Molecular Evaluation of Interleukin-8, Interleukin-27, and Vascular Endothelial Growth Factor Expression in Prostate Cancer Patients
DOI:
https://doi.org/10.14500/aro.12718Keywords:
Angiogenesis, Interleukin-8,, Interleukin-27, Prostate cancer, Vascular endothelial growth factorAbstract
Globally, prostate cancer (PCa) is becoming more prevalent and lethal. The progression of PCa is linked to both inflammation and angiogenesis. Pro-inflammatory cytokines, interleukin (IL)-8) and vascular endothelial growth factor (VEGF), promote inflammation, angiogenesis, and PCa progression. On the other hand, IL-27 (IL-27) has antitumor effects, modulates immune system activity, and thus serves as a suppressor of tumor growth. In the Kurdistan Region of Iraq, there is limited evidence linking these cytokines and their gene polymorphisms to PCa. This case–control study included 50 PCa patients and 30 age-matched healthy controls. Serum levels of these three cytokines were evaluated by enzyme-linked immunosorbent assay, whereas PCR and Sanger sequencing were used to find polymorphisms in IL-8 (rs4073, rs2227306), IL-27 (rs153109), and VEGF (rs2010963) in formalin-fixed paraffinembedded tissue DNA. GeneMANIA was used to assess gene-gene interaction networks. Statistical analyses were performed using Mann–Whitney U tests. Patients with PCa showed elevated IL-8 and VEGF levels and reduced IL-27 levels compared to controls (p < 0.05). Multiple single-nucleotide polymorphisms were found in all target genes, several of which were new to the GenBank. Gene-network analysis revealed that these three cytokines are involved in shared inflammatory, immunomodulatory, and angiogenic pathways. This study shows that altered serum levels and gene polymorphisms of these three cytokines may be biomarkers for PCa diagnosis and progression. It underlines the molecular interplay between inflammatory and angiogenic mediators and supports further cytokine-based diagnostic and therapeutic research.
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Alsamraae, M., Costanzo-Garvey, D., Teply, B.A., Boyle, S., Sommerville, G., Herbert, Z.T., Morrissey, C., Dafferner, A.J., Abdalla, M.Y., Fallet, R.W., Kielian, T., Jensen-Smith, H., DeOliveira, E.I., Chen, K., Bettencourt, I.A., Wang, J.M., MeVicar, D.W., Keeley, T., Yu, F., and Cook, L.M., 2023. Androgen receptor inhibition suppresses anti-tumor neutrophil response against bone metastatic prostate cancer via regulation of TβRI expression. Cancer Letters, 579, p.216468.
Archer, M., Dogra, N., and Kyprianou, N., 2020. Inflammation as a driver of prostate cancer metastasis and therapeutic resistance. Cancers (Basel), 12, p.2984.
Basagiannis, D., Zografou, S., Murphy, C., Fotsis, T., Morbidelli, L., Ziche, M., Bleck, C., Mercer, J., and Christoforidis, S., 2016. VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis. Journal of Cell Science, 129, pp.4091-4104.
Berenguer, C.V., Pereira, F., Câmara, J.S., and Pereira, J.A., 2023. Underlying features of prostate cancer-statistics, risk factors, and emerging methods for its diagnosis. Current Oncology, 30, pp.2300-2321.
Catena, R., Larzabal, L., Larrayoz, M., Molina, E., Hermida, J., Agorreta, J., Montes, R., Pio, R., Montuenga, L.M., and Calvo, A., 2010. VEGF121 b and VEGF165 b are weakly angiogenic isoforms of VEGF-A. Molecular Cancer, 9, p.320.
Chen, C.H., Ho, C.H., Hu, S.W., Tzou, K.Y., Wang, Y.H, and Wu, C.C., 2020. Association between interleukin-8 rs4073 polymorphism and prostate cancer: A meta-analysis. Journal of the Formosan Medical Association, 119, pp.1201-1210.
Chen, K., Jiang, K., Tang, L., Chen, X., Hu, J., and Sun, F., 2021. Analysis of clinical trials on therapies for prostate cancer in mainland China and globally from 2010 to 2020. Frontiers in Oncology, 11, p.647110.
Dahal, S., Chaudhary, P., Jung, Y.S., and Kim, J.A., 2023. MegakaryocyteDerived IL-8 acts as a paracrine factor for prostate cancer aggressiveness through CXCR2 activation and antagonistic AR downregulation. Biomolecules and Therapeutics, 31, pp.210-218.
