Integrated Bioinformatics Analysis Reveals Marker Genes and Potential Therapeutic Targets for Pulmonary Arterial Hypertension
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Selection
2.2. Data Preprocessing and DEGs Screening
2.3. GO and KEGG Functional Enrichment Analyses
2.4. Co-Expression Network Analysis
2.5. Identification of Candidate Marker Genes
2.6. Validation of Candidate Marker Genes and ROC Curve Analyses
2.7. PAH Model and qRT-PCR
2.8. Statistical Analysis
3. Results
3.1. Data Preprocessing and DEGs Screening
3.2. GO and KEGG Analyses of DEGs
3.3. Construction of WGCNA Network and Identification of the Key Module
3.4. GO and KEGG Analyses of the Key Module
3.5. Identification of Hub Genes
3.6. Validation of Candidate Marker Genes
3.7. ROC Curve Analyses of Hub Genes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Zolty, R. Pulmonary arterial hypertension specific therapy: The old and the new. Pharmacol. Ther. 2020, 214, 107576. [Google Scholar] [CrossRef] [PubMed]
- Humbert, M.; Sitbon, O.; Chaouat, A.; Bertocchi, M.; Habib, G.; Gressin, V.; Yaici, A.; Weitzenblum, E.; Cordier, J.-F.; Chabot, F.; et al. Pulmonary Arterial Hypertension in France. Am. J. Respir. Crit. Care Med. 2006, 173, 1023–1030. [Google Scholar] [CrossRef] [Green Version]
- Bhogal, S.; Khraisha, O.; Al Madani, M.; Treece, J.; Baumrucker, S.; Paul, T.K. Sildenafil for Pulmonary Arterial Hypertension. Am. J. Ther. 2019, 26, e520–e526. [Google Scholar] [CrossRef] [Green Version]
- Chen, X.; Zhai, Z.; Huang, K.; ** m6A-demethylated antiviral transcripts in the nucleus. Nat. Immunol. 2017, 18, 1094–1103. [Google Scholar] [CrossRef] [PubMed]
- Will, C.L.; Urlaub, H.; Achsel, T.; Gentzel, M.; Wilm, M.; Lührmann, R. Characterization of novel SF3b and 17S U2 snRNP proteins, including a human Prp5p homologue and an SF3b DEAD-box protein. EMBO J. 2002, 21, 4978–4988. [Google Scholar] [CrossRef] [PubMed]
- Hirabayashi, R.; Hozumi, S.; Higashijima, S.-I.; Kikuchi, Y. Ddx46 Is Required for Multi-Lineage Differentiation of Hematopoietic Stem Cells in Zebrafish. Stem Cells Dev. 2013, 22, 2532–2542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, B.; Li, Y.-M.; He, W.-T.; Chen, H.; Zhu, H.-W.; Liu, T.; Zhang, J.-H.; Song, T.-N.; Zhou, Y.-L. Knockdown of DDX46 inhibits proliferation and induces apoptosis in esophageal squamous cell carcinoma cells. Oncol. Rep. 2016, 36, 223–230. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Admoni-Elisha, L.; Nakdimon, I.; Shteinfer, A.; Prezma, T.; Arif, T.; Arbel, N.; Melkov, A.; Zelichov, O.; Levi, I.; Shoshan-Barmatz, V. Novel Biomarker Proteins in Chronic Lymphocytic Leukemia: Impact on Diagnosis, Prognosis and Treatment. PLoS ONE 2016, 11, e0148500. [Google Scholar] [CrossRef] [Green Version]
- Li, M.; Ma, Y.; Huang, P.; Du, A.; Yang, X.; Zhang, S.; **ng, C.; Liu, F.; Cao, J. Lentiviral DDX46 knockdown inhibits growth and induces apoptosis in human colorectal cancer cells. Gene 2015, 560, 237–244. [Google Scholar] [CrossRef] [PubMed]
