Increased TRIM5 is associated with a poor prognosis and immune infiltration in glioma patients_Journal of Biomedical Engineering

Authors：

Yue CHEN , Qin LI , Jie ZHANG , Rui GU , Kai LI , Gang ZHAO , Hang YUAN , Tianyu FENG , Deqiong OU ,  Ping LIN

1. Lab of Experimental Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;

Corresponding author：

Ping LIN, Email: linping@scu.edu.cn

Keywords：

TRIM5; glioma; biomarker; prognosis; immune infiltration

DOI：

10.7507/1001-5515.202004064

Video：

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Abstract Full text Figures/Tables Video References Cited by

Tripartite motif 5 (TRIM5) plays a significant function in autophagy and involves in immune and tumor processes. While the function of TRIM5 remains poorly understood in glioma. We purpose to evaluate the possible prognostic role of TRIM5 in glioma via bioinformatics analyses. The database clinical samples of glioma in this study included low grade glioma (LGG) and glioblastoma multiforme (GBM). TRIM5 expression in glioma tissues were explored in Oncomine, GEPIA and The Cancer Genome Atlas (TCGA) databases. Survival analysis and the multivariate Cox regression analysis of TRIM5 based on TCGA were used to evaluate the prognostic role of TRIM5. The protein networks of TRIM5 was detected by STRING database. KEGG enrichment analyses were performed to predict the potential molecular pathways of TRIM5 in glioma. In addition, immune infiltration analysis was conducted by CIBERSORT and TIMER databases. We found that TRIM5 was strongly increased in glioma samples compared with normal samples in Oncomine, GEPIA and TCGA databases. Higher TRIM5 was significantly contributed to worse overall survival (OS) in LGG+GBM patients and LGG patients, while was no correlated with OS of GBM patients. Interaction networks analysis identified that IRF3, IRF7, OAS1, OAS2, OAS3, OASL, GBP1, PML, BTBD1 and BTBD2 proteins were contacted with TRIM5. Moreover, KEGG revealed that apoptosis and cancer- and immune-related pathways were enriched with elevated TRIM5. Specifically, TRIM5 could influence the immune infiltration levels, such as activated NK cells, monocytes, activated mast cells and macrophages in glioma. In conclusion, our data indicated that TRIM5 was upregulated in glioma tissues and associated with poor prognosis and immune infiltration. TRIM5 may be acted as a biomarker in prognosis and immunotherapy guidance of glioma.

Citation： Yue CHEN, Qin LI, Jie ZHANG, Rui GU, Kai LI, Gang ZHAO, Hang YUAN, Tianyu FENG, Deqiong OU, Ping LIN. Increased TRIM5 is associated with a poor prognosis and immune infiltration in glioma patients. Journal of Biomedical Engineering, 2020, 37(3): 469-479. doi: 10.7507/1001-5515.202004064 Copy