Denmeade, S.R., Litvinov, I., Sokoll, L.J., Lilja, H., and Isaacs, J.T., 2003. Prostate‐specific antigen (PSA) protein does not affect growth of prostate cancer cells in vitro or prostate cancer xenografts in vivo. The Prostate, 56, pp.45-53.
Di Carlo, E., Sorrentino, C., Zorzoli, A., Di Meo, S., Tupone, M.G., Ognio, E., Mincione, G., and Airoldi, I., 2013. The antitumor potential of Interleukin-27 in prostate cancer. Oncotarget, 5, pp.10332-10341.
Elaimy, A.L., and Mercurio, A.M., 2018. Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology. Science Signaling, 11, p.eaau1165.
Ene, C., Nicolae, I., and Ene, C.D., 2023. Angiogenic systemic response to the hypoxic microenvironment in prostate tumorigenesis: A pilot study. Experimental and Therapeutic Medicine, 26, p.483.
Ferrer, F.A., Miller, L.J., Andrawis, R.I., Kurtzman, S.H., Albertsen, P.C., Laudone, V.P., and Kreutzer, D.L., 1998. Angiogenesis and prostate cancer: In vivo and in vitro expression of angiogenesis factors by prostate cancer cells. Urology, 51, pp.161-167.
Franz, M., Rodriguez, H., Lopes, C., Zuberi, K., Montojo, J., Bader, G.D., and Morris, Q., 2018. GeneMANIA update 2018. Nucleic Acids Research, 46, pp.W60-W64.
Furriol, J., Wik, E., Aziz, S., Askeland, C., Knutsvik, G., and Akslen, L.A., 2024. VEGFA gene variants are associated with breast cancer progression. The Journal of Pathology: Clinical Research, 10, p.e12393.
Ghazy, A.A., and Alenzi, M.J., 2021. Relevance of interleukins 6 and 8 single nucleotide polymorphisms in prostate cancer: A multicenter study. Prostate Cancer, 2021, p.3825525.
Guo, Y., Zang, Y., Lv, L., Cai, F., Qian, T., Zhang, G., and Feng, Q., 2017. IL8 promotes proliferation and inhibition of apoptosis via STAT3/AKT/NFκB pathway in prostate cancer. Molecular Medicine Reports, 16, pp.9035-9042.
He, W., Yan, L., Hu, D., Hao, J., Liou, Y.C., and Luo, G., 2025. Neutrophil heterogeneity and plasticity: Unveiling the multifaceted roles in health and disease. Medicine Communications, 6, p.e70063.
Karwan, M.A., Abdullah, O.S., Amin, A.M., Mohamed, Z.A., Hasan, B., Shekha, M., Najmuldeen, H.H., Rahman, F.M., Housein, Z., Salih, A.M., Mohammed A.S., Sulaiman, L.R., Barzingi, B.T., Mahmood, D., Othman, H.E.,… & Salihi, A., 2022. Cancer incidence in the Kurdistan region of Iraq: Results of a seven-year cancer registration in Erbil and Duhok Governorates. Asian Pacific Journal of Cancer Prevention, 23, pp.601-615.
Kluetz, P.G., Figg, W.D., and Dahut, W.L., 2010. Angiogenesis inhibitors in the treatment of prostate cancer. Expert Opinion on Pharmacotherapy, 11, pp.233-247.
Kourko, O., Smyth, R., Cino, D., Seaver, K., Petes, C., Eo, S.Y., Basta, S., and Gee, K., 2019. Poly(I: C)-mediated death of human prostate cancer cell lines is induced by interleukin-27 treatment. Journal of Interferon and Cytokine Research, 39, pp.483-494.
Larsson, P., Syed Khaja, A.S., Semenas, J., Wang, T., Sarwar, M., Dizeyi, N., Simoulis, A., Hedblom, A., Wai, S.N., Ødum, N., Persson, J.L., 2020. The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer. International Journal of Cancer, 146, pp.1686-1699.
Leach, D.A., Chatterjee, N., Spahr, K., De Almeida, G.S., Varela‐Carver, A., Shah, T.T., Winkler, M., Ahmed, H.U., and Bevan, C.L., 2025. Simultaneous inhibition of TRIM24 and TRIM28 sensitises prostate cancer cells to antiandrogen therapy, decreasing VEGF signalling and angiogenesis. Molecular Oncology. 19, pp.2797-2821.
Lilja, H., Ulmert, D., and Vickers, A.J., 2008. Prostate-specific antigen and prostate cancer: Prediction, detection and monitoring. Nature Reviews Cancer, 8, pp.268-278.
