OA Cancer

Critical review

Basic Cancer Biology

Prasad R, Gupta V, Kumar A. Advances on molecular basis of clear cell renal cell carcinoma. OA Cancer 2014 May 23;2(1):8.



Clear cell renal cell carcinoma (ccRCC) which is the major subtype of renal cell carcinoma is considerably characterised by inactivation of VHL gene due to presence of mutations/hyper-methylation/complete gene loss which results in HIF activation. These events lead to increased tyrosine kinase receptor signalling pathways (RAS/MEK/ERK pathway, PI3K/AKT/mTOR pathway and NF-κB pathway), which through their downstream effector proteins causes the cell to proliferate and migrate. Despite these studies, no effective therapeutics is yet known in ccRCC, establishing a clear need for understanding the molecular basis of ccRCC. Recent studies have shown that VHL inactivation alone is not sufficient to induce the tumour. Mutations in numerous other genes which codes for chromatin modifiers (PBRM1, SETD2 and BAP1), metabolic proteins (prolyl dehydrogenase) and signalling proteins like (PTEN and mTOR) have been identified and shown to be involved in the pathogenesis and poor prognosis of ccRCC. Also, activation of alternate signalling pathways like STAT pathway and Sonic Hedgehog (SHH) signalling pathway have been shown recently in ccRCC pathogenesis. It has also been shown that STAT pathway also works cooperatively with HIF to enhance the tumour progression. However, SHH pathway reactivation resulted in tumour regardless of the VHL status, indicating the complex nature of the tumour at the molecular level. So, understanding the complete aetiology of ccRCC is important and this review highlights some of recent advances in the molecular basis of ccRCC with major focus on its altered genetics and the downstream signalling.


Detailed understanding of these pathways including genetic mutations, chromatin modifiers, aberrant signalling pathways and their interaction from chromatin to the change in downstream proteomics pathways will help in further exploring the additional drug interventions which may help in treating the tumour or increasing the efficacy of traditional therapeutics.

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