Dichotomous Effects of Glypican-4 on Cancer Progression and Its Crosstalk with Oncogenes

Glypicans are linked to various aspects of neoplastic behavior, and their therapeutic value has been proposed in different cancers. Here, we have systematically assessed the impact of GPC4 on cancer progression through functional genomics and transcriptomic analyses across a broad range of cancers. Survival analysis using TCGA cancer patient data reveals divergent effects of GPC4 expression across various cancer types, revealing elevated GPC4 expression levels to be associated with both poor and favorable prognoses in a cancer-dependent manner. Detailed investigation of the role of GPC4 in glioblastoma and non-small cell lung adenocarcinoma by genetic perturbation studies displays opposing effects on these cancers, where the knockout of GPC4 with CRISPR/Cas9 attenuated proliferation of glioblastoma and augmented proliferation of lung adenocarcinoma cells and the overexpression of GPC4 exhibited a significant and opposite effect. Further, the overexpression of GPC4 in GPC4-knocked-down glioblastoma cells restored the proliferation, indicating its mitogenic effect in this cancer type. Additionally, a survival analysis of TCGA patient data substantiated these findings, revealing an association between elevated levels of GPC4 and a poor prognosis in glioblastoma, while indicating a favorable outcome in lung carcinoma patients. Finally, through transcriptomic analysis, we attempted to assign mechanisms of action to GPC4, as we find it implicated in cell cycle control and survival core pathways. The analysis revealed upregulation of oncogenes, including FGF5, TGF-β superfamily members, and ITGA-5 in glioblastoma, which were downregulated in lung adenocarcinoma patients. Our findings illuminate the pleiotropic effect of GPC4 in cancer, underscoring its potential as a putative prognostic biomarker and indicating its therapeutic implications in a cancer type dependent manner.