Visfatin Promotes Renal Cell Carcinoma Progression: Evidence from Clinical Samples and Cell Line Models
Main Article Content
Keywords
adipose tissue, adipocytokine, perirenal fat, renal cell carcinoma, visfatin
Abstract
The kidney is enveloped by perirenal fat, which secretes various hormones and cytokines, known as adipokines. Adipokines have been demonstrated to influence the development and progression of tumors, including renal cell carcinoma (RCC). Visfatin, an adipokine secreted by the adipose tissue, has been implicated in RCC, but its precise role remains unclear. In this study, we investigated the expression of visfatin in perire-nal fat from patients with RCC and its correlation with the RCC malignant phenotype, and we examined the role of visfatin in RCC cell lines in vitro. This study included adipose tissue samples from 57 Japanese patients with clear cell RCC who underwent partial or radical nephrectomy. We examined the mRNA expression level of visfatin using real-time PCR. In vitro MTT assay and western blot were performed using human RCC cell lines. The mRNA expression of visfatin in peri-tumor versus peri-normal fat was higher in Fuhrman grade ≥2 cases compared with Fuhrman grade 1 cases. Furthermore, the addition of visfatin to RCC cell lines promoted cell proliferation, which was accompanied by increased protein expression of HIF1α, p-Akt, and p-ERK. Conversely, the addition of FK866, a visfatin inhibitor, suppressed cell proliferation and reduced these proteins. Our findings suggest that visfatin from peri-tumor adipose tissue influences the malignancy of RCC and plays a role in promoting the growth of RCC. This indicates a potential mechanism by which adipose tissue contributes to the progression of RCC, providing a possible target for therapeutic intervention.
References
1. Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nature Reviews Disease primers. 2017;3:1–19.
2. Şenbabaoğlu Y, Gejman RS, Winer AG, Liu M, Van Allen EM, de Velasco G, et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biology. 2016;17:1–25.
3. Cao H. Adipocytokines in obesity and metabolic disease. Journal of Endocrinology 2014;220:T47–T59.
4. Mohammadi M, Mianabadi F, Mehrad,‐Majd H. Circulating visfatin levels and cancers risk: A systematic review and meta‐analysis. Journal of Cellular Physiology. 2019;234:5011–22.
5. Al-Suhaimi EA, Shehzad A. Leptin, resistin and visfatin: The missing link between endocrine metabolic disorders and immunity. European Journal of Medical Research. 2013;18:1–13.
6. Lin TC. The role of visfatin in cancer proliferation, angiogenesis, metastasis, drug resistance and clinical prognosis. Cancer Management and Research. 2019;3481–91.
7. Kashiwagi E, Imada K, Abe T, Kinoshita F, Monji K, Shiota M, et al. Thickness of perirenal fat predicts the growth pattern of renal cell carcinoma. Kidney Cancer. 2020;4;41–8.
8. Kashiwagi E, Inoue S, Mizushima T, Chen J, Ide H, Kawahara T, et al. Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression. British Journal of Cancer. 2018 Jan;118:213–23.
9. Naito S, von Eschenbach AC, Giavazzi R, Fidler IJ. Growth and metastasis of tumor cells isolated from a human renal cell carcinoma implanted into different organs of nude mice. Cancer Research. 1986;46:4109–15.
10. Naito S, Kanamori T, Hisano S, Tanaka K, Momose S, Kamata N. Human renal cell carcinoma: Establishment and characterization of two new cell lines. Journal of Urology. 1982;128:1117–21.
11. Kashiwagi E, Ide H, Inoue S, Kawahara T, Zheng Y, Reis LO, et al. Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer. Oncotarget. 2016 Jun;14:7:49169–79.
12. Gu Z, Gu L, Eils R, Schlesner M, Brors B. Circlize implements and enhances circular visualization in R. Bioinformatics 2014;30:2811-12.
13. Wickham H. ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag, New York, 2009. Preprint at 2016: 2:15545-50.
14. Ahlmann-Eltze C, Patil I. ggsignif: R package for displaying significance brackets for ‘ggplot2’. R package version 0.6.3. 2021. Available from: https://cran.r-project.org/package=ggsignif
15. Clarke E, Sherrill-Mix S, Dawson C, Clarke ME. ggbeeswarm: Categorical scatter (violin point) plots. R package version 0.7.2. 2023. Available from: https://cran.r-project.org/package=ggbeeswarm
16. Magar AG, Morya VK, Kwak MK, Oh JU, Noh KC. A molecular perspective on HIF-1α and angiogenic stimulator networks and their role in solid tumors: An update. International Journal of Molecular Sciences. 2024;25:3313.
17. Gudas LJ, Fu L, Minton DR, Mongan NP, Nanus DM. The role of HIF1α in renal cell carcinoma tumorigenesis. Journal of Molecular Medicine. 2014;92:825–36.
18. Maharati A, Moghbeli M. PI3K/AKT signaling pathway as a critical regulator of epithelial-mesenchymal transition in colorectal tumor cells. Cell Communication and Signaling. 2023;21:201.
19. Zhong WF, Wang XH, Pan B, Li F, Kuang L, Su ZX. Eupatilin induces human renal cancer cell apoptosis via ROS‑mediated MAPK and PI3K/AKT signaling pathways. Oncology Letters. 2016;12:2894–9.
20. Massagué J. TGFβ in cancer. Cell. 2008;134:215–30.
21. Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Reports. 2014; 15:1243–53.
22. Batlle E, Massagué J. Transforming growth factor- signaling in immunity and cancer. Immunity. 2019; 50:924–40.
23. Garten A, Schuster S, Penke M, Gorski T, De Giorgis T, Kiess W. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nature Reviews Endocrinology. 2015;11:535–46.
24. Zhang HP, Zou J, Xu ZQ, Ruan J, Yang SD, Yin Y, et al. Association of leptin, visfatin, apelin, resistin and adiponectin with clear cell renal cell carcinoma. Oncol Letters. 2017;13:463–8.
25. Choi SH, Chun SY, Kim TH, Kwon TG. Identifying the emerging role of adipokine as a diagnostic and prognostic biomarker of renal cell carcinoma. Urologic Oncology: Seminars and Original Investigations; 2016: Elsevier, 2016. p. 259. e15–. e19.
26. Shackelford RE, Abdulsattar J, Wei EX, Cotelingam J, Coppola D, Herrera GA. Increased nicotinamide phosphoribosyltransferase and cystathionine-β-synthase in renal oncocytomas, renal urothelial carcinoma, and renal clear cell carcinoma. Anticancer Research. 2017;37:3423–7.
27. Wei G, Sun H, Dong K, Hu L, Wang Q, Zhuang Q, et al. The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy. Cell Metabolism. 2021; 33:2021–39.e8.
28. Lee YC, Yang YH, Su JH, Chang HL, Hou MF, Yuan SSF. High visfatin expression in breast cancer tissue is associated with poor survival. Cancer Epidemiology, Biomarkers & Prevention. 2011; 20:1892–901.
29. Lv X, Zhang L, Zhu Y, Said HM, Shi J, Xu G. Regulative effect of Nampt on tumor progression and cell viability in human colorectal cancer. Journal of Cancer. 2015;6:849.
30. Neubauer K, Bednarz Misa I, Diakowska D, Kapturkiewicz B, Gamian A, Krzystek-Korpacka M. Nampt/PBEF/Visfatin upregulation in colorectal tumors, mirrored in normal tissue and whole blood of colorectal cancer patients, is associated with metastasis, hypoxia, IL1β, and anemia. BioMed Research International. 2015;2015:523930.
31. Grigoraș A, Amalinei C. The role of perirenal adipose tissue in carcinogenesis—From molecular mechanism to therapeutic perspectives. Cancers (Basel). 2025 Mar;23:17.
32. Hammoud SH, AlZaim I, Al-Dhaheri Y, Eid AH, El-Yazbi AF. Perirenal adipose tissue inflammation: Novel insights linking metabolic dysfunction to renal diseases. Frontiers in Endocrinology (Lausanne). 2021;12:707126.
33. Thiel DD, Davidiuk AJ, Meschia C, Serie D, Custer K, Petrou SP, et al. Mayo adhesive probability score is associated with localized renal cell carcinoma progression-free survival. Urology. 2016;89:54–62.
34. Ning K, Li Z, Liu H, Tian X, Wang J, Wu Y, et al. Perirenal fat thickness significantly associated with prognosis of metastatic renal cell cancer patients receiving anti-VEGF therapy. Nutrients. 2022;14:3388.
35. Maurits JSF, Sedelaar JPM, Aben KKH, Kiemeney LALM, Vrieling A. Association of visceral and subcutaneous adiposity with tumor stage and Fuhrman grade in renal cell carcinoma. Scientific Reports 2022 2022/10/06;12:16718.
36. Kaneko G, Miyajima A, Yuge K, Yazawa S, Mizuno R, Kikuchi E, et al. Visceral obesity is associated with better recurrence-free survival after curative surgery for Japanese patients with localized clear cell renal cell carcinoma. Japanese Journal of Clinical Oncology. 2014; 45:210–6.
