Oncotarget

Research Papers:

The pVHL172 isoform is not a tumor suppressor and up-regulates a subset of pro-tumorigenic genes including TGFB1 and MMP13

Pauline Hascoet, Franck Chesnel, Florence Jouan, Cathy Le Goff, Anne Couturier, Eric Darrigrand, Fabrice Mahé, Nathalie Rioux-Leclercq, Xavier Le Goff and Yannick Arlot-Bonnemains _

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Oncotarget. 2017; 8:75989-76002. https://doi.org/10.18632/oncotarget.18376

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Abstract

Pauline Hascoet1, Franck Chesnel1, Florence Jouan1,**, Cathy Le Goff1, Anne Couturier1, Eric Darrigrand2, Fabrice Mahe2, Nathalie Rioux-Leclercq3, Xavier Le Goff1,* and Yannick Arlot-Bonnemains1,*

1CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Rennes, France

2IRMAR, Université Rennes 1, Rennes, France

3CHU Rennes, Service d’Anatomo-Pathologie, Rennes, France

*Co-last authors

**Present address: INSERM U1242 –Université Rennes 1-Centre E Marquis Rennes, France

Correspondence to:

Yannick Arlot-Bonnemains, email: [email protected]

Xavier Le Goff, email: [email protected]

Keywords: von Hippel Lindau, tumor suppressor, human kidney cells, TGF-β signaling, metalloprotease

Received: February 14, 2017     Accepted: April 26, 2017     Published: June 06, 2017

ABSTRACT

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 (pVHL213, pVHL160 and pVHL172). 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 pVHL172 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 pVHL213 and pVHL160 isoforms, but no function was assigned to pVHL172. Here we show that pVHL172 stable expression in renal cancer cells does not regulate the level of HIF, exacerbates tumorigenicity when 786-O-pVHL172 cells were xenografted in mice. The pVHL172-induced tumors developed a sarcomatoid phenotype. Moreover, pVHL172 expression was shown to up regulate a subset of pro-tumorigenic genes including TGFB1, MMP1 and MMP13. In summary we identified that pVHL172 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 pVHL213.


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