Therapeutic and Predicted Significance of PKLR in Patients With Cholangiocarcinoma

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BACKGROUND: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy with a poor prognosis. However, the molecular mechanisms underlying CCA and its treatment options remain unclear and limited. AIMS: This study aims to identify novel prognostic biomarkers and potential therapeutic targets for CCA through transcriptomics and whole-exome sequencing analysis. METHODS AND RESULTS: We analyzed the relationship between overall survival and various risk factors in 255 CCA samples from a published dataset and 36 samples from The Cancer Genome Atlas (TCGA) database. Transcriptomics analysis was used to identify genes whose expression plays a crucial role in CCA development and progression. Targeted drug databases were used to examine which gene expression signatures represent potential therapeutic targets for CCA. Mutated genes were analyzed to explore potential mechanisms. Standard statistical methods were applied to analyze associations between clinical data and candidate targets. A nomogram was constructed to predict the prognostic impact of the optimal candidate. Cell experiments were used to demonstrate the role of PKLR in CCA growth and metastasis. We identified FOLH1, PKLR, PTH1R, GPR114, KCNH2, LCN2, MMP10, PORCN, RIPK3, and SRPK3 as potential therapeutic targets for CCA, with PKLR being the most promising candidate based on the computational analyses. PKLR was lowly expressed in CCA tissues. PKLR expression was closely associated with ARID1A and KRAS mutations. PKLR mRNA levels were significantly correlated with tumor size (p = 0.024) and metastasis (p = 0.014). Low PKLR expression in CCA was positively associated with poor survival. A nomogram accurately predicted the prognosis of CCA patients based on PKLR expression levels. Silencing PKLR expression promotes growth and metastasis of CCA in vitro. CONCLUSION: Our findings indicate that PKLR, an independent protective factor in CCA, is a potential prognostic biomarker and a candidate for further investigation as a therapeutic target. PKLR expression is significantly associated with ARID1A and KRAS mutations.

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