Expressions of SHOX2, RASSF1A and PTGER4, and the relationship between their methylation and clinicopathological characteristics in patients with lung cancer

Methylation of SHOX2, RASSF1A, PTGER4 in Lung Cancer

  • Haitao Su Affiliated Hospital of Hebei University of Technology
  • Qiaoye Lv Affiliated Hospital of Hebei University of Technology
  • Limei Wang Affiliated Hospital of Hebei University of Technology
  • Jigang Hu Affiliated Hospital of Hebei University of Technology
  • Yinggang Lv Affiliated Hospital of Hebei University of Technology
  • Liting Jia Affiliated Hospital of Hebei University of Technology
  • Qingbin Qi Affiliated Hospital of Hebei University of Technology
Keywords: Lung cancer, Short stature homobox2, Ras-association domain family 1A;, Prostaglandin E receptor 4, Methylation, Clinicopathology

Abstract


Background: To explore the expressions of short stature homobox2 (SHOX2), Ras-association domain family 1A (RASSF1A) and prostaglandin E receptor 4 (PTGER4), and the relationship between their methylation and clinicopathological characteristics in patients with lung cancer (LC).

Methods: The surgical specimens of cancer tissues and para-carcinoma tissues were collected from 50 patients with LC in the Affiliated Hospital of Hebei University of Engineering between January and November 2023. The expressions of SHOX, RASSF1A and PTGER4 proteins in cancer tissues and para-carcinoma tissues were detected by immunohistochemistry, and methylation status of SHOX, RASSF1A and PTGER4 genes in peripheral venous blood was detected by sulfite-modified real-time fluorescence quantification. The positive expression rates of SHOX2, RASSF1A and PTGER4, and positive rates of SHOX2, RASSF1A and PTGER4 genes methylation in cancer tissues and para-carcinoma tissues were compared. The relationship between SHOX2, RASSF1A, PTGER4 methylation and clinicopathological characteristics in LC patients was compared by real-time fluorescence quantitative PCR.

Results: The positive expression rates of SHOX2, RASSF1A and PTGER4 in cancer tissues were 44.0%, 54.00% and 50.00%, significantly lower than those in para-carcinoma tissues (90.00%, 96.00%, 82.00%, P<0.05). The methylation positive rates of SHOX2, RASSF1A and PTGER4 genes in cancer tissues were 48.00%, 32.00% and 64.00%, significantly higher than those in para-carcinoma tissues (16.00%, 4.0%, 14.00%, P<0.05). In terms of different pathological types and TNM staging, methylation positive rates of SHOX2 and RASSF1A genes were the highest in patients with adenocarcinoma and TNM staging at stage IV. In terms of different pathological types, methylation positive rate of PTGER4 gene was the highest in patients with TNM staging at stage IV (P<0.05).

Conclusion: The low expressions and high methylation of SHOX2, RASSF1A and PTGER4 are common in LC patients. The methylation positive rates of SHOX2 and RASSF1A genes are related to pathological types and TNM staging, and methylation positive rate of PTGER4 gene is only related to pathological types.

