Abstract: Background and purpose: Low-density lipoprotein receptor-related protein 8 (LRP8) plays an important role in the development of liver cancer, lung cancer, breast cancer, colorectal cancer and other tumors. This study aimed to explore the expression and prognostic role of LRP8 in gastric cancer, and evaluate the possibility of a new target for gastric cancer biotherapy. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were used to analyze the expression of LRP8 in gastric cancer tissues. The co-expressed gene with LRP8 in gastric cancer was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RNA interference (RNAi) was used for silencing the expression of LRP8 in AGS cell line, and functional assays were performed to evaluate the effects of LRP8 knockdown on the proliferation ability, invasiveness and the Wnt signaling pathway of AGS cell line in vitro. The relationship between LRP8 expression and prognosis of patients with gastric cancer was assessed by using Kaplan-Meier plotter database. To validate the 240 gastric cancer patients from TCGA database results, retrospective immunohistochemical analysis was performed to classify the relationship between the expression of LRP8 and clinical pathological features of 25 gastric cancer patients who underwent total or subtotal gastrectomy from August 2018 to July 2019 in the Fifth Affiliated Hospital of Zhengzhou University. Results: Data from the TCGA database showed LRP8 was overexpressed in gastric cancer tissues compared with normal gastric mucosa (P<0.000 1), and three studies from GEO database gave consistent results (P<0.05). Functional cell-based assays demonstrated that compared with the control group, proliferation ability and invasiveness of si-LRP8 AGS cell line were reduced in vitro, and the expressions of β-catenin, LRP5, POU5F1, CCND1 and AXIN2 were downregulated (all P<0.05). Survival analysis results of the two probes from Kaplan-Meier plotter database displayed the poor prognosis in patients with high expression of LRP8 (P<0.05). TCGA data containing 240 gastric cancer patients demonstrated a positive correlation between high expression of LRP8 and patient’s age (P<0.001), while the results from 25 patients showed a positive association with tumor stage (P=0.034). Conclusion: LRP8 is overexpressed in gastric cancer, which may promote the malignant transformation of gastric cancer cells by regulating Wnt/β-catenin signaling pathway activity and may be a new molecular mechanism of gastric tumorigenesis. Gastric cancer patients with high expression of LRP8 have decreased long-term survival, and LRP8 is expected to become a treatment or prognostic biomarker of gastric cancer.

Key words: Gastric cancer, Low-density lipoprotein receptor-related protein 8, The Cancer Genome Atlas, Gene Expression Omnibus, Kaplan-Meier plotter, Functional cell-based assays, Wnt signaling pathway