Abstract
XIAP has generally been thought to function in bladder cancer. However, the potential function of structure-based function of XIAP in human BC invasion has not been well explored before. We show here that ectopic expression of the BIR domains of XIAP specifically resulted in MMP2 activation and cell invasion in XIAP-deleted BC cells, while Src was further defined as an XIAP downstream negative regulator for MMP2 activation and BC cell invasion. The inhibition of Src expression by the BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation; which was resulted from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, respectively. The interaction of BIR2/BIR3 with E2F1/Sp1 unexpectedly occurred, which could be blocked by serum-induced XIAP translocation. Taken together, our studies, for the first time revealed that: (1) BIR2 and BIR3 domains of XIAP play their role in cancer cell invasion without affecting cell migration by specific activation of MMP2 in human BC cells; (2) by BIR2 interacting with E2F1 and BIR3 interacting with Sp1, XIAP initiates E2F1/Sp1 positive feedback loop-dependent transcription of miR-203, which in turn inhibits Src protein translation, further leading to MMP2-cleaved activation; (3) XIAP interaction with E2F1 and Sp1 is observed in the nucleus. Our findings provide novel insights into understanding the specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.
Highlights
Introduction TheX-linked inhibitor of apoptosis (XIAP) is an IAP protein family member and a well-defined inhibitor of the caspase/apoptosis pathway[1,2,3]
We found that the reduction of Matrix metalloproteinases-2 (MMP2) activation without affecting levels of pro-MMP2 protein and MMP9 protein by knockdown of XIAP expression was further reversed by ectopic expression of HA-ΔRING (XIAP in the presence of all three baculovirus IAP repeat (BIR) domains), but not reversed by ectopic expression of HAΔBIR (XIAP in the presence of the RING domain) in T24T cells and UMUC3 cells (Fig. 1b, c)
Our result showed that inhibition of XIAP expression dramatically reduces BC cell invasion (Fig. 1d)
Summary
X-linked inhibitor of apoptosis (XIAP) is an IAP protein family member and a well-defined inhibitor of the caspase/apoptosis pathway[1,2,3]. XIAP overexpression is associated with the progression and aggression of malignant cancer[4]. Downregulation of the tumor suppressor p63α protein expression by the RING domain of XIAP promotes malignant transformation of bladder epithelial cells[13]. Pro-MMP2 turns into activated MMP2 via proteolytic cleavage or chemical disruption to remove its pro-domain[15]. It has been reported that high expression of MMP2 could promote BC cell metastasis[16]. Our previous findings showed that MMP2 is increased in BBN-induced mouse BC tissues and plays a critical role in BC cell metastasis[17,18].
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