References

1. Lareau S, Slatore C, Smyth R. Lung Cancer. Am J Resp Crit Care 2021; 204(12): P21-2.
2. Li Y, Wu X, Yang P, Jiang G, Luo Y. Machine Learning for Lung Cancer Diagnosis, Treatment, and Prognosis. Genom Proteom Bioinf 2022; 20(5): 850-66.
3. Wang P, Zhao H, Ren F, Zhao Q, Shi R, Liu X, et al. [Research Progress of Epigenetics in Pathogenesis and Treatment of Malignant Tumors]. Zhongguo Fei Ai Za Zhi 2020; 23(2): 91-100.
4. Duan J, Zhong B, Fan Z, Zhang H, Xu M, Zhang X, et al. DNA methylation in pulmonary fibrosis and lung cancer. Expert Rev Resp Med 2022; 16(5): 519-28.
5. Teng Y, Loveless R, Benson EM, Sun L, Shull AY, Shay C. SHOX2 cooperates with STAT3 to promote breast cancer metastasis through the transcriptional activation of WASF3. J Exp Clin Canc Res 2021; 40(1): 274.
6. Li N, Zeng Y, Huang J. Signaling pathways and clinical application of RASSF1A and SHOX2 in lung cancer. J Cancer Res Clin 2020; 146(6): 1379-93.
7. Na YR, Jung D, Stakenborg M, Jang H, Gu GJ, Jeong MR, et al. Prostaglandin E(2) receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation. Gut 2021; 70(12): 2249-60.
8. Li N, Zeng Y, Huang J. Signaling pathways and clinical application of RASSF1A and SHOX2 in lung cancer. J Cancer Res Clin 2020; 146(6): 1379-93.
9. [Chinese Medical Association guidelines for clinical diagnosis and treatment of lung cancer (2019 edition)]. Zhonghua Zhong Liu Za Zhi 2020; 42(4): 257-87.
10. Wu X, Xin Z, Zou Z, Lu C, Yu Z, Feng S, et al. SRY-related high-mobility-group box 4: Crucial regulators of the EMT in cancer. Semin Cancer Biol 2020; 67(Pt 1): 114-21.
11. Xie B, Dong W, He F, Peng F, Zhang H, Wang W. The Combination of SHOX2 and RASSF1A DNA Methylation Had a Diagnostic Value in Pulmonary Nodules and Early Lung Cancer. Oncology-Basel 2024; 102(9): 759-74.
12. Zeng S, Lin C, Huang Y. miR-375 Combined with SHOX2 Methylation has Higher Diagnostic Efficacy for Non-Small-Cell Lung Cancer. Mol Biotechnol 2023; 65(7): 1187-97.
13. Zhao J, Lu Y, Ren X, Bian T, Feng J, Sun H, et al. Association of the SHOX2 and RASSF1A methylation levels with the pathological evolution of early-stage lung adenocarcinoma. Bmc Cancer 2024; 24(1): 687.
14. Chen S, Huang K, Zou L, Chen L, Hu P. Diagnostic value of SHOX2, RASSF1A gene methylation combined with CEA level detection in malignant pleural effusion. Bmc Pulm Med 2023; 23(1): 160.
15. Lin TC. RUNX1 and cancer. Bba-Rev Cancer 2022; 1877(3): 188715.
16. Fleischhacker M, Arslan E, Reinicke D, Eisenmann S, Theil G, Kollmeier J, et al. Cell-Free Methylated PTGER4 and SHOX2 Plasma DNA as a Biomarker for Therapy Monitoring and Prognosis in Advanced Stage NSCLC Patients. Diagnostics 2023; 13(13):
17. Li J, Shen J, Zhao Y, Du F, Li M, Wu X, et al. Role of miR‑181a‑5p in cancer (Review). Int J Oncol 2023; 63(4):
18. Xu Z, Wang Y, Wang L, Xiong J, Wang H, Cui F, et al. The performance of the SHOX2/PTGER4 methylation assay is influenced by cancer stage, age, type and differentiation. Biomark Med 2020; 14(5): 341-51.
19. Take Y, Koizumi S, Nagahisa A. Prostaglandin E Receptor 4 Antagonist in Cancer Immunotherapy: Mechanisms of Action. Front Immunol 2020; 11: 324.
20. Lu H, Lin D. Diagnostic value of exfoliated tumor cells combined with DNA methylation in bronchoalveolar lavage fluid for lung cancer. Medicine 2023; 102(36): e34955.
21. Gao H, Yang J, He L, Wang W, Liu Y, Hu Y, et al. The Diagnostic Potential of SHOX2 and RASSF1A DNA Methylation in Early Lung Adenocarcinoma. Front Oncol 2022; 12: 849024.
22. Huang W, Huang H, Zhang S, Wang X, Ouyang J, Lin Z, et al. A Novel Diagnosis Method Based on Methylation Analysis of SHOX2 and Serum Biomarker for Early Stage Lung Cancer. Cancer Control 2020; 27(1): 1148404967.
23. Xu Z, Wang Y, Wang L, Xiong J, Wang H, Cui F, et al. The performance of the SHOX2/PTGER4 methylation assay is influenced by cancer stage, age, type and differentiation. Biomark Med 2020; 14(5): 341-51.
Published
2024/12/14
Section
Original paper