miR-629 Targets TRIM33 to Promote TGFβ/Smad Signaling and Metastatic Phenotypes in ccRCC.
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 TGFβ/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 TGFβ-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 TGFβ on the expression of epithelial-mesenchymal transition-related factors as well as on the motility and invasion in ccRCC cells. These findings identify miR-629 as a potent regulator of the TGFβ/Smad signaling pathway via TRIM33 in ccRCC.


CONCLUSIONS
This study suggests that miR-629 has biomarker potential through its ability to regulate TGFβ/Smad signaling and accelerate ccRCC cell motility and invasion.
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan. jingushi-kk@phs.osaka-u.ac.jp.
Kentaro
K
Jingushi
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Yuko
Y
Ueda
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Kaori
K
Kitae
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Hiroaki
H
Hase
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Hiroshi
H
Egawa
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Ikumi
I
Ohshio
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Ryoji
R
Kawakami
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Yuri
Y
Kashiwagi
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Yohei
Y
Tsukada
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Takumi
T
Kobayashi
Department of Urology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Wataru
W
Nakata
Department of Urology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Kazutoshi
K
Fujita
Department of Urology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Motohide
M
Uemura
Department of Urology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Norio
N
Nonomura
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Kazutake
K
Tsujikawa
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; C569688:MIRN629 microRNA, human; D035683:MicroRNAs; D024101:Mitochondrial Proteins; C511956:TRIM33 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta