In addition, immunohistochemical staining demonstrated that transforming growth factor‑β (TGF‑β) and low expression of SMAD4 was associated with a lower Fuhrman grade and low expression of transcription intermediary factor 1‑γ was associated with a higher tumor Fuhrman grade (P<0.05), Therefore, based on the regulatory effect of SMAD4 on EMT‑associated transcription factors, SMAD4 which can form a SMAD3/SMAD4 complex induced by TGF‑β, could be a potential anticancer drug target inhibiting tumor invasion and metastasis in RCC.
We found a negative correlation between miR-17-5p and its two predicted targets, VEGF-A and EGLN3, and between miR-224 and its targets SMAD4 and SMAD5 in RCC specimens, suggesting that downstream signaling pathways are also modulated by clear cell RCC-dysregulated miRs.
In accordance with the result, transcriptional downregulation of Smad4 and post-transcriptional downregulation of TGF-beta type II receptor (TbetaR-II) were frequently found in RCC tissues compared to normal renal tissues.
The results suggest that inactivation of tumor suppressor genes at 18q21.3, including DCC and SMAD4 as candidates, may be involved in the tumorigenesis of some conventional RCCs.