- Lin, Q.; **, H.-J.; Zhang, D.; Gao, L. DDX46 silencing inhibits cell proliferation by activating apoptosis and autophagy in cutaneous squamous cell carcinoma. Mol. Med. Rep. 2020, 22, 4236–4242. [Google Scholar] [CrossRef]
- Jiang, F.; Zhang, D.; Li, G.; Wang, X. Knockdown of DDX46 Inhibits the Invasion and Tumorigenesis in Osteosarcoma Cells. Oncol. Res. Featur. Preclin. Clin. Cancer Ther. 2017, 25, 417–425. [Google Scholar] [CrossRef]
- Zhang, C.; Kuang, M.; Li, M.; Feng, L.; Zhang, K.; Cheng, S. SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression. Sci. Rep. 2016, 6, 34508. [Google Scholar] [CrossRef] [Green Version]
- Chen, L.; Xu, M.; Zhong, W.; Hu, Y.; Wang, G. Knockdown of DDX46 suppresses the proliferation and invasion of gastric cancer through inactivating Akt/GSK-3β/β-catenin pathway. Exp. Cell Res. 2021, 399, 112448. [Google Scholar] [CrossRef]
- Li, S.; Zhai, C.; Shi, W.; Feng, W.; **e, X.; Pan, Y.; Wang, J.; Yan, X.; Chai, L.; Wang, Q.; et al. Leukotriene B4 induces proliferation of rat pulmonary arterial smooth muscle cells via modulating GSK-3β/β-catenin pathway. Eur. J. Pharmacol. 2020, 867, 172823. [Google Scholar] [CrossRef]
- Yu, R.H.; Wang, L.M.; Hu, X.H. MiR-135a inhibitor alleviates pulmonary arterial hypertension through beta-Catenin/GSK-3beta signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 9574–9581. [Google Scholar] [CrossRef] [PubMed]
- Sitbon, O.; Channick, R.; Chin, K.; Frey, A.; Gaine, S.; Galiè, N.; Ghofrani, A.; Hoeper, M.; Lang, I.M.; Preiss, R.; et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N. Engl. J. Med. 2015, 373, 2522–2533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, L.; Roman-Campos, D.; Austin, E.D.; Eyries, M.; Sampson, K.S.; Soubrier, F.; Germain, M.; Trégouët, D.-A.; Borczuk, A.; Rosenzweig, E.B.; et al. A Novel Channelopathy in Pulmonary Arterial Hypertension. N. Engl. J. Med. 2013, 369, 351–361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, X.-J.; Lian, T.-Y.; Jiang, X.; Liu, S.-F.; Li, S.-Q.; Jiang, R.; Wu, W.-H.; Ye, J.; Cheng, C.-Y.; Du, Y.; et al. Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension. Eur. Respir. J. 2019, 53, 1801609. [Google Scholar] [CrossRef] [PubMed]
- Evans, J.D.W.; Girerd, B.; Montani, D.; Wang, X.-J.; Galiè, N.; Austin, E.D.; Elliott, G.; Asano, K.; Grünig, E.; Yan, Y.; et al. BMPR2 mutations and survival in pulmonary arterial hypertension: An individual participant data meta-analysis. Lancet Respir. Med. 2016, 4, 129–137. [Google Scholar] [CrossRef] [Green Version]
- Rol, N.; Kurakula, K.B.; Happé, C.; Bogaard, H.J.; Goumans, M.-J. TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family. Int. J. Mol. Sci. 2018, 19, 2585. [Google Scholar] [CrossRef] [Green Version]
- Drake, K.M.; Dunmore, B.J.; McNelly, L.N.; Morrell, N.W.; Aldred, M.A. Correction of NonsenseBMPR2andSMAD9Mutations by Ataluren in Pulmonary Arterial Hypertension. Am. J. Respir. Cell Mol. Biol. 2013, 49, 403–409. [Google Scholar] [CrossRef] [Green Version]
