The Role of TRPA1 as a Prognostic Marker in Colon Adenocarcinoma and its Correlation with Mutations and Immunity
Abstract
Background: This study aimed to investigate the prognostic value of TRP ion channel genes (TRPICGs) in colorectal adenocarcinoma (COAD) and explore its related mechanisms.
Methods: The COAD dataset was downloaded from the Cancer Genome Atlas (TCGA) database. The differential expression genes (DEGs) were screened between COAD and normal samples. The differentially expressed TRPICGs (DE-TRPICGs) were obtained via intersection of DEGs and 28 TRPICGs. The Kaplan-Meier (K-M) survival curve was used to screen DE-TRPICGs with survival differences as prognostic markers. Afterward, the correlation of prognostic marker with clinical, immune cell, copy number variation were explored. Finally, immunohistochemistry (IHC) was used to verify the expression of prognostic marker.
Results: Overall, 6003 DEGs were screened, and 6 DE-TRPICGs were obtained. Only TRPA1 was identified as prognostic biomarker. Survival and clinical correlation analyses implied that TRPA1 played an inhibitory role in colon adenocarcinoma pathogenesis and progression. Gene Set Enrichment Analysis (GSEA) indicated that TRPA1 was associated with cell cycle and immune-related pathways. Immune infiltration analysis showed that TRPA1 expression was significantly correlated with the infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils and dendritic cells. Eventually, TRPA1 expression was down-regulated at the protein level in COAD samples, which presented consistent results with expression in the database.
Conclusion: TRPA1 was identified in COAD as a prognostic marker associated with TRP ion channels, which provided a powerful reference value and a new direction for the diagnosis and treatment of COAD.
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33. Santarius T, Shipley J, Brewer D, et al (2010). A census of amplified and over-expressed human cancer genes. Nat Rev Cancer, 10 (1):59-64.
34. Liu S, Shao F, Wang Y, et al(2024). COX6C expression driven by copy amplification of 8q22.2 regulates cell proliferation via mediation of mitosis by ROS-AMPK signaling in lung adenocarcinoma. Cell Death Dis, 15 (1):74.
35. Zhang L, Yu X, Zheng L, et al (2018). Line-age tracking reveals dynamic relation-ships of T cells in colorectal cancer. Nature, 564 (7735):268-272.
36. Mantovani A, Cassatella MA, Costantini C, et al (2011). Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol, 11 (8):519-31.
37. Quail DF, Amulic B, Aziz M, et al (2022). Neutrophil phenotypes and functions in cancer: A consensus statement. J Exp Med, 219 (6): e20220011.
38. Tokunaga R, Naseem M, Lo JH, et al (2019). B cell and B cell-related pathways for novel cancer treatments. Cancer Treat Rev, 73:10-19.
39. Fanciulli M, Petretto E, Aitman TJ (2010). Gene copy number variation and com-mon human disease. Clin Genet, 77 (3):201-13.
40. Wang N, Liu D (2021). Identification and Validation a Necroptosis‑related Prog-nostic Signature and Associated Regula-tory Axis in Stomach Adenocarcinoma. Onco Targets Ther, 14:5373-5383.
41. Saitou M, Gokcumen O (2020). An Evolu-tionary Perspective on the Impact of Genomic Copy Number Variation on Human Health. J Mol Evol, 88 (1):104-119.
2. Biller LH, Schrag D (2021). Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA, 325 (7):669-685.
3. Garborg K, Holme Ø, Løberg M, et al (2013). Current status of screening for colorectal cancer. Ann Oncol, 24 (8):1963-72.
4. Das V, Kalita J, Pal M (2017). Predictive and prognostic biomarkers in colorectal cancer: A systematic review of recent advances and challenges. Biomed Pharma-cother, 87:8-19.
5. Stratton MR, Campbell PJ, Futreal PA (2009). The cancer genome. Nature, 458 (7239):719-24.
6. Angell HK, Bruni D, Barrett JC, et al (2020). The Immunoscore: Colon Cancer and Beyond. Clin Cancer Res, 26 (2):332-339.
7. Kasprzak A (2021). The Role of Tumor Mi-croenvironment Cells in Colorectal Cancer (CRC) Cachexia. Int J Mol Sci, 22 (4): 1565.
8. Alaimo A, Rubert J (2019). The Pivotal Role of TRP Channels in Homeostasis and Diseases throughout the Gastrointestinal Tract. Int J Mol Sci, 20 (21): 5277.
9. Matsumoto K, Suenaga M, Mizutani Y, et al (2021). Role of transient receptor poten-tial vanilloid subtype 2 in lower oesoph-ageal sphincter in rat acid reflux oe-sophagitis. J Pharmacol Sci, 146 (3):125-135.
10. Akbar A, Yiangou Y, Facer P, et al (2008). Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut, 57 (7):923-9.
11. Ibrahim S, Dakik H, Vandier C, et al (2019). Expression Profiling of Calcium Chan-nels and Calcium-Activated Potassium Channels in Colorectal Cancer. Cancers (Basel), 11 (4):561.
12. Kappel S, Stokłosa P, Hauert B, et al (2019). TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells. Mol Oncol, 13 (11):2393-2405.
13. Ritchie ME, Phipson B, Wu D, et al (2015). limma powers differential expression analyses for RNA-sequencing and mi-croarray studies. Nucleic Acids Res, 43 (7):e47.
14. Phipson B, Lee S, Majewski IJ, et al (2016). Robust hyperparameter estimation pro-tects against hypervariable genes and improves power to detect differential expression. Ann Appl Stat, 10 (2):946-963.
