Integrative Analysis of Genetic Variation, Immune Infiltration and ceRNA Network Construction of PDHA1 in Breast Cancer

GUO Miaolan; YI Jianing; YANG Qiuyi; FAN Peizhi; YU Jie; ZENG Jie

PDF(9932 KB)

Journal of Hunan Normal University(Medical Science) ›› 2024, Vol. 21 ›› Issue (6) : 11-21.

Basic Medicine

Integrative Analysis of Genetic Variation, Immune Infiltration and ceRNA Network Construction of PDHA1 in Breast Cancer

GUO Miaolan, YI Jianing, YANG Qiuyi, FAN Peizhi, YU Jie, ZENG Jie

Author information +

History +

Abstract

Objective To comprehensively analyze the expression and the biological role of the pyruvate dehydrogenase E1α subunit (PDHA1) in breast cancer using bioinformatics methods and clinical sample experiments. Methods TCGA and GTEx databases were mined to explore the mRNA expression levels of PDHA1 in breast cancer and normal tissues; clinical samples were collected from our hospital for immunohistochemistry experiments to verify the expression of PDHA1 proteins; The gene-disease network of PDHA1 was constructed on the OPENTARGET platform, and the cBioportal website was accessed to analyze the genetic variations of PDHA1, using the TIMER and GEPIA databases to analyze the relationship between PDHA1 expression and immune infiltrating cells and their markers in BRCA, analyzing the GO and KEGG enrichment of PDHA1 co-expressed genes. The breast cancer ceRNA regulatory network was constructed by miRcode, miRTarBase, TargetScan, and miRDB database analysis. Results The PDHA1 gene was lowly expressed in breast cancer tissues, which was statistically different in patients' clinical stage, T stage, ethnicity, tissue typing, and molecular typing; immunohistochemistry experiments of clinical samples suggested that the PDHA1 protein was lowly stained with BRCA staining; genetic variant analysis suggested that gene amplification and mutation were the most common genetic alterations of PDHA1 in breast cancer. Analysis of the TIMER and GEPIA databases showed that PDHA1 expression was associated with immune cell infiltration. The functions of PDHA1 co-expressed genes were enriched in chromosome segregation, DNA replication, and cell cycle pathways. Correlation analysis showed that 7 miRNAs and 38 lncRNAs associated with PDHA1 were involved in the construction of the breast cancer ceRNA regulatory network. Conclusion PDHA1 was lowly expressed in the breast cancer and associated with the ceRNA network and immune infiltration. The DEG and pathways identified in this study provide a preliminary basis for further research on the occurrence and development of the breast cancer.

Key words

breast cancer / pyruvate dehydrogenase E1α subunit / genetic variation / immune infiltration / bioinformatics analysis

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

GUO Miaolan, YI Jianing, YANG Qiuyi, FAN Peizhi, YU Jie, ZENG Jie. Integrative Analysis of Genetic Variation, Immune Infiltration and ceRNA Network Construction of PDHA1 in Breast Cancer[J]. Journal of Hunan Normal University(Medical Science). 2024, 21(6): 11-21