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2.	Bonavia R, Inda M M, Cavenee W K, et al. Heterogeneity maintenance in glioblastoma: a social network. Cancer Res, 2011, 71(12): 4055-4060.
3.	Liu Q, Zhang C, Yuan J, et al. PTK7 regulates Id1 expression in CD44-high glioma cells. Neuro Oncol, 2015, 17(4): 505-515.
4.	Malta T M, De Souza C F, Sabedot T S, et al. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications. Neuro Oncol, 2018, 20(5): 608-620.
5.	Ceccarelli M, Barthel F P, Malta T M, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell, 2016, 164(3): 550-563.
6.	Mandell M A, Jain A, Arko-Mensah J, et al. TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. Dev Cell, 2014, 30(4): 394-409.
7.	Mandell M A, Kimura T, Jain A, et al. TRIM proteins regulate autophagy: TRIM5 is a selective autophagy receptor mediating HIV-1 restriction. Autophagy, 2014, 10(12): 2387-2388.
8.	Srihari S, Ragan M A. Systematic tracking of dysregulated modules identifies novel genes in cancer. Bioinformatics, 2013, 29(12): 1553-1561.
9.	Leal F E, Menezes S M, Costa E A S, et al. Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex vivo and in vivo IFN-beta response in HTLV-1-associated neuroinflammation. Front Microbiol, 2018, 9: 985.
10.	Gene Ontology Consortium. The Gene Ontology (GO) project in 2006. Nucleic Acids Res, 2006, 34(Database issue): D322-D326.
11.	Murat A, Migliavacca E, Gorlia T, et al. Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol, 2008, 26(18): 3015-3024.
12.	Sun L, Hui A M, Su Q, et al. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell, 2006, 9(4): 287-300.
13.	Blum A, Wang P, Zenklusen J C. SnapShot: TCGA-analyzed tumors. Cell, 2018, 173(2): 530.
14.	Tang Z, Li C, Kang B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 2017, 45(W1): W98-W102.
15.	Franceschini A, Szklarczyk D, Frankild S, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res, 2013, 41(Database issue): D808-D815.
16.	Subramanian A, Kuehn H, Gould J, et al. GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics, 2007, 23(23): 3251-3253.
17.	Liu X, Wu S, Yang Y, et al. The prognostic landscape of tumor-infiltrating immune cell and immunomodulators in lung cancer. Biomed Pharmacother, 2017, 95: 55-61.
18.	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.
19.	Chen J, Wang Z, Wang W, et al. SYT16 is a prognostic biomarker and correlated with immune infiltrates in glioma: A study based on TCGA data. Int Immunopharmacol, 2020, 84: 106490.
20.	Nowak A K, Maujean J E, Jackson M, et al. A prospective study of surgical patterns of care for high grade glioma in the current era of multimodality therapy. J Clin Neurosci, 2011, 18(2): 227-231.
21.	Atkins R J, Ng W, Stylli S S, et al. Repair mechanisms help glioblastoma resist treatment. J Clin Neurosci, 2015, 22(1): 14-20.
22.	Wen P Y, Kesari S. Malignant gliomas in adults. N Engl J Med, 2008, 359(5): 492-507.
23.	Lin L, Cai J, Jiang C. Recent advances in targeted therapy for glioma. Curr Med Chem, 2017, 24(13): 1365-1381.
24.	Sanchez-Martin P, Komatsu M. Physiological stress response by selective autophagy. J Mol Biol, 2020, 432(1): 53-62.
25.	Keown J R, Black M M, Ferron A, et al. A helical LC3-interacting region mediates the interaction between the retroviral restriction factor Trim5alpha and mammalian autophagy-related ATG8 proteins. J Biol Chem, 2018, 293(47): 18378-18386.
26.	Imam S, Talley S, Nelson R S, et al. TRIM5alpha degradation via autophagy is not required for retroviral restriction. J Virol, 2016, 90(7): 3400-3410.
27.	White E. The role for autophagy in cancer. J Clin Invest, 2015, 125(1): 42-46.
28.	Mathew R, Karp C M, Beaudoin B, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell, 2009, 137(6): 1062-1075.
29.	Mathew R, Kongara S, Beaudoin B, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev, 2007, 21(11): 1367-1381.
30.	Karantza-Wadsworth V, Patel S, Kravchuk O, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev, 2007, 21(13): 1621-1635.
31.	Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell, 2006, 10(1): 51-64.
32.	Guo J Y, Chen H Y, Mathew R, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev, 2011, 25(5): 460-470.
33.	Yang S, Wang X, Contino G, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev, 2011, 25(7): 717-729.
34.	Ulasov I V, Lenz G, Lesniak M S. Autophagy in glioma cells: An identity crisis with a clinical perspective. Cancer Lett, 2018, 428: 139-146.
35.	Giatromanolaki A, Sivridis E, Mitrakas A, et al. Autophagy and lysosomal related protein expression patterns in human glioblastoma. Cancer Biol Ther, 2014, 15(11): 1468-1478.
36.	Vergara G A, Eugenio G C, Malheiros S M F, et al. RIPK3 is a novel prognostic marker for lower grade glioma and further enriches IDH mutational status subgrouping. J Neurooncol, 2020. DOI: 10.1007/s11060-020-03473-0.
37.	Zhang J, Hu M M, Shu H B, et al. Death-associated protein kinase 1 is an IRF3/7-interacting protein that is involved in the cellular antiviral immune response. Cell Mol Immunol, 2014, 11(3): 245-252.
38.	Hatesuer B, Hoang H T, Riese P, et al. Deletion of Irf3 and Irf7 genes in mice results in altered interferon pathway activation and granulocyte-dominated inflammatory responses to influenza A infection. J Innate Immun, 2017, 9(2): 145-161.
39.	Zhou A, Paranjape J, Brown T, et al. Interferon action and apoptosis are defective in mice devoid of 2', 5'-oligoadenylate-dependent RNase L. EMBO J, 1997, 16(21): 6355-663.
40.	Miyazato K, Hayakawa Y. Pharmacological targeting of natural killer cells for cancer immunotherapy. Cancer Sci, 2020. DOI: 10.1111/cas.14418.
41.	Muller-Hermelink N, Braumuller H, Pichler B, et al. TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell, 2008, 13(6): 507-518.
42.	Morvan M G, Lanier L L. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer, 2016, 16(1): 7-19.
43.	Groth C, Hu X, Weber R, et al. Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br J Cancer, 2019, 120(1): 16-25.
44.	Kumar R, De Mooij T, Peterson T E, et al. Modulating glioma-mediated myeloid-derived suppressor cell development with sulforaphane. PLoS One, 2017, 12(6): e0179012.
45.	Attarha S, Roy A, Westermark B, et al. Mast cells modulate proliferation, migration and stemness of glioma cells through downregulation of GSK3beta expression and inhibition of STAT3 activation. Cell Signal, 2017, 37: 81-92.

