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A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway

Background: 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 th...

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Autores principales: Tsujimoto, Hironori, Horiguchi, Hiroyuki, Matsumoto, Yusuke, Takahata, Risa, Shinomiya, Nariyoshi, Yamori, Takao, Miyazaki, Hiromi, Ono, Satoshi, Saitoh, Daizoh, Kishi, Yoji, Ueno, Hideki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408644/
https://www.ncbi.nlm.nih.gov/pubmed/32630328
http://dx.doi.org/10.3390/jcm9072074
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author Tsujimoto, Hironori
Horiguchi, Hiroyuki
Matsumoto, Yusuke
Takahata, Risa
Shinomiya, Nariyoshi
Yamori, Takao
Miyazaki, Hiromi
Ono, Satoshi
Saitoh, Daizoh
Kishi, Yoji
Ueno, Hideki
author_facet Tsujimoto, Hironori
Horiguchi, Hiroyuki
Matsumoto, Yusuke
Takahata, Risa
Shinomiya, Nariyoshi
Yamori, Takao
Miyazaki, Hiromi
Ono, Satoshi
Saitoh, Daizoh
Kishi, Yoji
Ueno, Hideki
author_sort Tsujimoto, Hironori
collection PubMed
description Background: 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. Methods: 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. Results: 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. Conclusions: 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.
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spelling pubmed-74086442020-08-13 A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway Tsujimoto, Hironori Horiguchi, Hiroyuki Matsumoto, Yusuke Takahata, Risa Shinomiya, Nariyoshi Yamori, Takao Miyazaki, Hiromi Ono, Satoshi Saitoh, Daizoh Kishi, Yoji Ueno, Hideki J Clin Med Article Background: 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. Methods: 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. Results: 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. Conclusions: 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. MDPI 2020-07-01 /pmc/articles/PMC7408644/ /pubmed/32630328 http://dx.doi.org/10.3390/jcm9072074 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tsujimoto, Hironori
Horiguchi, Hiroyuki
Matsumoto, Yusuke
Takahata, Risa
Shinomiya, Nariyoshi
Yamori, Takao
Miyazaki, Hiromi
Ono, Satoshi
Saitoh, Daizoh
Kishi, Yoji
Ueno, Hideki
A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway
title A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway
title_full A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway
title_fullStr A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway
title_full_unstemmed A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway
title_short A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway
title_sort potential mechanism of tumor progression during systemic infections via the hepatocyte growth factor (hgf)/c-met signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408644/
https://www.ncbi.nlm.nih.gov/pubmed/32630328
http://dx.doi.org/10.3390/jcm9072074
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