Luo, Y., Yang, Z., Yu, Y., and Zhang, P., 2022. HIF1α lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer. International Journal of Biological Macromolecules, 222, pp.2225-2243.
Maleki, A.H., Rajabivahid, M., Khosh, E., Khanali, Z., Tahmasebi, S., and Ghorbi, M.D., 2025. Harnessing IL-27: Challenges and potential in cancer immunotherapy. Clinical and Experimental Medicine, 25, p.34.
McClelland, S., Maxwell, P.J., Branco, C., Barry, S.T., Eberlein, C., and Labonte, M.J., 2024a. Targeting IL-8 and its receptors in prostate cancer: Inflammation, stress response, and treatment resistance. Cancers (Basel), 16, p.2797.
McClelland, S., Maxwell, P.J., Branco, C., Barry, S.T., Eberlein, C., and Labonte, M.J., 2024b. Targeting IL-8 and its receptors in prostate cancer: Inflammation, stress response, and treatment resistance. Cancers (Basel), 16, p.2797.
Mirlekar, B., and Pylayeva-Gupta, Y., 2021. IL-12 family cytokines in cancer and immunotherapy. Cancers (Basel), 13, p.167.
Occhipinti, S., Mengozzi, G., Oderda, M., Zitella, A., Molinaro, L., Novelli, F., Giovarelli, M., and Gontero, P., 2021. Low levels of urinary PSA better identify prostate cancer patients. Cancers (Basel), 13, p.3570.
Rizo-Téllez, S.A., and Filep, J.G., 2024. Beyond host defense and tissue injury: The emerging role of neutrophils in tissue repair. American Journal of Physiology-Cell Physiology, 326, pp.C661-C683.
Sarkar, C., Goswami, S., Basu, S., and Chakroborty, D., 2020. Angiogenesis inhibition in prostate cancer: An update. Cancers (Basel), 12, p.2382.
Schalken, J.A., 2004. Molecular and cellular prostate biology: Origin of prostatespecific antigen expression and implications for benign prostatic hyperplasia. BJU International, 93, pp.5-9.
Schneider, R., Yaneva, T., Beauseigle, D., El‐Khoury, L., and Arbour, N., 2011. IL‐27 increases the proliferation and effector functions of human naive CD8+ T lymphocytes and promotes their development into Tc1 cells . European Journal of Immunology, 41, pp.47-59.
Siegel, R.L., Kratzer, T.B., Giaquinto, A.N., Sung, H., and Jemal, A., 2025. Cancer statistics, 2025. CA: A Cancer Journal for Clinicians, 75, pp.10-45.
Veltri, R.W., Miller, M.C., Zhao, G., Ng, A., Marley, G.M., Wright G.L. Jr., Vessella, R.L., and Ralph, D., 1999. Interleukin-8 serum levels in patients with benign prostatic hyperplasia and prostate cancer. Urology, 53, pp.139-147.
Venet, F., and Monneret, G., 2018. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nature Reviews Nephrology, 14, pp.121-137.
Watts, E.L., Perez-Cornago, A., Kothari, J., Allen, N.E., Travis, R.C., and Key, T.J., 2020. Haematological markers and prostate cancer risk: A prospective analysis in UK Biobank. Cancer Epidemiology, Biomarkers and Prevention, 29, pp.1615-1626.
Wong, S.Y., Haack, H., Crowley, D., Barry, M., Bronson, R.T., and Hynes, R.O., 2005. Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Research, 65, pp.9789-9798.
Wu, T.T.L., Wang, J.S., Jiann, B.P., Yu, C.C., Tsai, J.Y., Lin, J.T., and Huang, J.K., 2007. Expression of vascular endothelial growth factor in Taiwanese benign and malignant prostate tissues. Journal of the Chinese Medical Association, 70, pp.380-384.
Zhang, Z., Zhou, B., Zhang, K., Song, Y., Zhang, L., and Xi, M., 2016. IL-27 suppresses SKOV3 cells proliferation by enhancing STAT3 and inhibiting the Akt signal pathway. Molecular Immunology, 78, pp.155-163.
Zolochevska, O., Diaz‐Quiñones, A.O., Ellis, J., and Figueiredo, M.L., 2013. Interleukin‐27 expression modifies prostate cancer cell crosstalk with bone and immune cells in vitro. Journal of Cellular Physiology, 228, pp.1127-1136.
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Copyright (c) 2026 Jutyar I. Saber, Hiwa R. Fatah, Fikry A. Qadir
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Accepted 2026-01-17
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