升高是已实现SVR的CHC患者发生肝癌的风险因素。
