Expression of HIF-α and their association with clinicopathological parameters in clinical renal cell carcinoma
Keywords:
renal cell carcinoma, ccRCC, non-ccRCC, HIF-1α, HIF-2α, HIF-3α, prognosis, tumor stage
Abstract
Objectives: This study aimed to assess the cellular localization and expression levels of hypoxia-inducible factor (HIF) -α proteins (specifically HIF-1α, HIF-2α, and HIF-3α) that play a role in the hypoxia pathway and to determine their correlation with clinicopathological parameters and patient survival in renal cell carcinoma (RCC).
Materials and methods: Tissue microarray (TMA) with cores from 150 clear cell RCCs and 31 non-ccRCC samples. HIF-1α, HIF-2α, and HIF-3α antibodies were used for immunohistochemistry (IHC) of TMA to evaluate the cellular localization and expression levels of HIF-α proteins, specifically in relation to the hypoxia pathway.
Results: The expression levels of the HIF-α proteins were higher in the nucleus than in the cytoplasm. Furthermore, the nuclear expression levels of all HIF-α proteins were significantly higher in clear cell RCC (ccRCC) than in non-ccRCC. Cytoplasmic HIF-3α expression was also higher in ccRCC than in non-ccRCC, whereas cytoplasmic HIF-1α and HIF-2α expression levels were similar between the different RCC types. In ccRCC, nuclear HIF-1α expression levels correlated with both nuclear HIF-2α and HIF-3α levels, whereas cytoplasmic HIF-3α expression levels were associated with HIF-1α only.
In non-ccRCC, there was a positive correlation observed between nuclear HIF-1α and HIF-3α expression, but no correlation was found with HIF-2α. In patients with ccRCC, the nuclear expressions of HIF-1α and HIF-3α was significantly associated with cancer-specific survival (CSS) in univariate analysis. This association was no longer evident in multivariate analysis. Notably, there was no correlation observed between nuclear HIF-2α expression and CSS in these patients. In contrast, cytoplasmic expression levels showed no association with CSS.
Conclusion: The expression levels of the three primary HIF-α proteins were found to be higher in the nucleus than in the cytoplasm. Furthermore, the results indicated that HIF-3α and HIF-1α expression levels were significant univariate factors associated with CSS in patients with clear cell RCC. These results highlight the critical role that HIF-3α and HIF-1α play in the hypoxia pathway.
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References
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37. Sandlund J, Ljungberg B, Wikstrom P, Grankvist K, Lindh G, Rasmuson T. Hypoxia-inducible factor-2alpha mRNA expression in human renal cell carcinoma. Acta Oncol. 2009;48:909–14. doi: 10.1080/02841860902824891
38. Moreno Roig E, Yaromina A, Houben R, Groot AJ, Dubois L, Vooijs M. Prognostic role of hypoxia-inducible factor-2alpha tumor cell expression in cancer patients: a meta-analysis. Front Oncol. 2018;8:224. doi: 10.3389/fonc.2018.00224
39. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 1996;56:4625–29.
40. Leek RD, Talks KL, Pezzella F, Turley H, Campo L, Brown NS, et al. Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer. Cancer Res. 2002;62:1326–9.
