Soluble programmed death-ligand 1 (sPD-L1) levels can be used as a biomarker for gastric cancer (GC). However, comprehensive information regarding the sPD-L1 expression profiles and their association with cachexia in GC is lacking. Therefore, the present study evaluated the association between clinicopathological findings and sPD-L1 levels in patients with GC. Serum samples were collected from patients with GC during their first visit to Department of Esophageal-Gastro-Intestinal Surgery, Chiba University Hospital, Chiba, Japan (January 2012-December 2017; n=173), and sPD-L1 levels were measured using an enzyme-linked immunosorbent assay. Survival rates among 116 patients, excluding cases with preoperative chemotherapy or no radical procedures, were analyzed. sPD-L1 levels were associated with factors such as neutrophil-to-lymphocyte ratio, hemoglobin (Hb) and albumin (Alb) levels, total cholesterol and C-reactive protein (CRP) levels, and related to inflammation and nutrition in patients. Notably, the higher the number of applicable indicators related to cachexia (Hb <12 g/dl, Alb <3.2 g/dl, CRP >0.5 mg/dl and low body mass index) was, the higher the sPD-L1 value was. However, the pathological stage did not significantly differ between the groups. Clinicopathologically, there was no association with tumor depth, lymph node metastasis or vascular invasion; however, patients with the intestinal type had significantly higher sPD-L1 levels than patients with the diffuse type (P=0.032; Wilcoxon test). The overall survival did not significantly differ between the groups with low and high sPD-L1 levels; however, among patients who received radical treatment, the relapse-free survival was significantly worse in the high-sPD-L1-level group than in the low-sPD-L1-level group (P=0.025; log-rank test). Multivariate Cox regression analysis revealed that a high sPD-L1 concentration was a sign of poor prognosis, independent of pathological stage and cancer antigen CA19-9 (P=0.0029). Therefore, the present findings suggest that sPD-L1 can reflect cachexia status in patients with GC and may serve as a prognostic marker for relapse-free survival after radical GC surgery.

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Hypoxia inducible factor -1α (HIF-1α) and Wnt/β-catenin signal pathway has been reported to be involved in tumor progression in various types of cancers. However, the molecular mechanism by which HIF-1α regulate malignant features in esophageal squamous cell carcninoma (ESCC) are still poorly understood. This study aimed to clarify the significance of the crosstalk between HIF-1α and the Wnt/β-catenin pathway in ESCC. The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. Then we performed qRT-PCR, western blotting, Cell Counting-8 assay, trans-well assay, flow cytometry, immunofluorescence, Co-IP and ChIP assays, chemo resistance test in vitro, tumor xenograft model in vivo. The expression level of HIF-1α, β-catenin, and TCF4/TCF7L2 in ESCC cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, igration/invasion and EMT progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-catenin and TCF4/TCF7L2 were increased in ESCC tumor tissues. High levels of HIF-1α and TCF4/TCF7L2 were correlated with poor prognosis in ESCC. HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/β-catenin pathway. Our study clarifies the critical role of HIF-1α in ESCC progression.