15. Shapovalov G, Ritaine A, Skryma R, et al (2016). Role of TRP ion channels in cancer and tumorigenesis. Semin Im-munopathol, 38 (3):357-69.
16. Venkatachalam K, Montell C (2007). TRP channels. Annu Rev Biochem, 76:387-417.
17. Ramsey IS, Delling M, Clapham DE (2006). An introduction to TRP channels. Annu Rev Physiol, 68:619-47.
18. Hao T, Peng W, Wang Q, et al (2016). Re-construction and Application of Pro-tein-Protein Interaction Network. Int J Mol Sci, 17 (6):907.
19. Li J, Li Z, Zhao S, et al (2020). Identifica-tion key genes, key miRNAs and key transcription factors of lung adenocar-cinoma. J Thorac Dis, 12 (5):1917-1933.
20. Mayakonda A, Lin DC, Assenov Y, et al (2018). Maftools: efficient and compre-hensive analysis of somatic variants in cancer. Genome Res, 28 (11):1747-1756.
21. Li T, Fu J, Zeng Z, et al (2020). TIMER2.0 for analysis of tumor-infiltrating im-mune cells. Nucleic Acids Res, 48 (W1):W509-W514.
22. Mermel CH, Schumacher SE, Hill B, et al(2011). GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol, 12 (4):R41.
23. Unberath P, Knell C, Prokosch H-U, et al(2019). Developing New Analysis Functions for a Translational Research Platform: Extending the cBioPortal for Cancer Genomics. Stud Health Technol In-form, 258:46-50.
24. Bray F, Ferlay J, Soerjomataram I, et al (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 68 (6):394-424.
25. Stokłosa P, Borgström A, Kappel S, et al (2020). TRP Channels in Digestive Tract Cancers. Int J Mol Sci, 21 (5): 1877.
26. Liu J, Peng Y, Wei W (2022). Cell cycle on the crossroad of tumorigenesis and can-cer therapy. Trends Cell Biol, 32 (1):30-44.
27. Sadras F, Monteith GR, Roberts-Thomson SJ (2021). An Emerging Role for Calci-um Signaling in Cancer-Associated Fi-broblasts. Int J Mol Sci, 22 (21):11366.
28. Han YH, Mun JG, Jeon HD, et al (2019). Betulin Inhibits Lung Metastasis by In-ducing Cell Cycle Arrest, Autophagy, and Apoptosis of Metastatic Colorectal Cancer Cells. Nutrients, 12 (1):66.
29. Chen Y, Liu F, Chen X, et al (2024). mi-croRNA-622 upregulates cell cycle pro-cess by targeting FOLR2 to promote CRC proliferation. BMC Cancer, 24 (1):26.
30. Hu T, Shen H, Li J, et al (2020). RFC2, a di-rect target of miR-744, modulates the cell cycle and promotes the prolifera-tion of CRC cells. J Cell Physiol, 235 (11):8319-8333.
31. Wang C, Chen J, Kuang Y, et al (2022). A novel methylated cation channel TRPM4 inhibited colorectal cancer me-tastasis through Ca(2+)/Calpain-mediated proteolysis of FAK and sup-pression of PI3K/Akt/mTOR signaling pathway. Int J Biol Sci, 18 (14):5575-5590.
32. Tomasetti C, Li L, Vogelstein B (2017). Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science, 355 (6331):1330-1334.
33. Santarius T, Shipley J, Brewer D, et al (2010). A census of amplified and over-expressed human cancer genes. Nat Rev Cancer, 10 (1):59-64.
34. Liu S, Shao F, Wang Y, et al(2024). COX6C expression driven by copy amplification of 8q22.2 regulates cell proliferation via mediation of mitosis by ROS-AMPK signaling in lung adenocarcinoma. Cell Death Dis, 15 (1):74.
35. Zhang L, Yu X, Zheng L, et al (2018). Line-age tracking reveals dynamic relation-ships of T cells in colorectal cancer. Nature, 564 (7735):268-272.
36. Mantovani A, Cassatella MA, Costantini C, et al (2011). Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol, 11 (8):519-31.
37. Quail DF, Amulic B, Aziz M, et al (2022). Neutrophil phenotypes and functions in cancer: A consensus statement. J Exp Med, 219 (6): e20220011.
38. Tokunaga R, Naseem M, Lo JH, et al (2019). B cell and B cell-related pathways for novel cancer treatments. Cancer Treat Rev, 73:10-19.
39. Fanciulli M, Petretto E, Aitman TJ (2010). Gene copy number variation and com-mon human disease. Clin Genet, 77 (3):201-13.
40. Wang N, Liu D (2021). Identification and Validation a Necroptosis‑related Prog-nostic Signature and Associated Regula-tory Axis in Stomach Adenocarcinoma. Onco Targets Ther, 14:5373-5383.
41. Saitou M, Gokcumen O (2020). An Evolu-tionary Perspective on the Impact of Genomic Copy Number Variation on Human Health. J Mol Evol, 88 (1):104-119.
| Files | ||
| Issue | Vol 54 No 4 (2025) | |
| Section | Original Article(s) | |
| Keywords | ||
| Colon adenocarcinoma Transient receptor potential channel Prognosis Infiltrating immune cells | ||
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How to Cite
1.
Wu X, Peng L, Zheng M, Mao Y, Li H, Sun S. The Role of TRPA1 as a Prognostic Marker in Colon Adenocarcinoma and its Correlation with Mutations and Immunity. Iran J Public Health. 2025;54(4):762-774.
