PHC2 as a novel predictive biomarker and therapeutic target for cisplatin resistance in lung adenocarcinoma

With the highest global mortality among all malignancies, lung cancer remains a critical concern for public health, burdening both clinical management and healthcare delivery systems.Currently, platinum-based combination chemotherapy remains the standard first-line treatment option for many lung cancer patients.Nevertheless, the emergence of intrinsic or acquired resistance to platinum agents poses a major challenge in clinical management, highlighting the urgent need to discover and characterize genetic determinants of resistance. Using CRISPR/Cas9 gene-editing technology in conjunction with a Human Epigenetic Library, we performed a genome-wide screen to identify novel genes associated with cisplatin resistance in lung adenocarcinoma (LUAD) cell lines. We further explored the biological function of PHC2 by analyzing The Cancer Genome Atlas (TCGA) database and validating its role through extensive in vitro functional assays. Notably, high-throughput sequencing and cisplatin resistance assays identified PHC2 as a novel gene implicated in cisplatin resistance. Functional experiments, including cell proliferation assays, wound healing assays, and apoptosis analyses, demonstrated that PHC2 substantially influences LUAD cell proliferation, migration, and apoptosis. Immunohistochemistry revealed a correlation between PHC2 expression levels and smoking history in LUAD tissue samples. However, Kaplan-Meier survival analysis indicated no statistically significant association between PHC2 expression and overall survival among LUAD patients. Mining of the TCGA database showed that in LUAD tumors, the PHC2 mRNA expression was significantly elevated relative to nearby noncancerous tissues and exhibited a significant link with lymph node metastasis and smoking history. Interestingly, immune infiltration analysis revealed that elevated PHC2 expression correlated with increased infiltration of macrophages, natural killer cells, dendritic cells, immature DCs, neutrophils, eosinophils, and mast cells. RNA sequencing analysis suggested that PHC2 may contribute to cisplatin resistance through the epigenetic reactivation and transcriptional upregulation of genes associated with the ABC transporter family, axon guidance pathways, and complement/coagulation cascades. Collectively, these findings suggest that PHC2 could serve as a predictive biomarker for cisplatin resistance and represent a promising therapeutic target for treating cisplatin resistance in LUAD.