1. Chen R, Smith-Cohn M, Cohen A L, et al. Glioma subclassifications and their clinical significance. Neurotherapeutics, 2017, 14(2): 284-297.
2. Bonavia R, Inda M M, Cavenee W K, et al. Heterogeneity maintenance in glioblastoma: a social network. Cancer Res, 2011, 71(12): 4055-4060.
3. Liu Q, Zhang C, Yuan J, et al. PTK7 regulates Id1 expression in CD44-high glioma cells. Neuro Oncol, 2015, 17(4): 505-515.
4. Malta T M, De Souza C F, Sabedot T S, et al. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications. Neuro Oncol, 2018, 20(5): 608-620.
5. Ceccarelli M, Barthel F P, Malta T M, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell, 2016, 164(3): 550-563.
6. Mandell M A, Jain A, Arko-Mensah J, et al. TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. Dev Cell, 2014, 30(4): 394-409.
7. Mandell M A, Kimura T, Jain A, et al. TRIM proteins regulate autophagy: TRIM5 is a selective autophagy receptor mediating HIV-1 restriction. Autophagy, 2014, 10(12): 2387-2388.
8. Srihari S, Ragan M A. Systematic tracking of dysregulated modules identifies novel genes in cancer. Bioinformatics, 2013, 29(12): 1553-1561.
9. Leal F E, Menezes S M, Costa E A S, et al. Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex vivo and in vivo IFN-beta response in HTLV-1-associated neuroinflammation. Front Microbiol, 2018, 9: 985.
10. Gene Ontology Consortium. The Gene Ontology (GO) project in 2006. Nucleic Acids Res, 2006, 34(Database issue): D322-D326.
11. Murat A, Migliavacca E, Gorlia T, et al. Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol, 2008, 26(18): 3015-3024.
12. Sun L, Hui A M, Su Q, et al. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell, 2006, 9(4): 287-300.
13. Blum A, Wang P, Zenklusen J C. SnapShot: TCGA-analyzed tumors. Cell, 2018, 173(2): 530.
14. Tang Z, Li C, Kang B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 2017, 45(W1): W98-W102.
15. Franceschini A, Szklarczyk D, Frankild S, et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res, 2013, 41(Database issue): D808-D815.
16. Subramanian A, Kuehn H, Gould J, et al. GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics, 2007, 23(23): 3251-3253.
17. Liu X, Wu S, Yang Y, et al. The prognostic landscape of tumor-infiltrating immune cell and immunomodulators in lung cancer. Biomed Pharmacother, 2017, 95: 55-61.
18. 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.
19. Chen J, Wang Z, Wang W, et al. SYT16 is a prognostic biomarker and correlated with immune infiltrates in glioma: A study based on TCGA data. Int Immunopharmacol, 2020, 84: 106490.
20. Nowak A K, Maujean J E, Jackson M, et al. A prospective study of surgical patterns of care for high grade glioma in the current era of multimodality therapy. J Clin Neurosci, 2011, 18(2): 227-231.
21. Atkins R J, Ng W, Stylli S S, et al. Repair mechanisms help glioblastoma resist treatment. J Clin Neurosci, 2015, 22(1): 14-20.
22. Wen P Y, Kesari S. Malignant gliomas in adults. N Engl J Med, 2008, 359(5): 492-507.
23. Lin L, Cai J, Jiang C. Recent advances in targeted therapy for glioma. Curr Med Chem, 2017, 24(13): 1365-1381.
24. Sanchez-Martin P, Komatsu M. Physiological stress response by selective autophagy. J Mol Biol, 2020, 432(1): 53-62.
