Abstract
Epithelial-mesenchymal transition (EMT) accompanying loss of E-cadherin is important for invasiveness and metastasis of bladder cancer. MicroRNAs (miRs) had been associated with cancer progression and differentiation in several cancers. Our goal is to find out the specific miR which modulates EMT in bladder cancer. Real-time quantitative polymerase chain reaction was used to measure the miRs expression in urothelial cell carcinoma (UCC) cell lines. MiR or siRNA mimics was used to regulate miR and mRNA level respectively. Migration and scratch assays were used to determine the migratory ability. Zymography assay was used to confirm the metalloproteinase activity. Western blotting was used to elucidate the mechanism which regulated by specific miR. MiR-429 was highly expressed in low grade UCC cell lines. Exogenous mimic of miR-429 treatment dramatically inhibited the migratory ability of T24 cells. MiR-429 downstream target ZEB1 was decreased, E-cadherin was restored, and β-catenin was contrarily decreased by exogenous mimic of miR-429 treatment in T24 cells. Cell invasive ability was also inhibited by exogenous mimic of miR-429 treatment through inactivating the MMP-2 activity in T24 cells. E-cadherin protein expression level was inhibited by E-cadherin siRNA accompanied with increasing cell migratory ability when compared with control group in low grade TSGH8301 cells. MiR-429 decreased the cell migratory and invasive abilities through reducing ZEB1 and β-catenin, restoring the E-cadherin expression and inactivation of MMP-2 of UCC cells. MiR-429 might be used as a progression marker of bladder cancer.
Highlights
Cancer ranks as the leading causes of mortality in Taiwan
After screening of 42 Epithelial-mesenchymal transition (EMT)-related miRs [summarized from reviews in [6, 10, 11], we found the expression of members of miR-200 family, such as miR-200b, miR-200c and miR-429, and several miR-200-associated miRNAs, such as miR-203, miR-205, and miR-206, are significantly distinguishable between distinct differential urothelial cell carcinoma (UCC) cell lines
E-cadherin is higher expressed in high-miR-429-expressed UCC cells whereas there is no E-cadherin detectable in lowmiR-429-expressed T24 cells (Figure 1B)
Summary
Cancer ranks as the leading causes of mortality in Taiwan. Totally 2,003 people were first diagnosed with bladder cancer and accompanied 807 (40.3% mortality rate) deaths in 2012 [1]. 30% of patients with papillary tumors of bladder will progress to invasive UCC, whereas radical cystectomy is the standard therapy. This disease recurs in up to 50% of these patients despite surgery, and is potentially lethal. Half of the patients with muscle invasive bladder carcinoma will develop into metastatic disease accompanied about 90% mortality rates [2]. Matrix metalloproteinase (MMP)-2 is the main enzymes involved in extra cellular matrix (ECM) degradation during EMT process, and considered to be important in tumor invasion and distal metastasis through blood vessel or lymphoid system in bladder cancer [4]
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