41. Tolonen JP, Heikkila M, Malinen M, Lee HM, Palvimo JJ, Wei GH, et al. A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin. Cell Mol Life Sci. 2020;77:3627–642. doi: 10.1007/s00018-019-03387-9
42. Zhang P, Bai Y, Lu L, Li Y, Duan C. An oxygen-insensitive Hif-3alpha isoform inhibits Wnt signaling by destabilizing the nuclear beta-catenin complex. Elife. 2016;5:e08996. doi: 10.7554/eLife.08996
2. Ljungberg B, Albiges L, Abu-Ghanem Y, Bedke J, Capitanio U, Dabestani S, et al. European Association of Urology guidelines on renal cell carcinoma: The 2022 update. Eur Urol. 2022;82(4):389–410. https://doi.org/10.1016/j.eururo.2022.03.006
3. Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik E, et al. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 2018;23:313–26 e315. doi: 10.1016/j.celrep.2018.03.075
4. Kovacs G. Molecular genetics of human renal cell tumours. Nephrol Dial Transplant. 1996;11(Suppl 6):62–5. https://doi.org/10.1093/ndt/11.supp6.62
5. Batavia AA, Schraml P, Moch H. Clear cell renal cell carcinoma with wild-type von Hippel-Lindau gene: a non-existent or new tumour entity? Histopathology. 2019;74:60–7. doi: 10.1111/his.13749
6. Sanjmyatav J, Hauke S, Gajda M, Hartmann A, Moch H, Meyer B, et al. Establishment of a multicolour fluorescence in situ hybridisation-based assay for subtyping of renal cell tumours. Eur Urol. 2013;64:689–91. https://doi.org/10.1016/j.eururo.2013.06.007
7. Yap NY, Rajandram R, Ng KL, Pailoor J, Fadzli A, Gobe GC. Genetic and chromosomal aberrations and their clinical significance in renal neoplasms. Biomed Res Int. 2015;2015:476508. doi: 10.1155/2015/476508
8. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol. 2003;27:612–24. https://doi.org/10.1097/00000478-200305000-00005
9. Frew IJ, Krek W. pVHL: a multipurpose adaptor protein. Sci Signal. 2008;1:e30. doi: 10.1126/scisignal.124pe30
10. Rankin EB, Giaccia AJ, Schipani E. A central role for hypoxic signaling in cartilage, bone, and hematopoiesis. Curr Osteoporos Rep. 2011;9:46–52. doi: 10.1007/s11914-011-0047-2
11. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23:9361–74. doi: 10.1128/mcb.23.24.9361-9374.2003
12. Klatte T, Seligson DB, Riggs SB, Leppert JT, Berkman MK, Kleid MD, et al. Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma. Clin Cancer Res. 2007;13:7388–93. doi: 10.1158/1078-0432.CCR-07-0411
13. Biswas S, Charlesworth PJ, Turner GD, Leek R, Thamboo PT, Campo L, et al. CD31 angiogenesis and combined expression of HIF-1alpha and HIF-2alpha are prognostic in primary clear-cell renal cell carcinoma (CC-RCC), but HIFalpha transcriptional products are not: implications for antiangiogenic trials and HIFalpha biomarker studies in primary CC-RCC. Carcinogenesis. 2012;33:1717–25. doi: 10.1093/carcin/bgs222
14. Gordan JD, Simon MC. Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev. 2007;17:71–7. doi: 10.1016/j.gde.2006.12.006
15. Minardi D, Lucarini G, Santoni M, Mazzucchelli R, Burattini L, Conti A, et al. Survival in patients with clear cell renal cell carcinoma is predicted by HIF-1alpha expression. Anticancer Res. 2015;35:433–8.
16. Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA. Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Exp. 1998;7:205–13.
17. Pasanen A, Heikkila M, Rautavuoma K, Hirsila M, Kivirikko KI, Myllyharju J. Hypoxia-inducible factor (HIF)-3alpha is subject to extensive alternative splicing in human tissues and cancer cells and is regulated by HIF-1 but not HIF-2. Int J Biochem Cell Biol. 2010;42:1189–200. doi: 10.1016/j.biocel.2010.04.008
18. Prabhakar NR, Semenza GL. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev. 2012;92:967–1003. doi: 10.1152/physrev.00030.2011
19. Heikkila M, Pasanen A, Kivirikko KI, Myllyharju J. Roles of the human hypoxia-inducible factor (HIF)-3alpha variants in the hypoxia response. Cell Mol Life Sci. 2011;68:3885–901. doi: 10.1007/s00018-011-0679-5
20. Li QF, Wang XR, Yang YW, Lin H. Hypoxia upregulates hypoxia inducible factor (HIF)-3alpha expression in lung epithelial cells: characterization and comparison with HIF-1alpha. Cell Res. 2006;16:548–58. doi: 10.1038/sj.cr.7310072
