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Predicting Survival Signature of Bladder Cancer Related to Cancer-Associated Fibroblast (CAF) Constructed by Intersecting Genes in TCGA and GEO

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Abstract

Bladder cancer was one of the most common carcinomas around the world. However, the mechanism of the disease still remained to be investigated. We expected to establish a prognostic survival model with 9 prognostic genes to predict overall survival (OS) in patients of bladder cancer. The gene expression data of bladder cancer were obtained from TCGA and GEO datasets. TCGA and GEO datasets were used for screening prognostic genes along with developing and validating a 9-gene prognostic survival model by method of weighted gene co-expression network analysis (WGCNA) and LASSO with Cox regression. The relative analysis of evaluate tumor burden mutation (TBM), GO, KEGG, chemotherapy drug and functional pathway were also performed based on CAF-related mRNAs. 151 Overlapping CAF-related genes were distinguished after intersecting differentially expressed genes from 945 genes in TCGA and 491 genes in GEO dataset. 9 Prognostic genes (MSRB2, AGMAT, KLF6, DDAH2, GADD45B, SERPINE2, STMN3, TEAD2, and COMP) were used for construction of prognostic model after LASSO with Cox regression. Receiver operating characteristic (ROC) curves showed a good survival prediction by this model. Functional analysis indicated chemokine, cytokine, ECM interaction, oxidative stress and apoptosis were highly appeared. Potential drugs targeted different CAF-related genes like vemurafenib, irofulven, ghiotepa, and idarubicin were found as well. We constructed a novel 9 CAF-related mRNAs prognostic model and explored the gene expression and potential functional information of related genes, which might be worthy of clinical application. In addition, potential chemotherapy drugs could provide useful insights into the potential clinical treatment of bladder cancer.

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The data sets supporting the results of this article are included within the article and its additional files.

References

  1. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer Journal for Clinicians, 68(6), 394–424.

    Article  PubMed  Google Scholar 

  2. Richters, A., Aben, K. K. H., & Kiemeney, L. (2020). The global burden of urinary bladder cancer: An update. World Journal of Urology, 38(8), 1895–1904.

    Article  PubMed  Google Scholar 

  3. Patel, V. G., Oh, W. K., & Galsky, M. D. (2020). Treatment of muscle-invasive and advanced bladder cancer in 2020. CA A Cancer Journal for Clinicians, 70(5), 404–423.

    Article  PubMed  Google Scholar 

  4. Musa, M. (2020). Single-cell analysis on stromal fibroblasts in the microenvironment of solid tumours. Advances in Medical Science, 65(1), 163–169.

    Article  Google Scholar 

  5. Gandellini, P., Andriani, F., Merlino, G., D’Aiuto, F., Roz, L., & Callari, M. (2015). Complexity in the tumour microenvironment: Cancer associated fibroblast gene expression patterns identify both common and unique features of tumour–stroma crosstalk across cancer types. Seminars in Cancer Biology, 35, 96–106.

    Article  CAS  PubMed  Google Scholar 

  6. Sukowati, C. H., Anfuso, B., Croce, L. S., & Tiribelli, C. (2015). The role of multipotent cancer associated fibroblasts in hepatocarcinogenesis. BMC Cancer, 15, 188.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bellmunt, J. (2018). Stem-like signature predicting disease progression in early stage bladder cancer. The role of E2F3 and SOX4. Biomedicines, 6(3), 85.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Miyamoto, D. T., Mouw, K. W., Feng, F. Y., Shipley, W. U., & Efstathiou, J. A. (2018). Molecular biomarkers in bladder preservation therapy for muscle-invasive bladder cancer. Lancet Oncology, 19(12), e683–e695.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, W., & Huang, P. (2011). Cancer–stromal interactions: Role in cell survival, metabolism and drug sensitivity. Cancer Biology and Therapy, 11(2), 150–156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Biffi, G., & Tuveson, D. A. (2021). Diversity and biology of cancer-associated fibroblasts. Physiological Review, 101(1), 147–176.

