Abstract
ABSTRACTOur previous studies have demonstrated that XIAP promotes bladder cancer metastasis through upregulating RhoGDIβ/MMP-2 pathway. However, the molecular mechanisms leading to the XIAP upregulation was unclear. In current studies, we found that XIAP was overexpressed in human high grade BCs, high metastatic human BCs, and in mouse invasive BCs. Mechanistic studies indicated that XIAP overexpression in the highly metastatic T24T cells was due to increased mRNA stability of XIAP that was mediated by downregulated miR-200c. Moreover, the downregulated miR-200c was due to CREB inactivation, while miR-200c downregulation reduced its binding to the 3’-UTR region of XIAP mRNA. Collectively, our results demonstrate the molecular basis leading to XIAP overexpression and its crucial role in BC invasion.
Highlights
Bladder cancer (BC) is a malignancy of the urinary tract, and is the fourth and eighth most commonly diagnosed cancer in males and females, respectively, in the USA [1,2]
We found that X-linked inhibitor of apoptosis protein (XIAP) expression was positively correlated to tumor grade and muscleinvasive tumors, and we elucidated the molecular mechanisms of ectopic expression of XIAP in BC invasion and metastasis
The results showed that xiap mRNA level was higher in T24T cells than T24 cells, indicating that XIAP was regulated at the mRNA level, either via transcriptional level expression or mRNA stability level
Summary
Bladder cancer (BC) is a malignancy of the urinary tract, and is the fourth and eighth most commonly diagnosed cancer in males and females, respectively, in the USA [1,2]. Unlike non-lethal superficial tumors, invasive/metastatic malignant tumors contribute to nearly 100% of BC-related deaths [3]. In addition to numerous studies elucidating the mechanisms of anti-apoptotic function of XIAP, our recent studies have revealed several non-apoptosis-related functions of XIAP, such as upregulation of Cyclin D1 to promote BC cell growth [6] and colon cancer cell invasion via inhibition of RhoGDIα SUMOylation at lys-138 [7]. XIAP functions as a metastatic driver by activation of the NFκB pathway viaitsE3 ligase activity in human prostate cancer cells [8]. XIAP can promote bladder epithelial cell malignant transformation through inhibition of p63α translation [9]. Our newly research reported that XIAP promotes bladder cancer metastasis through upregulating RhoGDIβ/MMP-2 pathway [10,11]. The molecular mechanisms leading to this XIAP alteration during BC metastasis have not been explored
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