References

[1] JIA T, LIU Y, FAN Y, et al.Association of Healthy Diet and Physical Activity With Breast Cancer: Lifestyle Interventions and Oncology Education[J]. Front Public Health, 2022, 10: 797794.
[2] NAGINI S.Breast Cancer: Current Molecular Therapeutic targets and New players[J]. Anticancer Agents Med Chem, 2017, 17(2): 152-163.
[3] KLEIBL Z, KRISTENSEN VN.Women at high risk of breast cancer: Molecular characteristics, clinical presentation and management[J]. Breast, 2016(28): 136-144.
[4] ASCHELL JC, OLSON KA, JIANG L, et al.A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth[J]. Mol Cell, 2014, 56(3): 400-413.
[5] GOGVADZE V, ZHIVOTOVSKY B, ORRENIUS S.The Warburg effect and mitochondrial stability in cancer cells[J]. Mol Aspects Med, 2010, 31(1): 60-74.
[6] GILLIES RJ, GATENBY RA.Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis?[J]. J Bioenerg Biomembr, 2007, 39(3): 251-257.
[7] ZHAO L, GENG R, HUANG Y, et al.AP2α negatively regulates PDHA1 in cervical cancer cells to promote aggressive features and aerobic glycolysis in vitro and in vivo[J]. Gynecol Oncol, 2023, 34(5): e59.
[8] CHEN TY, HSIEH YT, HUANG JM, et al.Determination of pyruvate metabolic fates modulates head and neck tumorigenesis[J]. Neoplasia, 2019, 21(7): 641-652.
[9] BIAN ZL, FAN R, XIE LM.A novel cuproptosis-related prognostic gene signature and validation of differential expression in clear cell renal cell carcinoma[J]. Genes, 2022, 13(5): 851.
[10] LI TW, FAN JY, WANG BB, et al.TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells[J]. Cancer Res, 2017, 77(21): e108-110.
[11] TANG Z, LI C, KANG B, et al.GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses[J]. Nucleic Acids Res, 2017, 45(W1): W98-W102.
[12] WANG ZN, JENSEN MA, ZENKLUSEN JC.A practical Guide to the cancer genome atlas (TCGA)[J]. Methods Mol Biol, 2016, 1418: 111-141.
[13] LIU CJ, HU FF, XIA MX, et al.GSCALite: a web server for gene set cancer analysis[J]. Bioinformatics, 2018, 34(21): 3771-3772.
[14] GAO J, AKSOY B A, DOGRUSOZ U, et al.Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal[J]. Sci Signal, 2013, 6(269): l1.
[15] SUBRAMANIAN A, TAMAYO P, MOOTHA VK, et al.Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profifiles[J]. Proc Natl Acad Sci USA, 2005, 102(43): 15545-15550.
[16] BINDEA G, MLECNIK B, TOSOLINI M, et al.Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer[J]. Immunity, 2013, 39(4): 782-795.
[17] LI J H, LIU S, ZHOU H, et al.starBase v2. 0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data[J]. Nucleic Acids Res, 2014, 42(D1): D92-D97.
[18] AGARWAL V, BELL G W, NAM J W, et al.Predicting effective microRNA target sites in mammalian mRNAs[J]. Elife, 2015, 4: e05005.
[19] CHANG L, ZHOU G, SOUFAN O, et al.2. 0: Network-based visual analytics for miRNA functional analysis and systems biology[J]. Nucleic Acids Res, 2020, 48(pp): W244-W251.
[20] GOGVADZE V, ZHIVOTOVSKY B, ORRENIUS S.The Warburg effect and mitochondrial stability in cancer cells[J]. Mol Aspects Med, 2010, 31(1): 60-74.
[21] 吴雅珣, 张邢松, 沈蓉, 等. 子宫颈鳞状细胞癌中PDHA1的表达及临床意义[J]. 临床与实验病理学杂志, 2022, 38(03): 284-288.
[22] SONG L, LIU D, ZHANG X, et al.Low expression of PDHA1 predicts poor prognosis in gastric cancer[J]. Pathol Res Pract, 2019, 215(3): 478-482.
[23] 杨秋怡, 易嘉宁, 郭妙兰, 等. 铜死亡相关基因PDHA1与乳腺癌的预后关系及列线图的构建[J]. 中国普通外科杂志, 2022, 31(11): 1471-1482.
[24] CHEN J, GUCCINI I, DI MITRI D, et al.Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer[J]. Nature genetics, 2018, 50(2): 219-228.
[25] GARNIS C, BUYS TP, LAM WL.Genetic alteration and gene expression modulation during cancer progression[J]. Mol Cancer, 2004, 3: 1-23.
[26] WANG M, CHANG M, LI C, et al.Tumor-Microenvironment-Activated Reactive Oxygen Species Amplifier for Enzymatic Cascade Cancer Starvation/Chemodynamic /Immunotherapy[J]. Adv Mater, 2022, 34(4): e2106010.
[27] SHARMA P, HU-LIESKOVAN S, WARGO JA, et al.Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy[J]. Cell, 2017, 168(4): 707-723.
[28] CARMENA M, WHEELOCK M, FUNABIKI H, et al.The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis[J]. Nat Rev Mol Cell Biol, 2012, 13(12): 789-803.
[29] SLACK FJ, CHINNAIYAN AM.The Role of Non-coding RNAs in Oncology[J]. Cell, 2019, 179(5): 1033-1055.
[30] SHAFAROUDI A M, SHARIFI-ZARCHI A, RAHMANI S, et al.Expression and function of C1orf132 long-noncoding RNA in breast cancer cell lines and tissues[J]. Int J Mol Sci, 2021, 22(13): 6768.
[31] LIU M, YANG J, LV W, et al. Down-regulating GRP78 reverses pirarubicin resistance of triple negative breast cancer by miR-495-3p mimics and involves the p-AKT/mTOR pathway[J]. Biosci Rep, 2022, 42(1): BSR20210245.
[32] GU J, ZHANG J, HUANG W, et al.Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4+ T cells[J]. Ann Transl Med, 2020, 8(6): 279-294.
[33] FU Y, SHAO Z M, HE Q Z, et al.Hsa-miR-206 represses the proliferation and invasion of breast cancer cells by targeting Cx43[J]. Eur Rev Med Pharmacol Sci, 2015, 19(11): 2091-2104.