Diagnostic Value of GDF10 for the Tumorigenesis and Immune Infiltration in Lung Squamous Cell Carcinoma
Lung squamous cell carcinoma (LUSC) is associated with a low survival rate. Evidence suggests that bone morphogenetic proteins (BMPs) and their receptors (BMPRs) play crucial roles in tumorigenesis and progression. However, a comprehensive analysis of their role in LUSC is lacking. Our study aimed to explore the relationship between BMPs/BMPRs expression levels and the tumorigenesis and prognosis of LUSC.
The “R/Limma” package was utilized to analyze the differential expression characteristics of BMPs/BMPRs in LUSC, using data from TCGA, GTEx, and GEO databases. Concurrently, the “survminer” packages were employed to investigate their prognostic value and correlation with clinical features in LUSC. The core gene associated with LUSC progression was further explored through weighted gene correlation network analysis (WGCNA). LASSO analysis was conducted to construct a prognostic risk model for LUSC. Clinical specimens were examined by immunohistochemical analysis to confirm the diagnostic value in LUSC. Furthermore, based on the tumor immune estimation resource database and tumor-immune system interaction database, the role of the core gene in the tumor microenvironment of LUSC was explored.
GDF10 had a significant correlation only with the pathological T stage of LUSC, and the protein expression level of GDF10 decreased with the tumorigenesis of LUSC. A prognostic risk model was constructed with GDF10 as the core gene and 5 hub genes ( HRASLS, HIST1H2BH, FLRT3, CHEK2, and ALPL) for LUSC. GDF10 showed a significant positive correlation with immune cell infiltration and immune checkpoint expression.
GDF10 might serve as a diagnostic biomarker reflecting the tumorigenesis of LUSC and regulating the tumor immune microenvironment to guide more effective treatment for LUSC.
lung squamous cell carcinoma / tumorigenesis / bone morphogenetic protein / GDF10 / tumor immune microenvironment
[1] | Patel MI, Cheng I, Gomez SL. US lung cancer trends by histologic type. Cancer, 2015,121(7):1150–1152 |
[2] | Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin, 2019,69(1):7–34 |
[3] | Relli V, Trerotola M, Guerra E, et al. Abandoning the Notion of Non-Small Cell Lung Cancer. Trends Mol Med, 2019,25(7):585–594 |
[4] | Coate LE, John T, Tsao MS, et al. Molecular predictive and prognostic markers in non-small-cell lung cancer. Lancet Oncol, 2009,10(10):1001–1010 |
[5] | Mascaux C, Angelova M, Vasaturo A, et al. Immune evasion before tumour invasion in early lung squamous carcinogenesis. Nature, 2019,571(7766):570–575 |
[6] | Scagliotti G, Brodowicz T, Shepherd FA, et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol, 2011,6(1):64–70 |
[7] | Kalemkerian GP, Narula N, Kennedy EB, et al. Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. J Clin Oncol, 2018,36(9):911–919 |
[8] | Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med, 2018,378(21):1976–1986 |
[9] | Chi LH, Burrows AD, Anderson RL. Bone morphogenetic protein signaling in breast cancer progression. Growth Factors, 2019,37(1–2):12–28 |
[10] | Ye L, Jiang WG. Bone morphogenetic proteins in tumour associated angiogenesis and implication in cancer therapies. Cancer Lett, 2016,380(2):586–597 |
[11] | Davis H, Raja E, Miyazono K, et al. Mechanisms of action of bone morphogenetic proteins in cancer. Cytokine Growth Factor Rev, 2016,27:81–92 |
[12] | Sountoulidis A, Stavropoulos A, Giaglis S, et al. Activation of the canonical bone morphogenetic protein (BMP) pathway during lung morphogenesis and adult lung tissue repair. PLoS One, 2012,7(8):e41460 |
[13] | Langenfeld EM, Calvano SE, Abou-Nukta F, et al. The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis, 2003,24(9):1445–1454 |
[14] | Meng W, Xiao H, Zhao R, et al. The Prognostic Value of Bone Morphogenetic Proteins and Their Receptors in Lung Adenocarcinoma. Front Oncol, 2021,11:608239 |
[15] | Ganjoo S, Puebla-Osorio N, Nanez S, et al. Bone morphogenetic proteins, activins, and growth and differentiation factors in tumor immunology and immunotherapy resistance. Front Immunol, 2022,13:1033642 |
[16] | Ning J, Zhao Y, Ye Y, et al. Opposing roles and potential antagonistic mechanism between TGF-beta and BMP pathways: Implications for cancer progression. EBioMedicine, 2019,41:702–710 |
[17] | Gyorffy B, Surowiak P, Budczies J, et al. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One, 2013,8(12):e82241 |
[18] | Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics, 2008,9:559 |
[19] | Botia JA, Vandrovcova J, Forabosco P, et al. An additional k-means clustering step improves the biological features of WGCNA gene co-expression networks. BMC Syst Biol, 2017,11(1):47 |
[20] | Li T, Fan J, Wang B, et al. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res, 2017,77(21):e108–e110 |
