Role of HIF in clear cell renal carcinoma

Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)

There are three HIFa family members called HIF1a, HIF2a, and HIF3a. Deregulation of HIFa, in particular HIF2a, appears to be a driving force in pVHL-defective kidney cancer. For example, the risk of renal carcinoma linked to different VHL mutations correlates with the degree to which those mutations deregulate HIF [55–57]. VHL-/renal carcinoma cells frequently silence the expression of FBP1, which is an other endogenous inhibitor of HIF activity [58].

pVHL-defective clear cell renal carcinomas overproduce HIF2a but, in some cases, fail to produce HIF1a [28, 42, 59, 60]. Production of a nonhydroxylatable version of HIF2a, but not HIF1a, can override the tumor suppressor activity of pVHL in preclinical models [61, 62]. Similarly, exogenous overexpression of HIF2a, but not HIF1a, promotes tumor formation by VHL-/renal cancer cells [63, 64]. Moreover, downregulation of HIF2a, but not HIF1a, is sufficient to suppress tumor formation by pVHL-defective clear cell renal carcinomas [65, 66]. The appearance of HIF2a in premalignant renal lesions in patients with VHL disease heralds malignant transformation [67, 68], and a human single nucleotide polymorphism (SNP) linked to HIF2a on chromosome 2p21 has been associated with the risk of developing clear cell renal carcinomas [69]. Finally, much of the pathology observed after VHL inactivation in genetically engineered mouse models can be linked to the inappropriate accumulation of HIF2a [68, 70–75]. It should be noted that VHL inactivation, but not bona fide hypoxia, is sufficient to induce HIF2a in mouse renal tubular epithelial cells and cause renal cyst formation [68, 72, 76]. Neither VHL inactivation nor increased HIF2a activity, however, is sufficient to cause clear cell renal carcinoma in genetically engineered mouse models [68, 72, 76, 77]. This presumably reflects the need for cooperating genetic events (see below) and perhaps species differences.

As noted above, some clear cell renal carcinoma cell lines and tumors produce low, or undetectable, amounts of HIF1a. Indeed, some VHL-/clear cell renal carcinoma lines harbor homozygous mutations of the HIF1a locus [60]. Reintroduction of wild-type HIF1a into such lines suppresses their proliferation in cell culture and in nude mice xenograft studies [60, 63, 64]. Conversely, downregulation of HIF1a in HIF1a-proficient VHL-/clear cell renal carcinoma lines enhances their proliferation in cell culture and in xenograft assays [59, 60]. Interestingly, HIF1a resides on chromosome 14q, which is frequently deleted in clear cell renal carcinomas (together with chromosome 3p loss and chromosome 5q amplification) [60]. Clear cell renal carcinomas with chromosome 14q deletions have gene expression signatures consistent with decreased HIF1a activity [60, 78]. In some VHL-/clear cell carcinomas that express both HIF1a and HIF2a, the ratio of HIF2a to HIF1a is enhanced by loss of specific microRNAs miR-30c-2-3p and miR-30A-3p that normally serve to repress HIF2a [79]. Finally, loss-of-function intragenic HIF1a mutations have occasionally been identified in VHL-/clear cell renal carcinomas [60, 80–82]. Collectively, these findings suggest that HIF1a, in contrast to HIF2a, acts as a tumor suppressor in VHL-/clear cell renal carcinoma.

In apparent disagreement with this contention, expression of a stabilized version of HIF1a, but not a stabilized version of HIF2a, in the proximal renal tubular epithelial cells of mice caused renal cell dysplasia, including evidence of increased proliferation, increased DNA damage, and clear cell histological changes [83, 84]. Similarly, ablation of VHL in primarily mouse collecting ducts caused hyperplastic changes that could be reversed by simultaneous inactivation of HIF1a [85]. Finally, it has also been shown that silencing HIF1a inhibits, rather than augments, tumor growth by human VHL+/+ renal carcinoma growth [86].

There are a number of caveats to these studies, however. For example, the cell of origin for VHL-/clear cell renal carcinoma is still debated but likely involves a distal tubular epithelial cell that is permissive for HIF2a accumulation and the expression of specific HIF2a target genes (e.g. cyclin D1) following pVHL loss [67, 68, 87]. In this regard, forced expression of a stabilized version of HIF2a in the murine proximal renal tubule did not recapitulate the induction of HIF targets seen in VHL-/clear cell renal carcinoma [83], perhaps because the wrong cell type was targeted. The genetically engineered mouse studies might also be confounded by biological differences between mice and men, as has been observed with many other cancer genes. Finally, the apparent dependence of human VHL+/+ renal carcinomas on HIF1a for tumor growth does not preclude a tumor suppressor role for HIF1a in VHL-/renal carcinomas, especially bearing in mind potential differences in cell of origin and cooperating genetic events.

There are a number of quantitative and qualitative differences between HIF1a and HIF2a that could account for their seemingly antagonistic effects in VHL-/clear cell renal carcinoma. These differences likely reflect the fact that some HIF target genes are preferentially activated by specific HIFa family members as well as by the existence of non-canonical HIF functions that are unique to specific HIFa proteins. HIF2a cooperates with c-Myc to promote the proliferation of VHL-/clear cell renal carcinoma cells, while HIF1a is capable of inhibiting c-Myc [88–91]. Both HIF1a and HIF2a can induce REDD1 and thereby suppress the activity of the TORC1 complex, which contains mTOR, and Cap-dependent translation [92–95]. HIF2a, however, and not HIF1a, can also stimulate translation. HIF2a transcriptionally induces the amino acid transporter SLC7A5 and thereby increases intracellular amino acid availability, which activates TORC1 [96]. In addition, HIF2a forms a complex with RBM4 and eIF4E that promotes Capdependent translation in cells with depressed TORC1 activity [97]. HIF1a and HIF2a also appear to differentially regulate p53 and the DNA damage response [59, 63, 98, 99].

pVHL has a number of other functions that, although incompletely understood biochemically, appear to be a least partly HIF-independent. These include a role in the maintenance of a specialized structure called the primary cilium on the cell surface that serves as a mechanosensor [76, 100–103], possibly by virtue of pVHL’s role in stabilization of microtubules [104–106]. Interestingly, a number of diseases characterized by visceral cyst formation, including VHL disease, are caused by mutations that disrupt the primary cilium [107, 108]. pVHL also suppresses autophagy via both HIF-independent and HIFdependent pathways, perhaps contributing to the increased autophagy seen in clear cell renal carcinomas [109, 110]. In addition, pVHL plays roles in extracellular matrix formation by fibronectin [111–114], epithelial-epithelial contacts [115, 116], NFkB signaling [117–120], control of atypical PKC activity [121–125], Rpb1 expression and activity [126–128], receptor internalization [129–131], and mRNA turnover [20, 26, 132–135]. It is possible that these other functions also contribute to tumor suppression by pVHL.

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