Tsujimoto Hironori, Horiguchi Hiroyuki, Matsumoto Yusuke, Takahata Risa, Shinomiya Nariyoshi, Yamori Takao, Miyazaki Hiromi, Ono Satoshi, Saitoh Daizoh, Kishi Yoji, Ueno Hideki
Department of Surgery, National Defense Medical College; 3-2 Namiki, Tokorozawa 359-8513, Japan.
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan.
J Clin Med. 2020 Jul 1;9(7):2074. doi: 10.3390/jcm9072074.
Increasing evidence has demonstrated that postoperative infectious complications (PICs) after digestive surgery are significantly associated with negative long-term outcomes; however, precise mechanisms of how PICs affect the poor long-term survival remain unclear. Here, we focused on the hepatocyte growth factor (HGF)/c-Met signaling pathway as one of those mechanisms. In the clinical setting, serum HGF levels were measured in the patients with sepsis and those with PICs after undergoing esophagectomy. Using a liver metastasis mouse model with cecal ligation and puncture (CLP), expressions of HGF and the roles of the HGF/c-Met pathway in the progression of tumor cells were examined. Serum HGF levels were very high in the patients with intra-abdominal infection on postoperative days (PODs) 1, 3, and 5; similarly, compared to the patients without PICs, those with PICs had significantly higher serum HGF levels on 1, 3, and 5 days after esophagectomy. The patients with PICs showed poorer overall survival than those without PICs, and the patients with high serum HGF levels on POD 3 showed poorer prognosis than those with low HGF levels. Similarly, at 24 and 72 h after operation, serum levels of HGF in CLP mice were significantly higher than those in sham-operated mice. Intraperitoneal injection of mouse recombinant HGF significantly promoted liver metastases in sham-operated mice on 14 days after surgery. Knocking down c-Met expression on NL17 tumor cells by RNAi technology significantly inhibited the promotion of CLP-induced liver metastases. Infections after surgery increased serum HGF levels in the clinical as well as experimental settings. Induction of high serum HGF levels by CLP promoted liver metastases in a murine liver metastasis model, suggesting the involvement of the HGF/c-Met signaling pathway in tumor promotion mechanisms. Thus, targeting the HGF/c-Met signaling pathway may be a promising approach for malignant tumors, particularly in the patients with PICs.
越来越多的证据表明，消化手术后的术后感染并发症（PICs）与长期不良预后显著相关；然而，PICs如何影响长期生存率低下的确切机制仍不清楚。在此，我们将肝细胞生长因子（HGF）/c-Met信号通路作为其中一种机制进行了研究。在临床环境中，对脓毒症患者和接受食管切除术后发生PICs的患者进行了血清HGF水平检测。使用盲肠结扎和穿刺（CLP）建立肝转移小鼠模型，检测了HGF的表达以及HGF/c-Met通路在肿瘤细胞进展中的作用。术后第1、3和5天，腹腔感染患者的血清HGF水平非常高；同样，与未发生PICs的患者相比，发生PICs的患者在食管切除术后第1、3和5天的血清HGF水平显著更高。发生PICs的患者总体生存率低于未发生PICs的患者，术后第3天血清HGF水平高的患者预后比HGF水平低的患者差。同样，术后24和72小时，CLP小鼠的血清HGF水平显著高于假手术小鼠。术后14天腹腔注射小鼠重组HGF显著促进了假手术小鼠的肝转移。通过RNAi技术敲低NL17肿瘤细胞上的c-Met表达显著抑制了CLP诱导的肝转移。手术感染在临床和实验环境中均增加了血清HGF水平。CLP诱导的高血清HGF水平促进了小鼠肝转移模型中的肝转移，提示HGF/c-Met信号通路参与了肿瘤促进机制。因此，靶向HGF/c-Met信号通路可能是治疗恶性肿瘤的一种有前景的方法，尤其是对于发生PICs的患者。