    Article  CAS  Google Scholar 

  11. Kato, K., Fukai, M., Hatanaka, K. C., Takasawa, A., Aoyama, T., Hayasaka, T., Matsuno, Y., Kamiyama, T., Hatanaka, Y., & Taketomi, A. (2022). Versican secreted by cancer-associated fibroblasts is a poor prognostic factor in hepatocellular carcinoma. Annals of Surgical Oncology, 29(11), 7135–7146.

    Article  PubMed  Google Scholar 

  12. Zheng, H., Liu, H., Li, H., Dou, W., & Wang, X. (2021). Weighted gene co-expression network analysis identifies a cancer-associated fibroblast signature for predicting prognosis and therapeutic responses in gastric cancer. Frontiers in Molecular Bioscience, 8, 744677.

    Article  CAS  Google Scholar 

  13. Hu, J., Jiang, Y., Wei, Q., Li, B., Xu, S., Wei, G., Li, P., Chen, W., Lv, W., Xiao, X., et al. (2022). Development of a cancer-associated fibroblast-related prognostic model in breast cancer via bulk and single-cell RNA sequencing. BioMed Research International, 2022, 2955359.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lulli, D., Carbone, M. L., & Pastore, S. (2017). The MEK inhibitors trametinib and cobimetinib induce a Type I interferon response in human keratinocytes. International Journal of Molecular Sciences, 18(10), 2227.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Madar, S., Goldstein, I., & Rotter, V. (2013). ‘Cancer associated fibroblasts’—More than meets the eye. Trends in Molecular Medicine, 19(8), 447–453.

    Article  CAS  PubMed  Google Scholar 

  16. Kalluri, R. (2016). The biology and function of fibroblasts in cancer. Nature Reviews Cancer, 16(9), 582–598.

    Article  CAS  PubMed  Google Scholar 

  17. Karagiannis, G. S., Poutahidis, T., Erdman, S. E., Kirsch, R., Riddell, R. H., & Diamandis, E. P. (2012). Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Molecular Cancer Research, 10(11), 1403–1418.

    Article  CAS  PubMed  Google Scholar 

  18. Dong, W., Xie, Y., & Huang, H. (2022). Prognostic value of cancer-associated fibroblast-related gene signatures in hepatocellular carcinoma. Frontiers in Endocrinology (Lausanne), 13, 884777.

    Article  Google Scholar 

  19. Zhang, J., Zhang, N., Fu, X., Wang, W., Liu, H., McKay, M. J., Dejkriengkraikul, P., & Nie, Y. (2022). Bioinformatic analysis of cancer-associated fibroblast related gene signature as a predictive model in clinical outcomes and immune characteristics of gastric cancer. Annals of Translational Medicine, 10(12), 698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zheng, H., Liu, H., Ge, Y., & Wang, X. (2021). Integrated single-cell and bulk RNA sequencing analysis identifies a cancer associated fibroblast-related signature for predicting prognosis and therapeutic responses in colorectal cancer. Cancer Cell International, 21(1), 552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Papanicolaou, M., Parker, A. L., Yam, M., Filipe, E. C., Wu, S. Z., Chitty, J. L., Wyllie, K., Tran, E., Mok, E., Nadalini, A., et al. (2022). Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis. Nature Communications, 13(1), 4587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Xia, H., Nho, R. S., Kahm, J., Kleidon, J., & Henke, C. A. (2004). Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. The Journal of Biological Chemistry, 279(31), 33024–33034.

    Article  CAS  PubMed  Google Scholar 

  23. Bond, K. H., Chiba, T., Wynne, K. P. H., Vary, C. P. H., Sims-Lucas, S., Coburn, J. M., & Oxburgh, L. (2021). The extracellular matrix environment of clear cell renal cell carcinoma determines cancer associated fibroblast growth. Cancers (Basel), 13(23), 5873.

    Article  CAS  PubMed  Google Scholar 

  24. Lee, S. H., Lee, S., Du, J., Jain, K., Ding, M., Kadado, A. J., Atteya, G., Jaji, Z., Tyagi, T., Kim, W. H., Herzog R. I., Patel A., Ionescu C. N., Martin K. A., Hwa J. (2019). Mitochondrial MsrB2 serves as a switch and transducer for mitophagy. EMBO Molecular Medicine, 11(8), e10409.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hao, J., Zhang, W., & Huang, Z. (2022). Bupivacaine modulates the apoptosis and ferroptosis in bladder cancer via phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Bioengineered, 13(3), 6794–6806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dallmann, K., Junker, H., Balabanov, S., Zimmermann, U., Giebel, J., & Walther, R. (2004). Human agmatinase is diminished in the clear cell type of renal cell carcinoma. International Journal of Cancer, 108(3), 342–347.

