Systematic Characterization of the Clinical Relevance of KPNA4 in Pancreatic Ductal Adenocarcinoma

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with poor prognosis. Karyopherin subunit alpha 4 (KPNA4) is a nuclear transport factor and plays tumor-promoting roles in multiple cancers. However, the roles of KPNA4 in PDAC still remain unknown. This study investigated the prognostic value of KPNA4 and its potential functions in PDAC and tumor microenvironment. METHODS: LinkedOmics was utilized to screen genes with survival significance in PDAC. KPNA4 expression was analyzed using multiple datasets and verified in PDAC cells and clinical samples by qRT-PCR and immunohistochemistry. Clinical correlation and survival analyses were conducted to identify the clinical significance and prognostic value of KPNA4 in PDAC patients. Subsequently, KPNA4 was knocked down in PDAC cell lines, and CCK-8, colony formation and wound healing assays were performed to test the functions of KPNA4 in vitro. Immune infiltration analysis was performed to explore the potential roles of KPNA4 in the tumor microenvironment of PDAC. Moreover, functional analyses were conducted to explore the underlying mechanism of KPNA4 in the progression of PDAC. RESULTS: We found KPNA4 was significantly upregulated in PDAC cells and tissues. KPNA4 expression was associated with tumor progression in PDAC patients. Survival analyses further revealed that KPNA4 could act as an independent predictor of unfavorable survival for PDAC patients. KPNA4 knockdown suppressed the viability, colony formation and migration of PDAC cells. Moreover, KPNA4 was correlated with immunosuppressive cells infiltration and T cell exhaustion in the tumor microenvironment of PDAC. Finally, functional analyses indicated the association of KPNA4 with focal adhesion kinase (FAK) signaling, and KPNA4 silencing significantly decreased the expression of FAK and PD-L1. CONCLUSIONS: This study revealed that KPNA4 is an independent prognostic biomarker for PDAC and plays a tumor-promoting role by facilitating proliferation and migration of cancer cells and participating in immune infiltration, which may be mediated by FAK signaling and PD-L1 expression. These results provide a novel and potential therapeutic target for pancreatic cancer.