Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
Department of General Medicine, Niigata University School of Medicine, 1-757, Asahimachido-ri, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
Sci Rep. 2021 Mar 18;11(1):6255. doi: 10.1038/s41598-021-85498-7.
Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients' condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).
顺铂(CDDP)是用于治疗各种癌症的化疗药物之一。尽管在许多情况下有效,但由于高剂量的 CDDP 会引起细胞毒性作用,可能会使患者病情恶化,因此需要一种 CDDP 敏感性的标志物来提高 CDDP 给药的安全性和效率。本研究专注于脂肪丰富的 2(APM2),以研究其作为 CDDP 敏感性标志物的潜力。使用肝癌(HCC)细胞、组织和 HCC 患者(n=71)的血清,在体外和体内研究了 APM2 表达与 CDDP 耐药机制的关系,这些患者最初接受肝内动脉输注 CDDP 治疗,然后进行手术切除。在另外 54 名 HCC 患者和 14 名胃癌(GC)患者中评估了血清 APM2 对 CDDP 敏感性的预测性。CDDP 耐药 HCC 患者的血清和组织中 APM2 表达均明显升高。生物信息学分析和组织学分析表明,APM2 上调 DNA 切除修复蛋白 ERCC6L(ERCC6 样),这解释了 APM2 表达的程度。评估了血清 APM2 水平和对 CDDP 的化疗敏感性,并确定了预测 CDDP 敏感性的血清 APM2 截断值为 18.7μg/mL。在 HCC(n=54)和 GC(n=14)患者中评估了该值对 CDDP 敏感性的预测性,分别得出了 77.3%和 100%的预测值。我们的研究表明,APM2 表达与 CDDP 敏感性相关,血清 APM2 可以作为 HCC 和 GC 确定对 CDDP 敏感性的有效生物标志物。
本研究在日本大学医院医疗信息网络临床试验注册中心(UMIN000028487)注册。