- Hamaguchi, Y.; Matsushita, T.; Hasegawa, M.; Ueda-Hayakawa, I.; Sato, S.; Takehara, K.; Fujimoto, M. High incidence of pulmonary arterial hypertension in systemic sclerosis patients with anti-centriole autoantibodies. Mod. Rheumatol. 2015, 25, 798–801. [Google Scholar] [CrossRef]
- Leisegang, M.S.; Fork, C.; Josipovic, I.; Richter, F.M.; Preussner, J.; Hu, J.; Miller, M.J.; Epah, J.; Hofmann, P.; Günther, S.; et al. Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function. Circulation 2017, 136, 65–79. [Google Scholar] [CrossRef]
- Lampron, M.-C.; Vitry, G.; Nadeau, V.; Grobs, Y.; Paradis, R.; Samson, N.; Tremblay, È.; Boucherat, O.; Meloche, J.; Bonnet, S.; et al. PIM1 (Moloney Murine Leukemia Provirus Integration Site) Inhibition Decreases the Nonhomologous End-Joining DNA Damage Repair Signaling Pathway in Pulmonary Hypertension. Arter. Thromb. Vasc. Biol. 2020, 40, 783–801. [Google Scholar] [CrossRef]
- Covella, M.; Rowin, E.J.; Hill, N.S.; Preston, I.R.; Milan, A.; Opotowsky, A.R.; Maron, B.J.; Maron, M.S.; Maron, B.A. Mechanism of Progressive Heart Failure and Significance of Pulmonary Hypertension in Obstructive Hypertrophic Cardiomyopathy. Circ. Heart Fail. 2017, 10, e003689. [Google Scholar] [CrossRef] [Green Version]
- Zhao, S.X.; Kwong, C.; Swaminathan, A.; Gohil, A.; Crawford, M.H. Clinical Characteristics and Outcome of Methamphetamine-Associated Pulmonary Arterial Hypertension and Dilated Cardiomyopathy. JACC Heart Fail. 2018, 6, 209–218. [Google Scholar] [CrossRef] [PubMed]
- Sargin, G.; Senturk, T.; Cildag, S. Systemic sclerosis and malignancy. Int. J. Rheum. Dis. 2018, 21, 1093–1097. [Google Scholar] [CrossRef] [PubMed]
- Wideman, R.F. Pathophysiology of heart/lung disorders: Pulmonary hypertension syndrome in broiler chickens. World’s Poult. Sci. J. 2001, 57, 289–307. [Google Scholar] [CrossRef]
- Julian, R.J. Physiological, management and environmental triggers of the ascites syndrome: A review. Avian Pathol. 2000, 29, 519–527. [Google Scholar] [CrossRef] [Green Version]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Li, A.; He, J.; Zhang, Z.; Jiang, S.; Gao, Y.; Pan, Y.; Wang, H.; Zhuang, L. Integrated Bioinformatics Analysis Reveals Marker Genes and Potential Therapeutic Targets for Pulmonary Arterial Hypertension. Genes 2021, 12, 1339. https://doi.org/10.3390/genes12091339
Li A, He J, Zhang Z, Jiang S, Gao Y, Pan Y, Wang H, Zhuang L. Integrated Bioinformatics Analysis Reveals Marker Genes and Potential Therapeutic Targets for Pulmonary Arterial Hypertension. Genes. 2021; 12(9):1339. https://doi.org/10.3390/genes12091339
Chicago/Turabian StyleLi, Aoqi, ** He, Zhe Zhang, Sibo Jiang, Yun Gao, Yuchun Pan, Huanan Wang, and Lenan Zhuang. 2021. "Integrated Bioinformatics Analysis Reveals Marker Genes and Potential Therapeutic Targets for Pulmonary Arterial Hypertension" Genes 12, no. 9: 1339. https://doi.org/10.3390/genes12091339