LPPR4 promotes peritoneal metastasis via Sp1/integrin α/FAK signaling in gastric cancer

Gastric cancer (GC) is one of the most common malignancies which has high incidence and mortality worldwide. Peritoneal dissemination is the main route of metastasis in advanced GC. However, few reliable diagnostic or prognostic biomarkers are available for peritoneal metastasis of GC. This study aimed to investigate the effect of lipid phosphate phosphatase-related protein type 4 (LPPR4) on the prognosis of peritoneal metastasis in GC, so as to explore the underlying molecular mechanisms and clinical significance of the process. Differentially expressed genes (DEGs) between tumor tissues and adjacent normal tissues were identified. The prognostic values of the DEGs were tested in two independent cohorts (TCGA-STAD cohort and GSE62254 cohort). Eight DEGs including LPPR4 with prognostic value in GC peritoneal metastasis were identified. The expression of LPPR4 increased in peritoneal metastasis of GC tissues, and high LPPR4 expression was associated with poor overall survival in GC. Loss- and gain-of functional experiments were performed to reveal that LPPR4 could promote the migration, invasion and adhesion abilities of GC cells in vitro. Tumor peritoneal dissemination was investigated in a mouse model to reveal that LPPR4 could promote peritoneal metastasis of GC cells in vivo. According to the Kyoto Encyclopedia of Genes and Genomics (KEGG) and gene set enrichment analysis (GSEA), LPPR4 was found to be related to focal adhesion, cell adhesion molecules (CAMs) and ECM-receptor interaction pathways. LPPR4 knockdown significantly inhibited the expression of integrin alpha 1, integrin alpha 2, integrin alpha 5, integrin alpha 6, integrin alpha 7, p-FAK, p-Akt, p-Src and MMP2. Moreover, this process was regulated by the Specificity Protein 1 (Sp1) transcription factor. Taken together, LPPR4 plays an essential role in promoting peritoneal metastasis of GC through Sp1/integrin alpha/FAK signaling, and acts as a novel biomarker of prognosis of GC peritoneal metastasis. The results suggest that LPPR4 may serve as a new therapeutic target for patients with GC peritoneal metastasis.