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.
Similar content being viewed by others
Data Availability
The data sets supporting the results of this article are included within the article and its additional files.
References
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.
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.
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.
Musa, M. (2020). Single-cell analysis on stromal fibroblasts in the microenvironment of solid tumours. Advances in Medical Science, 65(1), 163–169.
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.
Sukowati, C. H., Anfuso, B., Croce, L. S., & Tiribelli, C. (2015). The role of multipotent cancer associated fibroblasts in hepatocarcinogenesis. BMC Cancer, 15, 188.
Bellmunt, J. (2018). Stem-like signature predicting disease progression in early stage bladder cancer. The role of E2F3 and SOX4. Biomedicines, 6(3), 85.
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.
Zhang, W., & Huang, P. (2011). Cancer–stromal interactions: Role in cell survival, metabolism and drug sensitivity. Cancer Biology and Therapy, 11(2), 150–156.
Biffi, G., & Tuveson, D. A. (2021). Diversity and biology of cancer-associated fibroblasts. Physiological Review, 101(1), 147–176.
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.
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.
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.
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.
Madar, S., Goldstein, I., & Rotter, V. (2013). ‘Cancer associated fibroblasts’—More than meets the eye. Trends in Molecular Medicine, 19(8), 447–453.
Kalluri, R. (2016). The biology and function of fibroblasts in cancer. Nature Reviews Cancer, 16(9), 582–598.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Siracusano, S., Rizzetto, R., & Porcaro, A. B. (2020). Bladder cancer genomics. Urologia, 87(2), 49–56.
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.
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.
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.
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.
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.
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.
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.
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.
Piersma, B., Hayward, M.-K., & Weaver, V. M. (2020). Fibrosis and cancer: A strained relationship. Biochimica Biophysica Acta Reviews in Cancer, 1873(2), 188356.
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.
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.
Funding
The project was supported by Ningbo Natural Science Foundation (Grant No. 2021 J017).
Author information
Authors and Affiliations
Contributions
KZ: Writing-original draft, writing-reviewing and editing. ML: Data curation and methodology.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Ethical Approval
Not applicable.
Informed Consent
Not applicable.
Consent for Publication
All authors know and agree to publish the article.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12033-023-00892-y