POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma
DNA polymerase delta 1 catalytic subunit (POLD1) plays a vital role in genomic copy with high fidelity and DNA damage repair processes. However, the prognostic value of POLD1 and its relationship with tumor immunity in clear cell renal cell carcinoma (ccRCC) remains to be further explored. Transcrip...
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/7/6849 |
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| author | Junjie Tian Cheng Cheng Jianguo Gao Guanghou Fu Zhijie Xu Xiaoyi Chen Yunfei Wu Baiye Jin |
| author_facet | Junjie Tian Cheng Cheng Jianguo Gao Guanghou Fu Zhijie Xu Xiaoyi Chen Yunfei Wu Baiye Jin |
| author_sort | Junjie Tian |
| collection | DOAJ |
| description | DNA polymerase delta 1 catalytic subunit (POLD1) plays a vital role in genomic copy with high fidelity and DNA damage repair processes. However, the prognostic value of POLD1 and its relationship with tumor immunity in clear cell renal cell carcinoma (ccRCC) remains to be further explored. Transcriptional data sets and clinical information were obtained from the TCGA, ICGC, and GEO databases. Differentially expressed genes (DEGs) were derived from the comparison between the low and high POLD1 expression groups in the TCGA–KIRC cohort. KEGG and gene ontology (GO) analyses were performed for those DEGs to explore the potential influence of POLD1 on the biological behaviors of ccRCC. The prognostic clinical value and mutational characteristics of patients were described and analyzed according to the POLD1 expression levels. TIMER and TISIDB databases were utilized to comprehensively investigate the potential relevance between the POLD1 levels and the status of the immune cells, as well as the tumor infiltration of immune cells. In addition, RT-qPCR, Western blot, immunohistochemistry and several functional and animal experiments were performed for clinical, in vitro and in vivo validation. POLD1 was highly expressed in a variety of tumors including ccRCC, and further verified in a validation cohort of 60 ccRCC samples and in vitro cell line experiments. POLD1 expression levels in the ccRCC samples were associated with various clinical characteristics including pathologic tumor stage and histologic grade. ccRCC patients with high POLD1 expression have poor clinical outcomes and exhibit a higher rate of somatic mutations than those with low POLD1 expression. Cox regression analysis also showed that POLD1 could act as a potential independent prognostic biomarker. The DEGs associated with POLD1 were significantly enriched in the immunity-related pathways. Moreover, further immune infiltration analysis indicated that high POLD1 expression was associated with high NK CD56bright cells, Treg cells, and myeloid-derived suppressor cells’ (MDSCs) infiltration scores, as well as their marker gene sets of immune cell status. Meanwhile, POLD1 exhibited resistance to various drugs when highly expressed. Finally, the knockdown of POLD1 inhibited the proliferation and migration, and promoted the apoptosis of ccRCC cells in vitro and in vivo, as well as influenced the activation of oncogenic signaling. Our current study demonstrated that POLD1 is a potential prognostic biomarker for ccRCC patients. It might create a tumor immunosuppressive microenvironment and inhibit the susceptibility to ferroptosis leading to a poor prognosis. |
| first_indexed | 2024-03-11T05:33:41Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
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| spelling | doaj.art-421141f70da5466189836bb0f8b495702023-11-17T16:56:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01247684910.3390/ijms24076849POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell CarcinomaJunjie Tian0Cheng Cheng1Jianguo Gao2Guanghou Fu3Zhijie Xu4Xiaoyi Chen5Yunfei Wu6Baiye Jin7Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310024, ChinaDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310024, ChinaDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310024, ChinaDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310024, ChinaDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310024, ChinaDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310024, ChinaDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310024, ChinaDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310024, ChinaDNA polymerase delta 1 catalytic subunit (POLD1) plays a vital role in genomic copy with high fidelity and DNA damage repair processes. However, the prognostic value of POLD1 and its relationship with tumor immunity in clear cell renal cell carcinoma (ccRCC) remains to be further explored. Transcriptional data sets and clinical information were obtained from the TCGA, ICGC, and GEO databases. Differentially expressed genes (DEGs) were derived from the comparison between the low and high POLD1 expression groups in the TCGA–KIRC cohort. KEGG and gene ontology (GO) analyses were performed for those DEGs to explore the potential influence of POLD1 on the biological behaviors of ccRCC. The prognostic clinical value and mutational characteristics of patients were described and analyzed according to the POLD1 expression levels. TIMER and TISIDB databases were utilized to comprehensively investigate the potential relevance between the POLD1 levels and the status of the immune cells, as well as the tumor infiltration of immune cells. In addition, RT-qPCR, Western blot, immunohistochemistry and several functional and animal experiments were performed for clinical, in vitro and in vivo validation. POLD1 was highly expressed in a variety of tumors including ccRCC, and further verified in a validation cohort of 60 ccRCC samples and in vitro cell line experiments. POLD1 expression levels in the ccRCC samples were associated with various clinical characteristics including pathologic tumor stage and histologic grade. ccRCC patients with high POLD1 expression have poor clinical outcomes and exhibit a higher rate of somatic mutations than those with low POLD1 expression. Cox regression analysis also showed that POLD1 could act as a potential independent prognostic biomarker. The DEGs associated with POLD1 were significantly enriched in the immunity-related pathways. Moreover, further immune infiltration analysis indicated that high POLD1 expression was associated with high NK CD56bright cells, Treg cells, and myeloid-derived suppressor cells’ (MDSCs) infiltration scores, as well as their marker gene sets of immune cell status. Meanwhile, POLD1 exhibited resistance to various drugs when highly expressed. Finally, the knockdown of POLD1 inhibited the proliferation and migration, and promoted the apoptosis of ccRCC cells in vitro and in vivo, as well as influenced the activation of oncogenic signaling. Our current study demonstrated that POLD1 is a potential prognostic biomarker for ccRCC patients. It might create a tumor immunosuppressive microenvironment and inhibit the susceptibility to ferroptosis leading to a poor prognosis.https://www.mdpi.com/1422-0067/24/7/6849clear cell renal cell carcinomaPOLD1cell proliferationimmune infiltrationprognosis |
| spellingShingle | Junjie Tian Cheng Cheng Jianguo Gao Guanghou Fu Zhijie Xu Xiaoyi Chen Yunfei Wu Baiye Jin POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma International Journal of Molecular Sciences clear cell renal cell carcinoma POLD1 cell proliferation immune infiltration prognosis |
| title | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
| title_full | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
| title_fullStr | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
| title_full_unstemmed | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
| title_short | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
| title_sort | pold1 as a prognostic biomarker correlated with cell proliferation and immune infiltration in clear cell renal cell carcinoma |
| topic | clear cell renal cell carcinoma POLD1 cell proliferation immune infiltration prognosis |
| url | https://www.mdpi.com/1422-0067/24/7/6849 |
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