| dc.description.abstract | Clear-cell renal cell carcinoma (ccRCC) constitutes 60% renal malignancy and up to 70%
of ccRCC cases result from loss function of the von Hippel-Lindau (VHL) tumor suppressor
gene. Loss-of-function of VHL gene causes accumulation of hypoxia inducible factor 1 alpha
(HIF1-α) transcription factor, then HIF1-α can activate hypoxia-responsive genes such as
vascular endothelial growth factor (VEGF) gene that promotes angiogenesis. HIF transcription
factor also regulates other genes involved in metabolic adaption to the hypoxia condition
(Warburg effect). In previous research, we have found that the differentially expressed genes in
Vhlh (mouse allele of the VHL gene) conditional knockout kidney were mostly involved in cell
proliferation, cell differentiation, immune response, and cell metabolism. In addition, we also
linked the inflammatory response with ER-stress induced by VHL inactivation. However, gene
expression patterns specific to renal tubular epithelial cells are still unclear. We are also
interesting in whether deterioration of ER-stress can be induced by the activity of a calcium
channel genes ITPR2, the amplification of which has been shown to correlate with the risk of
developing ccRCC. Therefore, in this research, we used the primary renal proximal tubular
epithelial cells as a model and analyzed the differential transcriptome by RNA sequencing, and
analyzed genomic mutation by DNA sequencing. We found that some upregulated genes such
as Cxcl12, Vegfa, Tgfa, Cldn8, Cldn9 and Vasp may promote cancer formation, but some genes
such as Egln3, Peg3os, Cd82, Scnn1b, and Sulf1 may inhibit tumorigenesis. The downregulated
genes may promote cancer formation such as Adam9, lead to aberrant metabolism such as Cbs
and Kcnma1, or inhibit cell growth such as Sptan1. The global gene expression profile of Vhlh
loss-of-function kidney tubule cells provided us with information about the transformation that
promote cancer formation. In addition, we found the proportion of VHL dysfunction in ccRCC
patients in Taiwan was consistent with prevalence in the world. And, we also found that single
nucleotide polymorphism for ITPR2 may enhance ER-stress response induced by VHL
dysfunction. This provided us with more information to link ITPR2 and ccRCC formation | en_US |