TGF-β-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12.
OBJECTIVE
TGF-β promotes tumor invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT). However, the underlying mechanisms causing this are not entirely clear. Long noncoding RNAs (lncRNA) have been shown to play important regulatory roles in cancer progression. The lncRNA malat1 (metastasis associated lung adenocarcinoma transcript 1) is a critical regulator of the metastasis phenotype of lung cancer cells.


METHODS
We, therefore, investigated whether TGF-β regulates malat1 expression to promote tumor metastasis of bladder cancer. The expression levels of malat1 and EMT markers were assayed in specimens of bladder cancer. The role of malat1 in regulating bladder cancer metastasis was evaluated in cell and animal models.


RESULTS
TGF-β induces malat1 expression and EMT in bladder cancer cells. malat1 overexpression is significantly correlated with poor survival in patients with bladder cancer. malat1 and E-cadherin expression is negatively correlated in vitro and in vivo. malat1 knockdown inhibits TGF-β-induced EMT. malat1 is associated with suppressor of zeste 12 (suz12), and this association results in decrease of E-cadherin expression and increase of N-cadherin and fibronectin expression. Furthermore, targeted inhibition of malat1 or suz12 suppresses the migratory and invasive properties induced by TGF-β. Finally, we demonstrated that malat1 or suz12 knockdown inhibits tumor metastasis in animal models.


CONCLUSIONS
These data suggest that malat1 is an important mediator of TGF-β-induced EMT, and suggest that malat1 inhibition may represent a promising therapeutic option for suppressing bladder cancer progression.
Authors' Affiliation: Department of Renal Transplantation and Urology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
Yu
Y
Fan
Bing
B
Shen
Mingyue
M
Tan
Xinyu
X
Mu
Yan
Y
Qin
Fang
F
Zhang
Yong
Y
Liu
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
C557041:MALAT1 long non-coding RNA, human; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; C430461:SUZ12 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D063151:Polycomb Repressive Complex 2