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2017 ; 8
(44
): 75989-76002
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English Wikipedia
The pVHL(172) isoform is not a tumor suppressor and up-regulates a subset of
pro-tumorigenic genes including TGFB1 and MMP13
#MMPMID29100286
Hascoet P
; Chesnel F
; Jouan F
; Le Goff C
; Couturier A
; Darrigrand E
; Mahe F
; Rioux-Leclercq N
; Le Goff X
; Arlot-Bonnemains Y
Oncotarget
2017[Sep]; 8
(44
): 75989-76002
PMID29100286
show ga
The von Hippel-Lindau (VHL) tumor suppressor gene is often deleted or mutated in
ccRCC (clear cell renal cell carcinoma) producing a non-functional protein. The
gene encodes two mRNA, and three protein isoforms (pVHL(213), pVHL(160) and
pVHL(172)). The pVHL protein is part of an E3 ligase complex involved in the
ubiquitination and proteasomal degradation of different proteins, particularly
hypoxia inducible factors (HIF) that drive the transcription of genes involved in
the regulation of cell proliferation, angiogenesis or extracellular matrix
remodelling. Other non-canonical (HIF-independent) pVHL functions have been
described. A recent work reported the expression of the uncharacterized protein
isoform pVHL(172) which is translated from the variant 2 by alternative splicing
of the exon 2. This splice variant is sometimes enriched in the ccRCCs and the
protein has been identified in the respective samples of ccRCCs and different
renal cell lines. Functional studies on pVHL have only concerned the pVHL(213)
and pVHL(160) isoforms, but no function was assigned to pVHL(172). Here we show
that pVHL(172) stable expression in renal cancer cells does not regulate the
level of HIF, exacerbates tumorigenicity when 786-O-pVHL(172) cells were
xenografted in mice. The pVHL(172)-induced tumors developed a sarcomatoid
phenotype. Moreover, pVHL(172) expression was shown to up regulate a subset of
pro-tumorigenic genes including TGFB1, MMP1 and MMP13. In summary we identified
that pVHL(172) is not a tumor suppressor. Furthermore our findings suggest an
antagonistic function of this pVHL isoform in the HIF-independent aggressiveness
of renal tumors compared to pVHL(213).
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