37. Hasmann M, Schemainda I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Research. 2003;63:7436–42.
38. Naing A, Leong S, Pishvaian MJ, Razak ARA, Mahipal A, Berlin J, et al. A first in human phase 1 study of KPT-9274, a first in class dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies or NHL. Annals of Oncology. 2017;28:v125.
39. Holen K, Saltz LB, Hollywood E, Burk K, Hanauske AR. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Investigational New Drugs. 2008;26:45–51.
40. Kashiwagi E. Perirenal fat in disease progression: From inflammatory mediator to therapeutic target. International Journal of Urology2025; Epub ahead of print.
2. Şenbabaoğlu Y, Gejman RS, Winer AG, Liu M, Van Allen EM, de Velasco G, et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biology. 2016;17:1–25.
3. Cao H. Adipocytokines in obesity and metabolic disease. Journal of Endocrinology 2014;220:T47–T59.
4. Mohammadi M, Mianabadi F, Mehrad,‐Majd H. Circulating visfatin levels and cancers risk: A systematic review and meta‐analysis. Journal of Cellular Physiology. 2019;234:5011–22.
5. Al-Suhaimi EA, Shehzad A. Leptin, resistin and visfatin: The missing link between endocrine metabolic disorders and immunity. European Journal of Medical Research. 2013;18:1–13.
6. Lin TC. The role of visfatin in cancer proliferation, angiogenesis, metastasis, drug resistance and clinical prognosis. Cancer Management and Research. 2019;3481–91.
7. Kashiwagi E, Imada K, Abe T, Kinoshita F, Monji K, Shiota M, et al. Thickness of perirenal fat predicts the growth pattern of renal cell carcinoma. Kidney Cancer. 2020;4;41–8.
8. Kashiwagi E, Inoue S, Mizushima T, Chen J, Ide H, Kawahara T, et al. Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression. British Journal of Cancer. 2018 Jan;118:213–23.
9. Naito S, von Eschenbach AC, Giavazzi R, Fidler IJ. Growth and metastasis of tumor cells isolated from a human renal cell carcinoma implanted into different organs of nude mice. Cancer Research. 1986;46:4109–15.
10. Naito S, Kanamori T, Hisano S, Tanaka K, Momose S, Kamata N. Human renal cell carcinoma: Establishment and characterization of two new cell lines. Journal of Urology. 1982;128:1117–21.
11. Kashiwagi E, Ide H, Inoue S, Kawahara T, Zheng Y, Reis LO, et al. Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer. Oncotarget. 2016 Jun;14:7:49169–79.
12. Gu Z, Gu L, Eils R, Schlesner M, Brors B. Circlize implements and enhances circular visualization in R. Bioinformatics 2014;30:2811-12.
13. Wickham H. ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag, New York, 2009. Preprint at 2016: 2:15545-50.
14. Ahlmann-Eltze C, Patil I. ggsignif: R package for displaying significance brackets for ‘ggplot2’. R package version 0.6.3. 2021. Available from: https://cran.r-project.org/package=ggsignif
15. Clarke E, Sherrill-Mix S, Dawson C, Clarke ME. ggbeeswarm: Categorical scatter (violin point) plots. R package version 0.7.2. 2023. Available from: https://cran.r-project.org/package=ggbeeswarm
16. Magar AG, Morya VK, Kwak MK, Oh JU, Noh KC. A molecular perspective on HIF-1α and angiogenic stimulator networks and their role in solid tumors: An update. International Journal of Molecular Sciences. 2024;25:3313.
17. Gudas LJ, Fu L, Minton DR, Mongan NP, Nanus DM. The role of HIF1α in renal cell carcinoma tumorigenesis. Journal of Molecular Medicine. 2014;92:825–36.
18. Maharati A, Moghbeli M. PI3K/AKT signaling pathway as a critical regulator of epithelial-mesenchymal transition in colorectal tumor cells. Cell Communication and Signaling. 2023;21:201.
19. Zhong WF, Wang XH, Pan B, Li F, Kuang L, Su ZX. Eupatilin induces human renal cancer cell apoptosis via ROS‑mediated MAPK and PI3K/AKT signaling pathways. Oncology Letters. 2016;12:2894–9.
20. Massagué J. TGFβ in cancer. Cell. 2008;134:215–30.
21. Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Reports. 2014; 15:1243–53.
22. Batlle E, Massagué J. Transforming growth factor- signaling in immunity and cancer. Immunity. 2019; 50:924–40.
23. Garten A, Schuster S, Penke M, Gorski T, De Giorgis T, Kiess W. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nature Reviews Endocrinology. 2015;11:535–46.
