GPX2 and BMP4 as Significant Molecular Alterations in The Lung Adenocarcinoma Progression: Integrated Bioinformatics Analysis

Document Type : Original Article


1 Department of Microbiology and Microbial Biotechnology, Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran

2 Department of Cell and Molecular Biology, Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran

3 Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

4 Biophysics Department, Science Faculty, York University, Toronto, Canada

5 V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, Novosibirsk, Russia


Objective: Non-small cell lung adenocarcinoma (NSCLC) is the most common type of lung cancer, which is considered as the most lethal and prevalent cancer worldwide. Recently, molecular changes have been implicated to play a significant role in the cancer progression. Despite of numerous studies, the molecular mechanism of NSCLC pathogenesis in each sub-stage remains unclear. Studying these molecular alterations gives us a chance to design successful therapeutic plans which is aimed in this research.
Materials and Methods: In this bioinformatics study, we compared the expression profile of 7 minor stages of NSCLC
adenocarcinoma, including GSE41271, GSE42127, and GSE75037, to clarify the relation of molecular alterations and tumorigenesis. At first, 99 common differentially expressed genes (DEG) were obtained. Then, functional enrichment analysis and protein-protein interaction (PPI) network construction were performed to uncover the association of significant cellular and molecular changes. Finally, gene expression profile interactive analysis (GEPIA) was employed to validate the results by RNA-seq expression data.
Results: Primary analysis showed that BMP4 was downregulated through the tumor progression to the stage IB and
GPX2 was upregulated in the course of final tumor development to the stage IV and distant metastasis. Functional enrichment analysis indicated that BMP4 in the TGF-β signaling pathway and GPX2 in the glutathione metabolism pathway may be the key genes for NSCLC adenocarcinoma progression. GEPIA analysis revealed a correlation between BMP4 downregulation and GPX2 upregulation and lung adenocarcinoma (LUAD) progression and lower survival chances in LUAD patients which confirm microarray data.
Conclusion: Taken together, we suggested GPX2 as an oncogene by inhibiting apoptosis, promoting EMT and increasing glucose uptake in the final stages and BMP4 as a tumor suppressor via inducing apoptosis and arresting cell cycle in the early stages through lung adenocarcinoma (ADC) development to make them candidate genes to further cancer therapy investigations.


1. Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med Biol. 2016; 893: 1-19.
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394-424.
3. Collins LG, Haines C, Perkel R, Enck RE. Lung cancer: diagnosis and management. Am Fam Physician. 2007; 75(1): 56-63.
4. Nasim F, Sabath BF, Eapen GA. Lung cancer. Med Clin North Am. 2019; 103(3): 463-473.
5. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008; 83(5): 584-594.
6. Ginsberg MS, Grewal RK, Heelan RT. Lung cancer. Radiol Clin North Am. 2007; 45(1): 21-43.
7. de Groot P, Munden RF. Lung cancer epidemiology, risk factors, and prevention. Radiol Clin North Am. 2012; 50(5): 863-876.
8. Rodriguez-Canales J, Parra-Cuentas E, Wistuba II. Diagnosis and molecular classification of lung cancer. Cancer Treat Res. 2016; 170: 25-46. Zheng M. Classification and pathology of lung cancer. Surg Oncol Clin N Am. 2016; 25(3): 447-468.
10. Tsim S, O’Dowd CA, Milroy R, Davidson S. Staging of non-small cell lung cancer (NSCLC): a review. Respir Med. 2010; 104(12): 1767-1774.
11. Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest. 2009; 136(1): 260-271.
12. Woodard GA, Jones KD, Jablons DM. Lung cancer staging and prognosis. Cancer Treat Res. 2016; 170: 47-75.
13. Dachs GU, Dougherty GJ, Stratford IJ, Chaplin DJ. Targeting gene therapy to cancer: a review. Oncol Res. 1997; 9(6-7): 313-325.
14. Garnis C, Buys TP, Lam WL. Genetic alteration and gene expression modulation during cancer progression. Mol Cancer. 2004; 3: 9.
15. Anisimov SV. Application of DNA microarray technology to gerontological studies. Methods Mol Biol. 2007; 371: 249-265.
16. Hanai T, Hamada H, Okamoto M. Application of bioinformatics for DNA microarray data to bioscience, bioengineering and medical fields. J Biosci Bioeng. 2006; 101(5): 377-384.
17. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide
experimental datasets. Nucleic Acids Res. 2019; 47(D1): D607- D613.
18. Romaszko AM, Doboszyńska A. Multiple primary lung cancer: a literature review. Adv Clin Exp Med. 2018; 27(5): 725-730.
19. Cersosimo RJ. Lung cancer: a review. Am J Health Syst Pharm. 2002; 59(7): 611-642.
20. Virtanen C, Woodgett J. Clinical uses of microarrays in cancer research. Methods Mol Med. 2008; 141: 87-113.
21. Fang WT, Fan CC, Li SM, Jang TH, Lin HP, Shih NY, et al. Downregulation of a putative tumor suppressor BMP4 by SOX2 promotes growth of lung squamous cell carcinoma. Int J Cancer. 2014; 135(4): 809-819.
22. Su D, Zhu S, Han X, Feng Y, Huang H, Ren G, et al. BMP4-Smad signaling pathway mediates adriamycin-induced premature senescence in lung cancer cells. J Biol Chem. 2009; 284(18): 12153- 12164.
23. Colak S, Ten Dijke P. Targeting TGF-β signaling in cancer. Trends Cancer. 2017; 3(1): 56-71.
24. Mihajlović J, Diehl LAM, Hochhaus A, Clement JH. Inhibition of bone morphogenetic protein signaling reduces viability, growth and migratory potential of non-small cell lung carcinoma cells. J Cancer Res Clin Oncol. 2019; 145(11): 2675-2687.
25. Du H, Chen B, Jiao NL, Liu YH, Sun SY, Zhang YW. Elevated glutathione peroxidase 2 expression promotes cisplatin resistance in lung adenocarcinoma. Oxid Med Cell Longev. 2020; 2020: 7370157.
26. Naiki-Ito A, Asamoto M, Hokaiwado N, Takahashi S, Yamashita H, Tsuda H, et al. Gpx2 is an overexpressed gene in rat breast cancers induced by three different chemical carcinogens. Cancer Res. 2007; 67(23): 11353-11358.
27. Liu D, Sun L, Tong J, Chen X, Li H, Zhang Q. Prognostic significance of glutathione peroxidase 2 in gastric carcinoma. Tumour Biol. 2017; 39(6): 1010428317701443.
28. Liu T, Kan XF, Ma C, Chen LL, Cheng TT, Zou ZW, et al. GPX2 overexpression indicates poor prognosis in patients with hepatocellular carcinoma. Tumour Biol. 2017; 39(6): 1010428317700410.
29. Liu C, He X, Wu X, Wang Z, Zuo W, Hu G. Clinicopathological and prognostic significance of GPx2 protein expression in nasopharyngeal carcinoma. Cancer Biomark. 2017; 19(3): 335-340.
30. Lei Z, Tian D, Zhang C, Zhao S, Su M. Clinicopathological and prognostic significance of GPX2 protein expression in esophageal squamous cell carcinoma. BMC Cancer. 2016; 16: 410.
31. Emmink BL, Laoukili J, Kipp AP, Koster J, Govaert KM, Fatrai S, et al. GPx2 suppression of H2O2 stress links the formation of differentiated tumor mass to metastatic capacity in colorectal cancer. Cancer Res. 2014; 74(22): 6717-6730.
32. Naiki T, Naiki-Ito A, Asamoto M, Kawai N, Tozawa K, Etani T, et al. GPX2 overexpression is involved in cell proliferation and prognosis of castration-resistant prostate cancer. Carcinogenesis. 2014; 35(9): 1962-1967.
33. Chang IW, Lin VC, Hung CH, Wang HP, Lin YY, Wu WJ, et al. GPX2 underexpression indicates poor prognosis in patients with urothelial carcinomas of the upper urinary tract and urinary bladder. World J Urol. 2015; 33(11): 1777-1789.
34. Li F, Dai L, Niu J. GPX2 silencing relieves epithelial-mesenchymal transition, invasion, and metastasis in pancreatic cancer by downregulating Wnt pathway. J Cell Physiol. 2020; 235(11): 7780-7790.
35. Huang H, Zhang W, Pan Y, Gao Y, Deng L, Li F, et al. YAP suppresses lung squamous cell carcinoma progression via deregulation of the DNp63-GPX2 axis and ROS accumulation. Cancer Res. 2017; 77(21): 5769-5781.
36. Matadamas-Guzman M, Zazueta C, Rojas E, Resendis-Antonio O. Analysis of epithelial-mesenchymal transition metabolism identifies possible cancer biomarkers useful in diverse genetic backgrounds. Front Oncol. 2020; 10: 1309.
37. Moreno Leon L, Gautier M, Allan R, Ilié M, Nottet N, Pons N, et al. The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress. Oncogene. 2019; 38(46): 7146-7165.
38. Vanhove K, Graulus GJ, Mesotten L, Thomeer M, Derveaux E, Noben JP, et al. The metabolic landscape of lung cancer: new insights in a disturbed glucose metabolism. Front Oncol. 2019; 9: 1215.
39. Wang Y, Xia Y, Lu Z. Metabolic features of cancer cells. Cancer Commun (Lond). 2018; 38(1): 65.
40. Bansal A, Simon MC. Glutathione metabolism in cancer progression and treatment resistance. J Cell Biol. 2018; 217(7): 2291-2298.