Nuclear expression of hypoxia-inducible factor-1alpha in clear cell renal cell carcinoma is involved in tumor progression.
OBJECTIVE
The most frequent genomic abnormality in clear cell renal cell carcinoma (cc-RCC) is inactivation of Von Hippel-Lindau gene (VHL). pVHL19 is a ligase promoting proteosomal degradation of hypoxia-inducible factor-1alpha (HIF-1alpha); pVHL30 is associated with microtubules. VHL exert its oncogenetic action both directly and through HIF-1alpha activation. TNM classification is unable to define a correct prognostic evaluation of intracapsular cc-RCC. The nucleo-cytoplasmic trafficking in VHL/HIF-1alpha pathway could be relevant in understanding the molecular pathogenesis of renal carcinogenesis. This study analyzes VHL/HIF-1alpha proteins in a large series of intracapsular cc-RCCs, correlating their expression and cellular localization with prognosis.


METHODS
Two anti-pVHL (clones Ig32 and Ig33) and 1 anti-HIF-1alpha were used on tissue microarrays from 136 intracapsular cc-RCCs (mean follow-up: 74 mo). Clone 32 recognizes both pVHLs, whereas clone 33 only pVHL30. Results were matched with clinicopathologic variables and tumor-specific survival (TSS).


RESULTS
A strong cytoplasmic positivity was found for all antibodies in the largest part of cases, associated to a strong nuclear localization in the case of HIF-1alpha. All pVHL-negative cases were associated with high HIF-1alpha expression. pVHL negativity and HIF-1alpha nuclear positivity significantly correlated with shorter TSS. In multivariate analysis both pVHL negativity and HIF-1alpha nuclear expression were independent predictors of TSS.


CONCLUSIONS
The localization of the proteins well matches with their role and with the supposed tumor molecular pathways. The correlation with prognosis of VHL/HIF-1alpha alterations confirms the relevance of their molecular pathway and of the cellular trafficking of their products in the pathogenesis of renal cancer.
Department of Oncology, Division of Surgical, Molecular and Ultrastructural Pathology, University of Pisa and University Hospital of Pisa, Pisa, Italy. cldicri@tin.it
Claudio
C
Di Cristofano
Andrea
A
Minervini
Michele
M
Menicagli
Giuseppe
G
Salinitri
Gloria
G
Bertacca
Gerasimos
G
Pefanis
Lorenzo
L
Masieri
Francesca
F
Lessi
Paola
P
Collecchi
Riccardo
R
Minervini
Marco
M
Carini
Generoso
G
Bevilacqua
Andrea
A
Cavazzana
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality; D008875:Middle Aged; D011379:Prognosis; D021381:Protein Transport; D015996:Survival Rate; D046888:Tissue Array Analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D044767:Ubiquitin-Protein Ligases