miR-629 Targets TRIM33 to Promote TGFβ/Smad Signaling and Metastatic Phenotypes in ccRCC

Abstract

Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and clear cell RCC (ccRCC) represents its most common histological subtype. To identify a therapeutic target for ccRCC, miRNA expression signatures from ccRCC clinical specimens were analyzed. miRNA microarray and real-time PCR analyses revealed that miR-629 expression was significantly upregulated in human ccRCC compared with adjacent noncancerous renal tissue. Functional inhibition of miR-629 by a hairpin miRNA inhibitor suppressed ccRCC cell motility and invasion. Mechanistically, miR-629 directly targeted tripartite motif-containing 33 (TRIM33), which inhibits the TGFb/Smad signaling pathway. In clinical ccRCC specimens, downregulation of TRIM33 was observed with the association of both pathologic stages and grades. The miR-629 inhibitor significantly suppressed TGFb-induced Smad activation by upregulating TRIM33 expression and subsequently inhibited the association of Smad2/3 and Smad4. Moreover, a miR-629 mimic enhanced the effect of TGFb on the expression of epithelial-mesenchymal transitionrelated factors as well as on the motility and invasion in ccRCC cells. These findings identify miR-629 as a potent regulator of the TGFb/Smad signaling pathway via TRIM33 in ccRCC.Implications: This study suggests that miR-629 has biomarker potential through its ability to regulate TGFb/Smad signaling and accelerate ccRCC cell motility and invasion.

MicroRNA‐194 reduces inflammatory response and human dermal microvascular endothelial cells permeability through suppression of TGF‐β/SMAD pathway by inhibiting THBS1 in chronic idiopathic urticaria

“…Besides, we also found that miR-194 could target at THBS1. A former study also found that the TGF-β/SMAD pathway could be downregulated by miR-629, 40 suggesting that miRNA is correlated to TGF-β/SMAD pathway. 38 TGF-β, which is implicated in urticaria pathogenesis, functions as an anti-inflammatory cytokine.…”

“…39 We reported that miR-194 could inhibit the activation of TGF-β/ SMAD pathway. A former study also found that the TGF-β/SMAD pathway could be downregulated by miR-629, 40 suggesting that miRNA is correlated to TGF-β/SMAD pathway.…”

Suppression of microRNA-629 enhances sensitivity of cervical cancer cells to 1′S-1′-acetoxychavicol acetate via regulating RSU1

“…Past studies have demonstrated that miR-629 plays an important role in hepatocellular carcinogenesis by regulating HNF4α-miRNA inflammatory feedback circuit and increases lung cancer risk by targeting tumor suppressor NBS1 gene 21,22. It was also revealed that miR-629 is upregulated in clear cell renal cell carcinoma and accelerates cell motility and invasion by targeting tripartite motif-containing 33 (TRIMM33), a tumor suppressor 23. We have also previously reported that miR-629 expression is dysregulated following treatment with ACA in cervical cancer cells 7.…”

Role of Smad signaling in kidney disease

“…Smad7 may also be a therapeutic agent for AngIImediated hypertensive nephropathy by inhibiting the Sp1/ SMAD3/NF-κB/miR-29b regulatory network [116]. In renal cell carcinoma, miR-629, miR-192, miR-194 and miR-215 that are known to suppress tumor progression are significantly downregulated [117,118]. In diseased human kidney tissue, miR-214 was detected in the glomerulus and tubules and infiltrating immune cells and induced antifibrotic effects independent of Smad2 and Smad3 [119].…”