21. Svenson U, Ljungberg B, Roos G. Telomere length in peripheral blood predicts survival in clear cell renal cell carcinoma. Cancer Res. 2009;69:2896–901. doi: 10.1158/0008-5472.CAN-08-3513
22. Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, et al. The Heidelberg classification of renal cell tumours. J Pathol. 1997;183:131–3. doi: 10.1002/(SICI)1096-9896(199710)183:2<131::AID-PATH931>3.0.CO;2-G
23. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982;6:655–63. doi: 10.1097/00000478-198210000-00007
24. Haase VH. Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol. 2006;291:F271–81. doi: 10.1152/ajprenal.00071.2006
25. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32. doi: 10.1038/nrc1187
26. Kroeze SG, Vermaat JS, Van Brussel A, Van Melick HH, Voest EE, Jonges TG, et al. Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients. Eur J Cancer. 2010;46:3375–82. doi: 10.1016/j.ejca.2010.07.018
27. Schodel J, Grampp S, Maher ER, Moch H, Ratcliffe PJ, Russo P, et al. Hypoxia, hypoxia-inducible transcription factors, and renal cancer. Eur Urol. 2016;69:646–57. doi: 10.1016/j.eururo.2015.08.007
28. Toth K, Chintala S, Rustum YM. Constitutive expression of HIF-alpha plays a major role in generation of clear-cell phenotype in human primary and metastatic renal carcinoma. Appl Immunohistochem Mol Morphol. 2014;22:642–7. doi: 10.1097/PAI.0000000000000012
29. Gimm T, Wiese M, Teschemacher B, Deggerich A, Schodel J, Knaup KX, et al. Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J. 2010;24:4443–58. doi: 10.1096/fj.10-159806
30. Sundelin JP, Stahlman M, Lundqvist A, Levin M, Parini P, Johansson ME, et al. Increased expression of the very low-density lipoprotein receptor mediates lipid accumulation in clear-cell renal cell carcinoma. PLoS One. 2012;7:e48694. doi: 10.1371/journal.pone.0048694
31. Dengler VL, Galbraith M, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol Biol. 2014;49:1–15. doi: 10.3109/10409238.2013.838205
32. Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol. 2005;25:5675–86. doi: 10.1128/MCB.25.13.5675-5686.2005
33. Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell. 2002;1:459–68. doi: 10.1016/s1535-6108(02)00071-5
34. Fan Y, Li H, Ma X, Gao Y, Chen L, Li X, et al. Prognostic significance of hypoxia-inducible factor expression in renal cell carcinoma: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2015;94:e1646. doi: 10.1097/MD.0000000000001646
35. Tumkur Sitaram R, Landstrom M, Roos G, Ljungberg B. Significance of PI3K signalling pathway in clear cell renal cell carcinoma in relation to VHL and HIF status. J Clin Pathol. 2020;74(4):216–22. doi: 10.1136/jclinpath-2020-206693
36. Tumkur Sitaram R, Landström, M., Roos, G., Ljungberg, B. Role of Wnt signaling pathways in clear cell renal cell carcinoma pathogenesis in relation to VHL and HIF status. Clin Oncol Res. 2020;3. doi: 10.31487/j.COR.2020.03.09
37. Sandlund J, Ljungberg B, Wikstrom P, Grankvist K, Lindh G, Rasmuson T. Hypoxia-inducible factor-2alpha mRNA expression in human renal cell carcinoma. Acta Oncol. 2009;48:909–14. doi: 10.1080/02841860902824891
38. Moreno Roig E, Yaromina A, Houben R, Groot AJ, Dubois L, Vooijs M. Prognostic role of hypoxia-inducible factor-2alpha tumor cell expression in cancer patients: a meta-analysis. Front Oncol. 2018;8:224. doi: 10.3389/fonc.2018.00224
39. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 1996;56:4625–29.
40. Leek RD, Talks KL, Pezzella F, Turley H, Campo L, Brown NS, et al. Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer. Cancer Res. 2002;62:1326–9.
41. Tolonen JP, Heikkila M, Malinen M, Lee HM, Palvimo JJ, Wei GH, et al. A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin. Cell Mol Life Sci. 2020;77:3627–642. doi: 10.1007/s00018-019-03387-9
42. Zhang P, Bai Y, Lu L, Li Y, Duan C. An oxygen-insensitive Hif-3alpha isoform inhibits Wnt signaling by destabilizing the nuclear beta-catenin complex. Elife. 2016;5:e08996. doi: 10.7554/eLife.08996
Published
2024-03-21
How to Cite
T. Sitaram R., & Ljungberg B. (2024). Expression of HIF-α and their association with clinicopathological parameters in clinical renal cell carcinoma. Upsala Journal of Medical Sciences, 129, e9407. https://doi.org/10.48101/ujms.v129.9407
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