Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
Clinical Research Center, Aichi Medical University Hospital, Nagakute, Japan.
Ann Surg. 2018 Mar;267(3):495-503. doi: 10.1097/SLA.0000000000002096.
To develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of gastric cancer (GC).
Advanced GC frequently recurs because of undetected micrometastases even after curative resection. Peritoneal metastasis has been the most frequent recurrent pattern after gastrectomy and is incurable.
We conducted a recurrence pattern-specific transcriptome analysis in an independent cohort of 16 patients with stage III GC who underwent curative gastrectomy and adjuvant S-1 for screening candidate molecules specific for peritoneal metastasis of GC. Next, another 340 patients were allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value of the candidate molecule. The results of quantitative reverse-transcription PCR and immunohistochemical analysis were correlated with clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model.
Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. In the discovery set, the optimal cut-off of SYT8 expression was established as 0.005. Expression levels of SYT8 mRNA in GC tissues were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. SYT8 levels above the cut-off value were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between patients with SYT8 levels above and below the cut-off was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells.
SYT8 represents a promising target for the detection, prediction, and treatment of peritoneal metastasis of GC.
开发针对胃癌（GC）腹膜转移的新型诊断和治疗靶点。
即使在根治性切除后，由于未检测到微转移，晚期 GC 仍经常复发。腹膜转移是胃切除术后最常见的复发模式，且无法治愈。
我们对 16 例接受根治性胃切除术和辅助 S-1 治疗的 III 期 GC 患者进行了复发模式特异性转录组分析，以筛选针对 GC 腹膜转移的候选分子。然后，将另外 340 例患者分配到发现和验证组（1:2），以评估候选分子的诊断和预测价值。定量逆转录 PCR 和免疫组织化学分析的结果与临床特征和生存相关。在体外评估了 siRNA 介导的敲低对 GC 细胞表型和氟尿嘧啶敏感性的影响，并使用小鼠异种移植模型评估了 siRNA 的治疗效果。
突触结合蛋白 VIII（SYT8）被鉴定为一种针对腹膜转移的候选生物标志物。在发现组中，SYT8 表达的最佳截断值确定为 0.005。在包括腹膜复发或转移患者的验证组中，GC 组织中 SYT8 mRNA 的表达水平升高。SYT8 水平高于截断值与腹膜转移显著相关，并且是 II/III 期 GC 患者腹膜无复发生存的独立预后标志物。SYT8 水平高于和低于截断值的患者之间的生存差异与接受辅助化疗的患者有关。GC 细胞中 SYT8 表达的抑制与侵袭、迁移和氟尿嘧啶耐药性降低相关。腹腔内给予 SYT8-siRNA 可抑制腹膜结节的生长并延长 GC 细胞移植小鼠的存活时间。
SYT8 代表了检测、预测和治疗 GC 腹膜转移的有前途的靶点。
