Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression

详细信息    查看全文

• 作者：Dong Gwang Lee¹ ; ² ; ^&dagger ; ; Sang-Hyun Lee¹ ; ^&dagger ; ; Jang-Seong Kim¹ ; Jongjin Park¹ ; ² ; Young-Lai Cho³ ; Koon Soon Kim⁴ ; Deog Yeon Jo⁵ ; Ik-Chan Song⁵ ; Nayoung Kim⁵ ; Hwan-Jung Yun⁵ ; Young-Jun Park¹ ; Seon-Jin Lee¹ ; Hee Gu Lee¹ ; Kwang-Hee Bae¹ ; Sang Chul Lee¹ ; Sungbo Shim⁶ ; Young-Myeong Kim⁷ ; Young-Guen Kwon⁸ ; Jin-Man Kim⁹ ; ^{jinmank@cnu.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; Hyo Jin Lee⁵ ; ^{cymed@cnu.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; Jeong-Ki Min¹ ; ² ; ^{jekmin@kribb.re.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ECM ; extracellular matrix ; EMT ; epithelial-to-mesenchymal transition ; GBC ; gallbladder carcinoma ; MMP ; matrix metalloproteinase ; NDRG2 ; N-myc downstream-regulated gene 2 ; RTKs ; receptor tyrosine kinases ; shCtrl ; sh-control ; shRNA ; small hairpin RNA ; siRNA ; small interfering RNA
• 刊名：Journal of Hepatology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：63
• 期：6
• 页码：1429-1439
• 全文大小：3834 K

文摘

Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and one of the most lethal forms of human cancer. However, there is limited information about the molecular pathogenesis of GBC. Here, we examined the functional role of the tumor suppressor N-myc downstream-regulated gene 2 (NDRG2) and the underlying molecular mechanisms of disease progression in GBC.

Methods

Clinical correlations between NDRG2 expression and clinicopathological factors were determined by immunohistochemical analysis of tumor tissues from 86 GBC patients. Biological functions of NDRG2 and NDRG2-mediated signaling pathways were determined in GBC cell lines with NDRG2 knockdown or overexpression.

Results

Loss of NDRG2 expression was an independent predictor of decreased survival and was significantly associated with a more advanced T stage, higher cellular grade, and lymphatic invasion in patients with GBC. GBC cells with loss of NDRG2 expression showed significantly enhanced proliferation, migration, and invasiveness in vitro, and tumor growth and metastasis in vivo. Loss of NDRG2 induced the expression of matrix metalloproteinase-19 (MMP-19), which regulated the expression of Slug at the transcriptional level. In addition, MMP-19-induced Slug, increased the expression of a receptor tyrosine kinase, Axl, which maintained Slug expression through a positive feedback loop, and stabilized epithelial-mesenchymal transition of GBC cells.

Conclusions

The results of our study help to explain why the loss of NDRG2 expression is closely correlated with malignancy of GBC. These results strongly suggest that NDRG2 could be a favorable prognostic indicator and promising target for therapeutic agents against GBC.