    Article  CAS  PubMed  Google Scholar 

  27. Celik, V. K., Kapancik, S., Kacan, T., Kacan, S. B., Kapancik, S., & Kilicgun, H. (2017). Serum levels of polyamine synthesis enzymes increase in diabetic patients with breast cancer. Endocrine Connections, 6(8), 574–579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhao, Y., Yu, Z., Ma, R., Zhang, Y., Zhao, L., Yan, Y., Lv, X., Zhang, L., Su, P., Bi, J., et al. (2021). lncRNA-Xist/miR-101-3p/KLF6/C/EBPalpha axis promotes TAM polarization to regulate cancer cell proliferation and migration. Molecular Therapy Nucleic Acids, 23, 536–551.

    Article  CAS  PubMed  Google Scholar 

  29. Khor, G. H., Froemming, G. R., Zain, R. B., Abraham, M. T., Omar, E., Tan, S. K., Tan, A. C., Vincent-Chong, V. K., & Thong, K. L. (2013). DNA methylation profiling revealed promoter hypermethylation-induced silencing of p16, DDAH2 and DUSP1 in primary oral squamous cell carcinoma. International Journal of Medical Science, 10(12), 1727–1739.

    Article  CAS  Google Scholar 

  30. Wang, Q., Wu, W., Gao, Z., Li, K., Peng, S., Fan, H., Xie, Z., Guo, Z., & Huang, H. (2021). GADD45B is a potential diagnostic and therapeutic target gene in chemotherapy-resistant prostate cancer. Frontiers in Cell and Developmental Biology, 9, 716501.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chuang, H. W., Hsia, K. T., Liao, J. B., Yeh, C. C., Kuo, W. T., & Yang, Y. F. (2021). SERPINE2 overexpression is associated with poor prognosis of urothelial carcinoma. Diagnostics (Basel), 11(10), 1928.

    Article  CAS  PubMed  Google Scholar 

  32. Park, S., Mossmann, D., Chen, Q., Wang, X., Dazert, E., Colombi, M., Schmidt, A., Ryback, B., Ng, C. K. Y., Terracciano, L. M., et al. (2022). Transcription factors TEAD2 and E2A globally repress acetyl-CoA synthesis to promote tumorigenesis. Molecular Cell, 82(22), 4246-4261.e4211.

    Article  CAS  PubMed  Google Scholar 

  33. Sun, L., Wang, Y., Wang, L., Yao, B., Chen, T., Li, Q., Liu, Z., Liu, R., Niu, Y., Song, T., et al. (2019). Resolvin D1 prevents epithelial–mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP. Journal of Experimental and Clinical Cancer Research, 38(1), 170.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ishii, K., Mizokami, A., Tsunoda, T., Iguchi, K., Kato, M., Hori, Y., Arima, K., Namiki, M., & Sugimura, Y. (2011). Heterogenous induction of carcinoma-associated fibroblast-like differentiation in normal human prostatic fibroblasts by co-culturing with prostate cancer cells. Journal of Cell Biochemistry, 112(12), 3604–3611.

    Article  CAS  Google Scholar 

  35. Tvedt, K. E., Halgunset, J., Kopstad, G., & Haugen, O. A. (1989). Intracellular distribution of calcium and zinc in normal, hyperplastic, and neoplastic human prostate: X-ray microanalysis of freeze-dried cryosections. Prostate, 15(1), 41–51.

    Article  CAS  PubMed  Google Scholar 

  36. Xu, H., Zhao, J., Li, J., Zhu, Z., Cui, Z., Liu, R., Lu, R., Yao, Z., & Xu, Q. (2022). Cancer associated fibroblast-derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1alpha/ZEB1 axis. Cell Death and Disease, 13(5), 478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Siracusano, S., Rizzetto, R., & Porcaro, A. B. (2020). Bladder cancer genomics. Urologia, 87(2), 49–56.

