Aberrant ALPP Expression Serves as a Prognostic Biomarker and Facilitates Cholangiocarcinoma Progression through Immune Evasion and PI3K-Akt Signaling Activation

TL;DR

Aberrant ALPP expression is linked to poor outcomes in cholangiocarcinoma by promoting immune evasion and activating the PI3K-Akt pathway.

Contribution

This study identifies ALPP as a novel prognostic biomarker in cholangiocarcinoma and reveals its role in immune evasion and oncogenic signaling.

Findings

Elevated ALPP expression correlates with higher CA19-9 levels and reduced survival in CCA patients.

ALPP is associated with increased infiltration of B cells and dendritic cells in CCA tumors.

ALPP expression is linked to PI3K-Akt signaling activation and hypomethylation at a specific CpG site.

Abstract

Cholangiocarcinoma (CCA) is a highly aggressive malignancy and represents the most common form of adenocarcinoma in the hepatobiliary system. Placental alkaline phosphatase (ALPP), a member of the alkaline phosphatase (ALP) isoenzyme family, catalyzes phosphate ester hydrolysis under alkaline conditions. While ALPP overexpression has been observed in various germ cell tumors and specific cancers, its functional relevance and regulatory mechanisms in CCA remain poorly understood. In this study, we evaluated ALPP expression in CCA patient cohorts and explored its correlation with clinicopathological features and patient prognosis. We further assessed the relationship between ALPP expression and tumor-infiltrating immune cells, focusing on B cells and dendritic cells (DCs). To elucidate ALPP-associated molecular networks, weighted gene co-expression network analysis (WGCNA) was performed, followed by functional enrichment analyses using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The methylation landscape of the ALPP gene was also examined. Our findings demonstrated that elevated ALPP expression is significantly associated with increased serum CA19-9 levels and reduced overall survival in CCA patients. Immune infiltration analyses revealed a positive correlation between ALPP expression and the abundance of infiltrating B cells and DCs. WGCNA identified a gene module associated with ALPP that was highly enriched in the PI3K-Akt signaling pathway. Additionally, hypomethylation of a specific CpG site (cg19654061) within the ALPP gene was significantly associated with its upregulation. Collectively, these results suggest that ALPP functions as a potential prognostic biomarker in CCA and may contribute to disease progression through modulation of the immune microenvironment and activation of oncogenic signaling pathways.

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