UBQLN4 Is a Prognostic Biomarker in Intrahepatic Cholangiocarcinoma That Is Associated with Cisplatin Resistance

Abstract

Highlights What are the main findings? Ubiquilin-4 (UBQLN4) mRNA expression was significantly elevated in intrahepatic cholangiocarcinoma (iCCA) compared to normal liver tissue. Elevated UBQLN4 mRNA expression was associated with shorter recurrence-free and overall survival across independent multicenter iCCA patient cohorts. What are the implications of the main findings? These findings identify UBQLN4 as a clinically relevant biomarker associated with aggressive tumor progression and cisplatin resistance in iCCA. Assessment of UBQLN4 mRNA expression in tumor tissues may improve risk stratification after curative-intent resection and help identify iCCA patients who may benefit from intensified surveillance or future biomarker-guided therapeutic strategies. Abstract Background: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive biliary tract malignancy with limited treatment options and poor prognosis. Platinum-based drugs are one of the major therapies; however, resistance remains a major therapeutic challenge. Ubiquilin-4 (UBQLN4), a ubiquitin-binding protein implicated in cancer progression and DNA damage responses, is located at chromosome 1q22, a region recurrently amplified in several cancers. We investigated the clinical and functional relevance of UBQLN4 in iCCA. Methods: Public datasets (TCGA-CHOL and GSE107943) were analyzed to identify genomic alterations and UBQLN4 expression in iCCA. UBQLN4 mRNA expression was evaluated in an independent clinical cohort and correlated with patient outcomes. Functional studies using iCCA cell lines and three-dimensional spheroid models examined the role of UBQLN4 in cisplatin resistance. Results: Chromosome 1q22, containing UBQLN4, was among the recurrently amplified regions in TCGA-CHOL. UBQLN4 mRNA expression correlated with copy number amplification and was significantly higher in iCCA than in normal liver tissue in both datasets. In the validation cohort, higher UBQLN4 mRNA expression was associated with shorter recurrence-free survival (p = 0.025) and remained associated with shorter recurrence-free survival after adjustment for clinicopathological factors (HR = 2.44; 95% CI 1.14–5.20; p = 0.022). Higher UBQLN4 expression was also associated with poorer pathological response to cisplatin-containing neoadjuvant chemotherapy. In iCCA cell lines, UBQLN4 knockdown increased cisplatin sensitivity, whereas cisplatin-resistant derivatives showed increased UBQLN4 expression. Conclusions: Elevated UBQLN4 expression is associated with adverse clinical outcomes and reduced response to cisplatin-containing chemotherapy in iCCA, while functional studies support a potential role for UBQLN4 in modulating cisplatin sensitivity. These findings identify UBQLN4 as a potential biomarker and therapeutic candidate that warrants further independent and prospective validation.