    Article  PubMed  Google Scholar 

  38. Chirravuri-Venkata, R., Dam, V., Nimmakayala, R. K., Alsafwani, Z. W., Bhyravbhatla, N., Lakshmanan, I., Ponnusamy, M. P., Kumar, S., Jain, M., Ghersi, D., et al. (2023). MUC16 and TP53 family co-regulate tumor–stromal heterogeneity in pancreatic adenocarcinoma. Frontiers in Oncology, 13, 1073820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhuang, J., Shen, L., Li, M., Sun, J., Hao, J., Li, J., Zhu, Z., Ge, S., Zhang, D., Guo, H., et al. (2023). Cancer-associated fibroblast-derived miR-146a-5p generates a niche that promotes bladder cancer stemness and chemoresistance. Cancer Research, 83(10), 1611–1627.

    Article  CAS  PubMed  Google Scholar 

  40. Rodriguez-Brenes, I. A., Kurtova, A. V., Lin, C., Lee, Y. C., Xiao, J., Mims, M., Chan, K. S., & Wodarz, D. (2017). Cellular hierarchy as a determinant of tumor sensitivity to chemotherapy. Cancer Research, 77(9), 2231–2241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu, Z., Qi, T., Li, X., Yao, Y., Othmane, B., Chen, J., Zu, X., Ou, Z., & Hu, J. (2021). A novel TGF-beta risk score predicts the clinical outcomes and tumour microenvironment phenotypes in bladder cancer. Frontiers in Immunology, 12, 791924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nallasamy, P., Nimmakayala, R. K., Karmakar, S., Leon, F., Seshacharyulu, P., Lakshmanan, I., Rachagani, S., Mallya, K., Zhang, C., Ly, Q. P., et al. (2021). Pancreatic tumor microenvironment factor promotes cancer stemness via SPP1-CD44 axis. Gastroenterology, 161(6), 1998–2013.

    Article  CAS  PubMed  Google Scholar 

  43. Song, M., He, J., Pan, Q.-Z., Yang, J., Zhao, J., Zhang, Y.-J., Huang, Y., Tang, Y., Wang, Q., He, J., et al. (2021). Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology, 73(5), 1717–1735.

    Article  CAS  PubMed  Google Scholar 

  44. Denton, A. E., Roberts, E. W., & Fearon, D. T. (2018). Stromal cells in the tumor microenvironment. Advances in Experimental Medicine and Biology, 1060, 99–114.

    Article  CAS  PubMed  Google Scholar 

  45. Li, Y., Li, X., Deng, M., Ye, C., Peng, Y., & Lu, Y. (2022). Cancer-associated fibroblasts hinder lung squamous cell carcinoma oxidative stress-induced apoptosis via METTL3 mediated m(6)A methylation of COL10A1. Oxidative Medicine and Cellular Longevity, 2022, 4320809.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Piersma, B., Hayward, M.-K., & Weaver, V. M. (2020). Fibrosis and cancer: A strained relationship. Biochimica Biophysica Acta Reviews in Cancer, 1873(2), 188356.

    Article  CAS  Google Scholar 

  47. Mao, X., Xu, J., Wang, W., Liang, C., Hua, J., Liu, J., Zhang, B., Meng, Q., Yu, X., & Shi, S. (2021). Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: New findings and future perspectives. Molecular Cancer, 20(1), 131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Obradovic, A., Graves, D., Korrer, M., Wang, Y., Roy, S., Naveed, A., Xu, Y., Luginbuhl, A., Curry, J., Gibson, M., et al. (2022). Immunostimulatory cancer-associated fibroblast subpopulations can predict immunotherapy response in head and neck cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 28(10), 2094–2109.

    Article  CAS  PubMed  Google Scholar 

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Funding

The project was supported by Ningbo Natural Science Foundation (Grant No. 2021 J017).

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KZ: Writing-original draft, writing-reviewing and editing. ML: Data curation and methodology.

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Correspondence to Kaifeng Zheng.

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Zheng, K., Li, M. Predicting Survival Signature of Bladder Cancer Related to Cancer-Associated Fibroblast (CAF) Constructed by Intersecting Genes in TCGA and GEO. Mol Biotechnol (2023). https://doi.org/10.1007/s12033-023-00892-y

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