24. Zhang HP, Zou J, Xu ZQ, Ruan J, Yang SD, Yin Y, et al. Association of leptin, visfatin, apelin, resistin and adiponectin with clear cell renal cell carcinoma. Oncol Letters. 2017;13:463–8.
25. Choi SH, Chun SY, Kim TH, Kwon TG. Identifying the emerging role of adipokine as a diagnostic and prognostic biomarker of renal cell carcinoma. Urologic Oncology: Seminars and Original Investigations; 2016: Elsevier, 2016. p. 259. e15–. e19.
26. Shackelford RE, Abdulsattar J, Wei EX, Cotelingam J, Coppola D, Herrera GA. Increased nicotinamide phosphoribosyltransferase and cystathionine-β-synthase in renal oncocytomas, renal urothelial carcinoma, and renal clear cell carcinoma. Anticancer Research. 2017;37:3423–7.
27. Wei G, Sun H, Dong K, Hu L, Wang Q, Zhuang Q, et al. The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy. Cell Metabolism. 2021; 33:2021–39.e8.
28. Lee YC, Yang YH, Su JH, Chang HL, Hou MF, Yuan SSF. High visfatin expression in breast cancer tissue is associated with poor survival. Cancer Epidemiology, Biomarkers & Prevention. 2011; 20:1892–901.
29. Lv X, Zhang L, Zhu Y, Said HM, Shi J, Xu G. Regulative effect of Nampt on tumor progression and cell viability in human colorectal cancer. Journal of Cancer. 2015;6:849.
30. Neubauer K, Bednarz Misa I, Diakowska D, Kapturkiewicz B, Gamian A, Krzystek-Korpacka M. Nampt/PBEF/Visfatin upregulation in colorectal tumors, mirrored in normal tissue and whole blood of colorectal cancer patients, is associated with metastasis, hypoxia, IL1β, and anemia. BioMed Research International. 2015;2015:523930.
31. Grigoraș A, Amalinei C. The role of perirenal adipose tissue in carcinogenesis—From molecular mechanism to therapeutic perspectives. Cancers (Basel). 2025 Mar;23:17.
32. Hammoud SH, AlZaim I, Al-Dhaheri Y, Eid AH, El-Yazbi AF. Perirenal adipose tissue inflammation: Novel insights linking metabolic dysfunction to renal diseases. Frontiers in Endocrinology (Lausanne). 2021;12:707126.
33. Thiel DD, Davidiuk AJ, Meschia C, Serie D, Custer K, Petrou SP, et al. Mayo adhesive probability score is associated with localized renal cell carcinoma progression-free survival. Urology. 2016;89:54–62.
34. Ning K, Li Z, Liu H, Tian X, Wang J, Wu Y, et al. Perirenal fat thickness significantly associated with prognosis of metastatic renal cell cancer patients receiving anti-VEGF therapy. Nutrients. 2022;14:3388.
35. Maurits JSF, Sedelaar JPM, Aben KKH, Kiemeney LALM, Vrieling A. Association of visceral and subcutaneous adiposity with tumor stage and Fuhrman grade in renal cell carcinoma. Scientific Reports 2022 2022/10/06;12:16718.
36. Kaneko G, Miyajima A, Yuge K, Yazawa S, Mizuno R, Kikuchi E, et al. Visceral obesity is associated with better recurrence-free survival after curative surgery for Japanese patients with localized clear cell renal cell carcinoma. Japanese Journal of Clinical Oncology. 2014; 45:210–6.
37. Hasmann M, Schemainda I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Research. 2003;63:7436–42.
38. Naing A, Leong S, Pishvaian MJ, Razak ARA, Mahipal A, Berlin J, et al. A first in human phase 1 study of KPT-9274, a first in class dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies or NHL. Annals of Oncology. 2017;28:v125.
39. Holen K, Saltz LB, Hollywood E, Burk K, Hanauske AR. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Investigational New Drugs. 2008;26:45–51.
40. Kashiwagi E. Perirenal fat in disease progression: From inflammatory mediator to therapeutic target. International Journal of Urology2025; Epub ahead of print.
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Sep 26, 2025
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Visfatin Promotes Renal Cell Carcinoma Progression: Evidence from Clinical Samples and Cell Line Models. (2025). Journal of Kidney Cancer, 12(3), 58-65. https://doi.org/10.15586/jkcvhl.v12i3.427
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Kidney Cancer: Original Articles
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How to Cite
Visfatin Promotes Renal Cell Carcinoma Progression: Evidence from Clinical Samples and Cell Line Models. (2025). Journal of Kidney Cancer, 12(3), 58-65. https://doi.org/10.15586/jkcvhl.v12i3.427