, miR222 and miR-7 during the RCC development. Bars indicate mean standard error of mean. , P<0.050. doi:10.1371/journal.pone.0103258.g004 10 / 15 EGF/TGF1 Polymorphisms and MiR-7-221/222 in Renal Cell Carcinoma The tumor suppressor gene VHL is frequently lost in approximately 80% of all clear cell RCC, being this alterations a hallmark feature of this neoplasia, however additional events are required. This molecular event stops the degradation of HIF resulting in its accumulation in the cytoplasm and further migration to nucleus where it can activate the transcription of hypoxia related genes, such as TGF, VEGF and PDGF. Zhou and co-workers describe that during the RCC development, the VHL inactivation can also lead to an increase of the EGFR. Their study demonstrated that after EGF stimulation the phospho-AKT and the phospho-ERK signals lasted longer in 786-mock cells than in 786-VHL cells . Previous studies have shown that up-regulation of EGFR is associated with high tumor grade and worse prognosis. Recently, Brannon and co-workers proposed, that even within ccRCC occur different gene expression patterns, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19659763 suggesting that the molecular profile could be responsible for different biological behaviors. These authors distinguish two ccRCC subtypes, the ccA and ccB, considering the gene expression patterns and consequently the molecular pathways implicated in tumor development. The authors define a better prognosis group, the ccA group, associated with the overexpression of genes involved in hypoxia, angiogenesis, fatty acid and organic acid metabolisms. On the other hand, the ccB group was associated with the overexpression of more aggressive genes involved in cell differentiation, epithelial to mesenchymal transition, cell cycle, TGF pathway and 
wound healing, suggesting that these subgroup acquired additional genetic events that contribute to a more aggressive phenotype. Brooks and co-workers also developed a biomarker signature which include the expression analysis of 34 genes, considering the two distinct ccRCC subtypes classification, good risk and poor risk . Genetic and expression changes of several genes, that include TGF1, TGFRII, EGFR, PTEN, AMPK among others, and their products interaction are involved in the ccRCC high complex molecular network. The simultaneous deregulation of TGF1 signaling pathway is also implicated in renal carcinogenesis. This deregulation compromises the inhibition of cell cycle progression through G1-arrest, apoptosis, cyclin-dependent kinases inhibitors including p21WAF1 and p15Ink4b and suppression of c-myc. The higher expression levels of TGF1 are observed in advanced disease. However, these higher circulating levels could be consequence of the impossibility of TGF1 binding to the type II receptor. During tumor development, TGF1 binds to TGFRII, initiating a signaling transduction that culminates in cell cycle control and induction of apoptosis. However, attenuation of this pathway could be partially explained by the loss of the TGFRII. On the other hand, the LY-411575 site restoration of this pathway is associated with an increase in the sensitivity of RCC cells to TGF1. Recently, we demonstrated that low expression levels of TGFBR2 mRNA are associated with more aggressive prostate cancer phenotypes and with a higher risk to develop resistance to anticancer treatment. It is evident that EGF and TGF1 signaling networks require a delicate balance of interactions within the cellular and tumoral microenvironment. Der