pVHL status in clear cell renal cell carcinoma regulates HIF-α and E-cadherin expression levels and their implications for tumor progression
Keywords:
Renal cell carcinoma, ccRCC, E-cadherin, HIF-1α, HIF-2α, HIF-3α, EMT, tumor progression
Abstract
Objectives: This study aimed to determine the effects of von Hippel–Lindau protein (VHL) expression on hypoxia-inducible factor (HIF) and E-cadherin proteins. Furthermore, to evaluate the influence of the VHL–HIF–E-cadherin pathway in clear cell renal cell carcinoma (ccRCC).
Materials and Methods: This study used tissue samples collected from 150 patients with ccRCC and 24 adjacent kidney cortex samples. Immunoblotting was performed to measure the expression levels of VHL and E-cadherin. Additionally, nuclear expression of HIF-α was evaluated by immunohistochemistry (IHC) using a tissue microarray (TMA).
Results: pVHL levels were lower in ccRCC than in the adjacent kidney cortex; however, pVHL levels showed no correlation with clinicopathological parameters. Nuclear HIF-1α levels were higher in stage IV tumors, whereas HIF-2α levels increased with tumor size. No correlation was observed between HIF-3α levels and clinicopathological parameters. E-cadherin protein expression was reduced in ccRCC tissues and in higher-stage and larger tumors. In pVHL-high ccRCC, E-cadherin levels were lower in advanced-stage and larger tumors. Higher levels of HIF-1α and HIF-3α were observed in pVHL-low tumors. E-cadherin expression negatively correlated with nuclear HIF-1α expression. In pVHL-high ccRCCs, E-cadherin was negatively correlated with HIF-1α, while in pVHL-low ccRCCs, E-cadherin was negatively correlated with HIF-2α. E-cadherin was not associated with cancer-specific survival in patients with pVHL-low tumors, whereas E-cadherin expression was linked to improved survival in patients with pVHL-high tumors.
Conclusion: VHL inactivation causes HIF-α activation and suppresses E-cadherin expression, thereby promoting ccRCC progression. This study provides insights into the potential biomarkers and therapeutic targets for ccRCC treatment.
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References
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31. 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;74:216–22. doi: 10.1136/jclinpath-2020-206693
32. 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
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34. Yao Q, Zhang P, Lu L, Liu Y, Li Y, Duan C. Nuclear localization of Hif-3alpha requires two redundant NLS motifs in its unique C-terminal region. FEBS Lett. 2018;592:2769–75. doi: 10.1002/1873-3468.13202
35. Albadari N, Deng S, Li W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin Drug Discov. 2019;14:667–82. doi: 10.1080/17460441.2019.1613370
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37. Chachami G, Paraskeva E, Mingot JM, Braliou GG, Gorlich D, Simos G. Transport of hypoxia-inducible factor HIF-1alpha into the nucleus involves importins 4 and 7. Biochem Biophys Res Commun. 2009;390:235–40. doi: 10.1016/j.bbrc.2009.09.093
38. Wang Y, Zhong S, Schofield CJ, Ratcliffe PJ, Lu X. Nuclear entry and export of FIH are mediated by HIF1alpha and exportin1, respectively. J Cell Sci. 2018;131:cs219782. doi: 10.1242/jcs.219782
39. Andreiana BC, Stepan AE, Margaritescu C, Taisescu O, Osman A, Simionescu C. Snail and E-cadherin immunoexpression in clear cell renal cell carcinoma. Curr Health Sci J. 2019;45:185–9. doi: 10.12865/CHSJ.45.02.09
40. Zhang X, Yang M, Shi H, Hu J, Wang Y, Sun Z, et al. Reduced E-cadherin facilitates renal cell carcinoma progression by WNT/beta-catenin signaling activation. Oncotarget. 2017;8:19566–76. doi: 10.18632/oncotarget.15361
41. Jang NR, Choi JH, Gu MJ. Aberrant expression of E-cadherin, N-cadherin, and P-cadherin in clear cell renal cell carcinoma: association with adverse clinicopathologic factors and poor prognosis. Appl Immunohistochem Mol Morphol. 2021;29:22330. doi: 10.1097/PAI.0000000000000861
42. Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, et al. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 2006;66:2725–31. doi: 10.1158/0008-5472.CAN-05-3719
43. Gao Q, Ren Z, Jiao S, Guo J, Miao X, Wang J, et al. HIF-3alpha-induced miR-630 expression promotes cancer hallmarks in cervical cancer cells by forming a positive feedback loop. J Immunol Res. 2022;2022:5262963. doi: 10.1155/2022/5262963
2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49. doi: 10.3322/caac.21820
3. 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. doi: 10.1097/00000478-200305000-00005
4. Kaelin WG, Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002;2:673–82. doi: 10.1038/nrc885
5. Kovacs G. Molecular genetics of human renal cell tumours. Nephrol Dial Transplant. 1996;11 Suppl 6:62–5. doi: 10.1093/ndt/11.supp6.62
6. 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
7. Mallikarjuna P, Sitaram RT, Landstrom M, Ljungberg B. VHL status regulates transforming growth factor-beta signaling pathways in renal cell carcinoma. Oncotarget. 2018;9:16297–310. doi: 10.18632/oncotarget.24631
8. Shuin T, Kondo K, Torigoe S, Kishida T, Kubota Y, Hosaka M, et al. Frequent somatic mutations and loss of heterozygosity of the von hippel-lindau tumor-suppressor gene in primary human renal-cell carcinomas. Cancer Res. 1994;54:2852–5.
9. Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, et al. Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A. 1999;96:12436–41. doi: 10.1073/pnas.96.22.12436
10. Frew IJ, Krek W. pVHL: a multipurpose adaptor protein. Sci Signal. 2008;1:pe30. doi: 10.1126/scisignal.124pe30
11. Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature. 2001;414:550–4. doi: 10.1038/35107085
12. 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
13. 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
14. 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
15. 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 Expr. 1998;7:205–13.
16. 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
17. 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
18. Sitaram RT, Ljungberg B. Expression of HIF‑alpha and their association with clinicopathological parameters in clinical renal cell carcinoma. Ups J Med Sci. 2024;129:e9407. doi: 10.48101/ujms.v129.9407
19. 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
20. 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
21. Evans AJ, Russell RC, Roche O, Burry TN, Fish JE, Chow VW, et al. VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol. 2007;27:157–69. doi: 10.1128/MCB.00892-06
22. van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008;65:3756–88. doi: 10.1007/s00018-008-8281-1
23. Esteban MA, Tran MG, Harten SK, Hill P, Castellanos MC, Chandra A, et al. Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res. 2006;66:3567–75. doi: 10.1158/0008-5472.CAN-05-2670
24. Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015;67:913–24. doi: 10.1016/j.eururo.2015.01.005
25. 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)
26. Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80:1803–4. doi: 10.1002/(sici)1097-0142(19971101)80:9<1803::aid-cncr16>3.0.co;2-9
27. 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
28. Sitaram RT, Mallikarjuna P, Landstrom M, Ljungberg B. Transforming growth factor-beta promotes aggressiveness and invasion of clear cell renal cell carcinoma. Oncotarget. 2016;7:35917–31. doi: 10.18632/oncotarget.9177
29. Gu Y, Tang S, Wang Z, Cai L, Lian H, Shen Y, et al. A pan-cancer analysis of the prognostic and immunological role of beta-actin (ACTB) in human cancers. Bioengineered. 2021;12:6166–85. doi: 10.1080/21655979.2021.1973220
30. 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
31. 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;74:216–22. doi: 10.1136/jclinpath-2020-206693
32. 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
33. Depping R, Steinhoff A, Schindler SG, Friedrich B, Fagerlund R, Metzen E, et al. Nuclear translocation of hypoxia-inducible factors (HIFs): involvement of the classical importin alpha/beta pathway. Biochim Biophys Acta. 2008;1783:394–404. doi: 10.1016/j.bbamcr.2007.12.006
34. Yao Q, Zhang P, Lu L, Liu Y, Li Y, Duan C. Nuclear localization of Hif-3alpha requires two redundant NLS motifs in its unique C-terminal region. FEBS Lett. 2018;592:2769–75. doi: 10.1002/1873-3468.13202
35. Albadari N, Deng S, Li W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin Drug Discov. 2019;14:667–82. doi: 10.1080/17460441.2019.1613370
36. Berchner-Pfannschmidt U, Frede S, Wotzlaw C, Fandrey J. Imaging of the hypoxia-inducible factor pathway: insights into oxygen sensing. Eur Respir J. 2008;32:210–7. doi: 10.1183/09031936.00013408
37. Chachami G, Paraskeva E, Mingot JM, Braliou GG, Gorlich D, Simos G. Transport of hypoxia-inducible factor HIF-1alpha into the nucleus involves importins 4 and 7. Biochem Biophys Res Commun. 2009;390:235–40. doi: 10.1016/j.bbrc.2009.09.093
38. Wang Y, Zhong S, Schofield CJ, Ratcliffe PJ, Lu X. Nuclear entry and export of FIH are mediated by HIF1alpha and exportin1, respectively. J Cell Sci. 2018;131:cs219782. doi: 10.1242/jcs.219782
39. Andreiana BC, Stepan AE, Margaritescu C, Taisescu O, Osman A, Simionescu C. Snail and E-cadherin immunoexpression in clear cell renal cell carcinoma. Curr Health Sci J. 2019;45:185–9. doi: 10.12865/CHSJ.45.02.09
40. Zhang X, Yang M, Shi H, Hu J, Wang Y, Sun Z, et al. Reduced E-cadherin facilitates renal cell carcinoma progression by WNT/beta-catenin signaling activation. Oncotarget. 2017;8:19566–76. doi: 10.18632/oncotarget.15361
41. Jang NR, Choi JH, Gu MJ. Aberrant expression of E-cadherin, N-cadherin, and P-cadherin in clear cell renal cell carcinoma: association with adverse clinicopathologic factors and poor prognosis. Appl Immunohistochem Mol Morphol. 2021;29:22330. doi: 10.1097/PAI.0000000000000861
42. Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, et al. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 2006;66:2725–31. doi: 10.1158/0008-5472.CAN-05-3719
43. Gao Q, Ren Z, Jiao S, Guo J, Miao X, Wang J, et al. HIF-3alpha-induced miR-630 expression promotes cancer hallmarks in cervical cancer cells by forming a positive feedback loop. J Immunol Res. 2022;2022:5262963. doi: 10.1155/2022/5262963
Published
2025-12-22
How to Cite
Sitaram , R. T., & Ljungberg , B. (2025). pVHL status in clear cell renal cell carcinoma regulates HIF-α and E-cadherin expression levels and their implications for tumor progression. Upsala Journal of Medical Sciences, 130, e12982. https://doi.org/10.48101/ujms.v130.12982
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