Klotho and LRP6 as Emerging Biomarkers in Gastric Adenocarcinoma: Expression Patterns and Clinical Relevance

Gastric cancer (GC) is often diagnosed at an advanced stage, limiting treatment options and leading to poor outcomes. Klotho, a transmembrane anti-aging protein, generally functions as a tumor suppressor, while low-density lipoprotein receptor-related protein 6 (LRP6), a member of the low-density lipoprotein receptor family, is frequently overexpressed in various cancers. Klotho and LRP6 proteins are emerging regulators of Wnt/β-catenin signaling with potential roles in tumor biology. This retrospective study aimed to assess the prognostic significance of Klotho and LRP6 expression in gastric adenocarcinoma (GAC). Immunohistochemical analysis was conducted on tumor samples from 73 GAC patients. Low Klotho expression was significantly associated with younger age at diagnosis (P=0.006), poorly cohesive carcinoma (PCC) and mucinous adenocarcinoma (MAC) variants (P<0.001), diffuse type according to Lauren classification (P=0.001), high-grade tumors (P<0.001), lymph node (L.N) metastasis (P=0.038), and distant metastases (P=0.010), and advanced TNM stage (P=0.033). High LRP6 expression was significantly correlated with diffuse type (P=0.023), distant metastasis (P=0.011), and advanced TNM staging (P=0.046). Both low Klotho and high LRP6 expressions were associated with reduced overall survival (OS). Multivariate analysis identified high LRP6 expression as an independent predictor of poor OS and progression-free survival (PFS). In conclusion, low Klotho-high LRP6 expression was associated with poor OS, supporting its role as a prognostic biomarker and potential therapeutic target. Validation in larger patient cohorts is warranted to confirm their clinical utility.