[21] | Ru B, Wong CN, Tong Y, et al. TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics, 2019,35(20):4200–4202 |
[22] | Shu DY, Lovicu FJ. Insights into Bone Morphogenetic Protein-(BMP-) Signaling in Ocular Lens Biology and Pathology. Cells, 2021,10(10):2604 |
[23] | Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of TGF-beta/BMP signaling. J Cell Physiol, 2001,187(3):265–276 |
[24] | Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol, 2010,31(6):220–227 |
[25] | Kim BG, Malek E, Choi SH, et al. Novel therapies emerging in oncology to target the TGF-? pathway. J Hematol Oncol, 2021,14(1):55 |
[26] | Ehrlich M. Endocytosis and trafficking of BMP receptors: Regulatory mechanisms for fine-tuning the signaling response in different cellular contexts. Cytokine Growth Factor Rev, 2016,27:35–42 |
[27] | Hino J, Kangawa K, Matsuo H, et al. Bone morphogenetic protein-3 family members and their biological functions. Front Biosci, 2004,9:1520–1529 |
[28] | Zhou T, Yu L, Huang J, et al. GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple-negative breast cancer via upregulation of Smad7. Aging (Albany NY), 2019,11(10):3298–3314 |
[29] | Du L, Gao Y. PGM5-AS1 impairs miR-587-mediated GDF10 inhibition and abrogates progression of prostate cancer. J Transl Med, 2021,19(1):12 |
[30] | Zhang D, Song Y, Li D, et al. Cancer-associated fibroblasts promote tumor progression by lncRNA-mediated RUNX2/GDF10 signaling in oral squamous cell carcinoma. Mol Oncol, 2022,16(3):780–794 |
[31] | Cheng CW, Hsiao JR, Fan CC, et al. Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma. Mol Carcinog, 2016,55(5):499–513 |
[32] | Dai Z, Popkie AP, Zhu WG, et al. Bone morphogenetic protein 3B silencing in non-small-cell lung cancer. Oncogene, 2004,23(20):3521–3529 |
[33] | Tandon M, Gokul K, Ali SA, et al. Runx2 mediates epigenetic silencing of the bone morphogenetic protein-3B (BMP-3B/GDF10) in lung cancer cells. Mol Cancer, 2012,11:27 |
[34] | Kraunz KS, Nelson HH, Liu M, et al. Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer. Br J Cancer, 2005,93(8):949–952 |
[35] | Uyama T, Ikematsu N, Inoue M, et al. Generation of N-acylphosphatidylethanolamine by members of the phospholipase A/acyltransferase (PLA/AT) family. J Biol Chem, 2012,287(38):31905–31919 |
[36] | Li J, Wang J, Chen Y, et al. A prognostic 4-gene expression signature for squamous cell lung carcinoma. J Cell Physiol, 2017,232(12):3702–3713 |
[37] | Zhang YQ, Yuan Y, Zhang J, et al. Evaluation of the roles and regulatory mechanisms of PD-1 target molecules in NSCLC progression. Ann Transl Med, 2021,9(14):1168 |
[38] | Ma H, Tong L, Zhang Q, et al. Identification of 5 Gene Signatures in Survival Prediction for Patients with Lung Squamous Cell Carcinoma Based on Integrated Multiomics Data Analysis. Biomed Res Int, 2020,2020:6427483 |
[39] | Zeng Z, Lu J, Wu D, et al. Poly(ADP-ribose) glycohydrolase silencing-mediated H2B expression inhibits benzo(a)pyrene-induced carcinogenesis. Environ Toxicol, 2021,36(3):291–297 |
[40] | Ogata S, Morokuma J, Hayata T, et al. TGF-beta signaling-mediated morphogenesis: modulation of cell adhesion via cadherin endocytosis. Genes Dev, 2007,21(14):1817–1831 |
[41] | Kleiblova P, Stolarova L, Krizova K, et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer, 2019,145(7):1782–1797 |
[42] | Zheng F, Guo S, Zeng F, et al. Ratiometric fluorescent probe for alkaline phosphatase based on betaine-modified polyethylenimine via excimer/monomer conversion. Anal Chem, 2014,86(19):9873–9879 |
[43] | Lou Z, Lin W, Zhao H, et al. Alkaline phosphatase downregulation promotes lung adenocarcinoma metastasis via the c-Myc/RhoA axis. Cancer Cell Int, 2021,21(1):217 |
[44] | Kou F, Wu L, Guo Y, et al. Somatic copy number alterations are predictive of progression-free survival in patients with lung adenocarcinoma undergoing radiotherapy. Cancer Biol Med, 2021,19(5):685–695 |
[45] | Wang F, Wang S, Zhou Q. The Resistance Mechanisms of Lung Cancer Immunotherapy. Front Oncol, 2020,10:568059 |
[46] | Du W, Yang M, Turner A, et al. TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action. Int J Mol Sci, 2017,18(3):645 |
[47] | Wolchok JD, Saenger Y. The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist, 2008,13(Suppl 4):2–9 |
[48] | Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med, 2016,8(328):328rv4 |
[49] | Chen D, Menon H, Verma V, et al. Response and outcomes after anti-CTLA4 versus anti-PD1 combined with stereotactic body radiation therapy for metastatic non-small cell lung cancer: retrospective analysis of two single-institution prospective trials. J Immunother Cancer, 2020,8(1):e000492 |
[50] | Liu SY, Wu YL. Tislelizumab: an investigational anti-PD-1 antibody for the treatment of advanced non-small cell lung cancer (NSCLC). Expert Opin Investig Drugs, 2020,29(12): 1355–1364 |
[51] | Middleton G, Brock K, Savage J, et al. Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial. Lancet Respir Med, 2020,8(9):895–904 |
/
〈 | 〉 |