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Published on: January 19, 2019
Comprehensive analysis of POLD2 as a potential biomarker for modulating the immune microenvironment and predicting
Wu Zhu1, Hong Zhang2, Zhiqin Guo2
1Department of Blood Transfusion, Affiliated Women and Children Hospital of Jiaxing University, Jiaxing, China.
Background:
Lung adenocarcinoma (LUAD) is the leading cause of global cancer mortality. Although significant progress has been made in treatment modalities, including surgery, radiation, chemotherapy, targeted agents and immunotherapies, clinical outcomes for patients continue to be unfavorable. Key obstacles include disease recurrence, metastasis and the development of treatment resistance. This study aimed to explore molecular mechanisms driving LUAD progression and identify novel prognostic biomarkers and therapeutic targets.
Methods:
Gene expression data for LUAD were retrieved from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases to conduct a preliminary investigation. The differential expression of POLD2 was validated by analyzing gene expression datasets from the Gene Expression Omnibus (GEO). Clinical patient data with survival information from the TCGA and GEO databases were employed to investigate and validate the prognostic significance of POLD2. The association of POLD2 with the tumor immune microenvironment (TIME) was examined through RNA transcript-based single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE algorithm, which quantifies stromal and immune cell components in malignant tumor tissues based on expression data. The Tumor Immune Dysfunction and Exclusion (TIDE) model was used to evaluate the potential therapeutic response of POLD2 to immune checkpoint inhibitors (ICIs). Molecular docking and molecular dynamics (MD) simulations were used to investigate the binding interactions between POLD2 and specific therapeutic agents. In vitro functional assays were performed to validate the role of POLD2 in the progression of LUAD.
Results:
Our study demonstrated that POLD2 is markedly upregulated in LUAD, which is associated with unfavorable patient outcomes and more advanced disease stages. Functional analyses revealed that POLD2 is critically involved in essential biological process (BP), including DNA repair, cell cycle control, and epithelial-mesenchymal transition (EMT), all of which are key contributors to tumor progression. Furthermore, immunological investigations, the core focus of this study, indicated that POLD2 is linked to an immunosuppressive microenvironment, a factor that may impair the efficacy of ICIs and thus compromise immunotherapy response. As an extended exploratory analysis to further explore POLD2's therapeutic potential, molecular docking and MD simulations revealed strong binding interactions between POLD2 and MEK inhibitors, including PD0325901, selumetinib and trametinib. In vitro studies showed that suppressing POLD2 expression significantly decreased the proliferation, colony-forming ability and migratory capacity of A549 LUAD cells.
Conclusions:
Our results identify POLD2 as a promising prognostic biomarker and a potential therapeutic target in LUAD, with particular relevance to predicting immunotherapy response-consistent with the core focus of this study. This finding not only provides important insights into the mechanisms underlying LUAD progression and treatment resistance but also lays a preliminary foundation for subsequent research on both immunotherapeutic optimization and targeted therapy (via MEK inhibitors) for LUAD.
