Suchergebnisse

Qijue Lu,* Xinyu Wang,* Ji Zhu,* Xiang Fei, Hezhong Chen, Chunguang Li Department of Thoracic Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, People's Republic of China*These authors contributed equally to this workCorrespondence: Chunguang LiDepartment of Thoracic Surgery, Changhai Hospital, The Second Military Medical University, No. 168 Changhai Road, Shanghai 200433, People's Republic of ChinaTel +86 2131161764Email dr_lichunguang@sina.comIntroduction: Hypoxia and tumor-associated macrophage (TAM) are key regulators in remodeling the microenvironment of esophageal squamous cell carcinoma (ESCC). Hypoxia could stimulate tumor cells to secrete more exosomes and activate TAMs to M2 type. Here, we investigated the function and the underlying mechanism of tumor-derived exosomal hsa-circ-0048117 in TAM polarization in ESCC. Collectively, these data indicate that PC cells generate miR-301a-3p-rich exosomes in a hypoxic microenvironment, which then polarize macrophages to promote malignant behaviors of PC cells.Methods: Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to analyze the physical characteristics of exosomes. High-throughput sequencing and bioinformatic analysis were performed to screen the potential exosomal circRNA. FISH, Ago2 RIP, pull-down and dual-luciferase reporter assay were conducted to figure out the correlation among hsa-circ-0048117, miR-140 and toll-like receptor 4 (TLR4). Flow cytometry and Western blot were used to evaluate their joint effect in macrophages polarization. Then, the invasion and migration ability were evaluated by transwell experiment. At last, serum exo-hsa-circ-0048117 in ESCC patients was compared and the correlation between its expression and T stage, N stage and TNM grades was analyzed.Results: Hsa-circ-0048117 was significantly upregulated and enriched in exosomes secreted by hypoxia pre-challenged tumor cells and contributed to M2 macrophage polarization. Hsa-circ-0048117 depletion in macrophage led to inhibition of M2 polarization while restoration of hsa-circ-0048117 could rescue the process. Moreover, hsa-circ-0048117 could act as sponge of miR-140 by competing with TLR4 to facilitate the M2 macrophage polarization. Exo-hsa-circ-0048117 could be transmitted to macrophages to promote M2 polarization and M2 macrophages could enhance the ability of invasion and migration of tumor cells by secreting Arg1, IL-10 and TGF-β. Higher serum exo-hsa-circ-0048117 predicted an advanced T and N stage and positively correlated with TNM grade.Conclusion: Our findings indicated that ESCC cells generate hsa-circ-0048117-rich exosomes in a hypoxic microenvironment; hsa-circ-0048117 was believed to promote M2 macrophage polarization which favors the malignant behaviors of ESCC cells. These results reminded us that exosomal hsa-circ-0048117 may play a key role in remodeling the microenvironment and modulating progression in ESCC.Keywords: esophageal squamous cell carcinoma, hypoxia, tumor-associated macrophage, exosomes, hsa-circ-0048117

Xinyu Wang,* Qijue Lu,* Xiang Fei,* Yue Zhao, Bowen Shi, Chunguang Li, Hezhong Chen Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, People's Republic of China*These authors contributed equally to this workCorrespondence: Hezhong Chen; Chunguang LiDepartment of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, People's Republic of ChinaTel +86 186 2127 9206Fax +86 21 5578 6638Email chzchangahai@163.com; smmuchanghai@163.comBackground: Our previous study demonstrated that Id-1 may promote the tumorigenicity of esophageal squamous cell carcinoma (ESCC). Id-4 is another member of Id family, which is rare to be studied in ESCC. In this study, we investigated the expression of Id-4 in human ESCC specimens and determined whether Id-4 expression was associated with the clinicopathologic characteristic and the prognosis of ESCC patients.Methods: We examined Id-4 expression using immunohistochemistry in 92 ESCC tissues and adjacent normal tissues. The association between Id-4 expression and clinical parameters and survival was evaluated by statistical analysis. Cox regression analyses were conducted to identify prognostic factors associated with overall survival (OS). In addition, we explored the functional mechanism of Id-4 in ESCC.Results: Id-4 expression was significantly downregulated in ESCC tissues compared with adjacent normal tissues. The expression of Id-4 was associated negatively with pT stage (p=0.002), AJCC stage (p=0.008) and histologic differentiation (p< 0.001). OS was more unfavorable in patients with low expression of Id-4 than those with high expression of ESCC patients (p=0.007). In subgroup analysis, low expression of Id-4 could reveal unfavorable OS of patients with pT1b/T2 stage (p=0.024) or with pN0/N1 stage (p=0.004). By univariate analysis, pT stage and Id-4 expression showed statistically significant associations with OS (p=0.025, p=0.01, respectively). By multivariate analysis, Id-4 expression was an independent prognostic factor in ESCC (p =0.038). In addition, we observed that Id-4 could decrease the levels of the p-Smad2, p-Smad3 and TGF-β 1 in both Eca109 and TE1 cells, indicating Id-4 may inactivate the TGF-β signaling pathway.Conclusion: Low expression of Id-4 suggested unfavorable prognosis for ESCC patients and could identify the prognosis in patients of early-stage tumors. The potential mechanism for Id-4's tumor suppressor role in ESCC may be related to its inhibitory effect on TGF-β signaling pathway. Thus, we believe that Id-4 may be a promising prognostic marker and a therapeutic target in ESCC.Keywords: Id-4, esophageal squamous cell carcinoma, prognosis, TGF-β signaling pathway