25. Keown J R, Black M M, Ferron A, et al. A helical LC3-interacting region mediates the interaction between the retroviral restriction factor Trim5alpha and mammalian autophagy-related ATG8 proteins. J Biol Chem, 2018, 293(47): 18378-18386.
26. Imam S, Talley S, Nelson R S, et al. TRIM5alpha degradation via autophagy is not required for retroviral restriction. J Virol, 2016, 90(7): 3400-3410.
27. White E. The role for autophagy in cancer. J Clin Invest, 2015, 125(1): 42-46.
28. Mathew R, Karp C M, Beaudoin B, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell, 2009, 137(6): 1062-1075.
29. Mathew R, Kongara S, Beaudoin B, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev, 2007, 21(11): 1367-1381.
30. Karantza-Wadsworth V, Patel S, Kravchuk O, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev, 2007, 21(13): 1621-1635.
31. Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell, 2006, 10(1): 51-64.
32. Guo J Y, Chen H Y, Mathew R, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev, 2011, 25(5): 460-470.
33. Yang S, Wang X, Contino G, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev, 2011, 25(7): 717-729.
34. Ulasov I V, Lenz G, Lesniak M S. Autophagy in glioma cells: An identity crisis with a clinical perspective. Cancer Lett, 2018, 428: 139-146.
35. Giatromanolaki A, Sivridis E, Mitrakas A, et al. Autophagy and lysosomal related protein expression patterns in human glioblastoma. Cancer Biol Ther, 2014, 15(11): 1468-1478.
36. Vergara G A, Eugenio G C, Malheiros S M F, et al. RIPK3 is a novel prognostic marker for lower grade glioma and further enriches IDH mutational status subgrouping. J Neurooncol, 2020. DOI: 10.1007/s11060-020-03473-0.
37. Zhang J, Hu M M, Shu H B, et al. Death-associated protein kinase 1 is an IRF3/7-interacting protein that is involved in the cellular antiviral immune response. Cell Mol Immunol, 2014, 11(3): 245-252.
38. Hatesuer B, Hoang H T, Riese P, et al. Deletion of Irf3 and Irf7 genes in mice results in altered interferon pathway activation and granulocyte-dominated inflammatory responses to influenza A infection. J Innate Immun, 2017, 9(2): 145-161.
39. Zhou A, Paranjape J, Brown T, et al. Interferon action and apoptosis are defective in mice devoid of 2', 5'-oligoadenylate-dependent RNase L. EMBO J, 1997, 16(21): 6355-663.
40. Miyazato K, Hayakawa Y. Pharmacological targeting of natural killer cells for cancer immunotherapy. Cancer Sci, 2020. DOI: 10.1111/cas.14418.
41. Muller-Hermelink N, Braumuller H, Pichler B, et al. TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell, 2008, 13(6): 507-518.
42. Morvan M G, Lanier L L. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer, 2016, 16(1): 7-19.
43. Groth C, Hu X, Weber R, et al. Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br J Cancer, 2019, 120(1): 16-25.
44. Kumar R, De Mooij T, Peterson T E, et al. Modulating glioma-mediated myeloid-derived suppressor cell development with sulforaphane. PLoS One, 2017, 12(6): e0179012.
45. Attarha S, Roy A, Westermark B, et al. Mast cells modulate proliferation, migration and stemness of glioma cells through downregulation of GSK3beta expression and inhibition of STAT3 activation. Cell Signal, 2017, 37: 81-92.

Journal of Biomedical Engineering

Increased TRIM5 is associated with a poor prognosis and immune infiltration in glioma patients

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