Sasamori Ryohei, Sato Yusuke, Nomura Kyoko, Wakita Akiyuki, Nagaki Yushi, Kemuriyama Kohei, Sasaki Yoshihiro, Nozaki Shu, Takahashi Tsukasa, Terata Kaori, Imai Kazuhiro, Minamiya Yoshihiro
Department of Esophageal Surgery, Akita University Hospital Akita 010-8543, Japan.
Department of Thoracic Surgery, Akita University Graduate School of Medicine Akita 010-8543, Japan.
Am J Cancer Res. 2024 Jul 15;14(7):3497-3512. doi: 10.62347/EIKE6128. eCollection 2024.
Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal squamous cell carcinoma (ESCC). Our previous findings suggest that high expression of toll-like receptor (TLR) 4, which recognizes lipopolysaccharide (LPS) released from periodontal pathogens, correlates with a poor prognosis after esophagectomy for ESCC. We therefore hypothesized that LPS influences cancer cell proliferation and disease progression in ESCC. We used 8 ESCC cell lines to investigate how LPS affects ESCC cell proliferation and migration activity. We also assessed mRNA and protein expression to determine how LPS affects cytokine production and whether blocking TLR4 signaling attenuates that effect. We also used a mouse xenograft model to investigate whether LPS upregulates ESCC tumor progression in vivo. We then determined whether C-C motif chemokine ligand 2 (CCL2) expression in clinical samples correlates with 5-year overall survival (OS) and disease-specific survival (DSS) in ESCC patients after esophagectomy. LPS significantly upregulated cell proliferation and migration in all ESCC lines. It also upregulated CCL2 production. In vivo, subcutaneous LPS administration significantly increased ESCC tumor volume in mice. In clinical samples, high CCL2 expression significantly correlated with 5-year OS and DSS. There was also a significant correlation between CCL2 and TLR4 expression status, suggesting the involvement of an LPS-TLR4-CCL2 cascade in clinical settings. LPS significantly upregulates cell proliferation and tumor progression through an LPS-TLR4-CCL2 cascade and influences prognosis after esophagectomy for ESCC. This suggests improving the oral environment has the potential to improve the prognosis of ESCC patients after esophagectomy.
口腔健康不佳是包括食管鳞状细胞癌（ESCC）在内的上消化道癌症的独立危险因素。我们之前的研究结果表明，识别牙周病原体释放的脂多糖（LPS）的Toll样受体（TLR）4高表达与ESCC食管切除术后的不良预后相关。因此，我们推测LPS会影响ESCC中的癌细胞增殖和疾病进展。我们使用8种ESCC细胞系来研究LPS如何影响ESCC细胞增殖和迁移活性。我们还评估了mRNA和蛋白质表达，以确定LPS如何影响细胞因子产生，以及阻断TLR4信号传导是否会减弱这种影响。我们还使用小鼠异种移植模型来研究LPS在体内是否会上调ESCC肿瘤进展。然后，我们确定临床样本中C-C基序趋化因子配体2（CCL2）的表达是否与ESCC患者食管切除术后的5年总生存期（OS）和疾病特异性生存期（DSS）相关。LPS显著上调了所有ESCC细胞系中的细胞增殖和迁移。它还上调了CCL2的产生。在体内，皮下注射LPS显著增加了小鼠的ESCC肿瘤体积。在临床样本中，高CCL2表达与5年OS和DSS显著相关。CCL2与TLR4表达状态之间也存在显著相关性，表明在临床环境中存在LPS-TLR4-CCL2级联反应。LPS通过LPS-TLR4-CCL2级联反应显著上调细胞增殖和肿瘤进展，并影响ESCC食管切除术后的预后。这表明改善口腔环境有可能改善ESCC患者食管切除术后的预后。
