TGF-β upregulates miR-182 expression to promote gallbladder cancer metastasis by targeting CADM1.
Transforming growth factor β (TGF-β) plays important roles in tumor metastasis by regulating miRNAs expression. miR-182 is an important molecule in the regulation of cancer progression. The aim of the study is to assess the role of miR-182 in TGF-β-induced cancer metastasis. In the present study, we found that miR-182 levels are significantly upregulated in GBC tissues compared with normal controls, and miR-182 expression is remarkably increased in primary tumors that subsequently metastasized, when compared to those primary tumors that did not metastasize. TGF-β induces miR-182 expression in GBC cells, and overexpression of miR-182 promotes GBC cell migration and invasion, whereas miR-182 inhibition suppresses TGF-β-induced cancer cell migration and invasion. The blockage of miR-182 by a specific inhibitor effectively inhibits pulmonary metastases in vivo. We further identified that the cell adhesion molecule1 (CADM1) is a new target gene of miR-182. miR-182 negatively regulates CADM1 expression in vitro and in vivo. Importantly, re-expression of CADM1 in GBC cells partially abrogates miR-182-induced cell invasion.


CONCLUSIONS
miR-182 is an important mediator of GBC metastasis, thus offering a new target for the development of therapeutic agents against GBC.
The Second Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medicine University, 225 Changhai Road, Shanghai 200438, China. binyismmu@sohu.com.
Yinghe
Y
Qiu
Xiangji
X
Luo
Tong
T
Kan
Yongjie
Y
Zhang
Wenlong
W
Yu
Yongpeng
Y
Wei
Ningjia
N
Shen
Bin
B
Yi
Xiaoqing
X
Jiang
D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D016212:Transforming Growth Factor beta