Hypoxia Inducible Factor (HIF) regulates key processes within the cell and its dysregulation is involved in the development of renal cell carcinoma (RCC), including those associated with VHL, HLRCC, TSC and also BHD syndrome. HIF is a potential therapeutic target for RCC and examples of HIF inhibitors have been described in this previous blog. Despite this, the regulation of HIF and its involvement in tumourigenesis remains poorly understood.
A recent paper by Schietke et al. (2012) has investigated the expression of HIF subunits within the human kidney and the contribution each subunit makes towards tumourigenesis. HIF is a heterodimeric transcription factor composed of a HIF-β subunit bound to either a HIF-1α subunit or a HIF-2α subunit. Both α subunits are regulated by VHL but they control transcription of different genes, and have distinct expression patterns in rat kidneys (Rosenberger et al., 2002). Previously, the HIF-2α subunit, rather than HIF-1α, has been described as the driving force for tumourigenesis (Raval et al., 2005).
Schietke et al. used immunohistochemistry to show that the expression pattern of the HIF-1α and HIF-2α protein in human kidneys matched that seen in the rat kidney. Under hypoxic conditions, HIF-1α was expressed exclusively in tubular epithelial cells, whereas HIF-2α was expressed in interstitial cells and glomeruli. HIF-2α was never seen in the tubular cells. See this page for images describing the location of different cell types within the kidney.
The authors then knocked out VHL in mouse tubular cells and repeated the expression profiling. The HIF-1α expression pattern did not change, but surprisingly, HIF-2α was now strongly expressed in the tubular cells, suggesting VHL specifically represses HIF-2α in this region. A mouse model with HIF-2α overexpressed in renal tubular cells was used to study the effect of this expression. These mice had impaired renal function, fibrosis and cysts in the kidney, however RCC did not develop. The authors suggest that HIF-2α overexpression may be an important early step in tumourigenesis but it is not sufficient to induce RCC.
The levels and activity of HIF-2α have been investigated in BHD syndrome by Preston et al. (2011). Here, the authors found no change in the protein level of HIF-2α after FLCN inactivation, but saw an increase in its activity. Perhaps this increase in activity mimics the increased expression seen in VHL-deficient kidneys, both leading to renal dysfunction. Despite this, Adams et al. (2011) and Ooi et al. (2011) recently identified a HIF-independent mechanism of cyst development in HLRCC (described here). It is clear that more research is required to fully understand the role of HIF in RCC, including that associated with BHD syndrome.
- Schietke RE, Hackenbeck T, Tran M, Günther R, Klanke B, Warnecke CL, Knaup KX, Shukla D, Rosenberger C, Koesters R, Bachmann S, Betz P, Schley G, Schödel J, Willam C, Winkler T, Amann K, Eckardt KU, Maxwell P, & Wiesener MS (2012). Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts. PloS one, 7 (1) PMID: 22299048
- Rosenberger C, Mandriota S, Jürgensen JS, Wiesener MS, Hörstrup JH, Frei U, Ratcliffe PJ, Maxwell PH, Bachmann S, & Eckardt KU (2002). Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. Journal of the American Society of Nephrology : JASN, 13 (7), 1721-32 PMID: 12089367
- Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, & Pollard PJ (2011). Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer cell, 20 (4), 524-37 PMID: 22014577
- Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BW, Tan MH, Zhang Z, Yang XJ, Zhou M, Gardie B, Molinié V, Richard S, Tan PH, Teh BT, & Furge KA (2011). An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer cell, 20 (4), 511-23 PMID: 22014576
- Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, & Tee AR (2011). Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene, 30 (10), 1159-73 PMID: 21057536
- Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, Pugh CW, Maxwell PH, Harris AL, & Ratcliffe PJ (2005). Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Molecular and cellular biology, 25 (13), 5675-86 PMID: 15964822