RhoGDIβ promotes Sp1/MMP‐2 expression and bladder cancer invasion through perturbing miR‐200c‐targeted JNK2 protein translation

Abstract

Our most recent studies demonstrate that RhoGDIβ is able to promote human bladder cancer (BC) invasion and metastasis in an X‐link inhibitor of apoptosis protein‐dependent fashion accompanied by increased levels of matrix metalloproteinase (MMP)‐2 protein expression. We also found that RhoGDIβ and MMP‐2 protein expressions are consistently upregulated in both invasive BC tissues and cell lines. In the present study, we show that knockdown of RhoGDIβ inhibited MMP‐2 protein expression accompanied by a reduction of invasion in human BC cells, whereas ectopic expression of RhoGDIβ upregulated MMP‐2 protein expression and promoted invasion as well. The mechanistic studies indicated that MMP‐2 was upregulated by RhoGDIβ at the transcriptional level by increased specific binding of the transcription factor Sp1 to the mmp‐2 promoter region. Further investigation revealed that RhoGDIβ overexpression led to downregulation of miR‐200c, whereas miR‐200c was able directly to target 3′‐UTR of jnk2 mRNA and attenuated JNK2 protein translation, which resulted in attenuation of Sp1 mRNA and protein expression in turn, inhibiting Sp1‐dependent mmp‐2 transcription. Collectively, our studies demonstrate that RhoGDIβ overexpression inhibits miR‐200c abundance, which consequently results in increases of JNK2 protein translation, Sp1 expression, mmp‐2 transcription, and BC invasion. These findings, together with our previous results showing X‐link inhibitor of apoptosis protein mediating mRNA stabilization of both RhoGDIβ and mmp‐2, reveal the nature of the MMP‐2 regulatory network, which leads to MMP‐2 overexpression and BC invasion.

Overexpressed miR-200a promotes bladder cancer invasion through direct regulating Dicer/miR-16/JNK2/MMP-2 axis

“…3e). Previous studies have also reported that transcription factors, including AP-1 [30], Ets-1 [31], HSF1 [29], and Sp1 [32], are involved in initiating MMP-2 transcription in different experimental systems. The protein levels of HSF1,…”

“…Since our previous studies indicate that MMP-2 plays a key role in human BC invasion [26,29], the potential effect of miR-200a overexpression on MMP-2 expression was evaluated in both T24T and UMUC3. The results showed that miR-200a overexpression led to a profound upregulation of MMP-2 levels in both T24T and UMUC3 cells compared with their vector (Fig.…”

Knockdown of ZNF280A Inhibits Cell Proliferation and Promotes Cell Apoptosis of Bladder Cancer

“…For example, Pang et al reported that JNK2 acted as the target to mediate the miR-146a induced increase of cisplatin resistance in non-small cell lung cancer 24 . More importantly, in bladder cancer, JNK2 was also reported to be the target of miR-200c in the RhoGDIβ induced up-regulation of Sp1/MMP2 and promotion of bladder cancer invasion 25 .…”

Downregulation of miR-200c stabilizes XIAP mRNA and contributes to invasion and lung metastasis of bladder cancer

“…Muscular invasive bladder cancer represents a major therapeutic challenge of this disease; therefore, understanding the mechanisms underlying invasion and progression are crucial to potential drug discovery against the invasive malignant disease. In the current studies, we explored XIAP could promote invasion and lung metastasis of human BCs through RhoGDIb/MMP-2 pathway [10,11], but the molecular mechanism of XIAP upregulation in human BC remains unclear. Our result showed that XIAP was overexpressed in human high-grade BCs, high metastatic human T24T cells, and in mouse invasive BCs.…”

“…Furthermore, 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]. But the molecular mechanisms leading to this XIAP alteration during BC metastasis have not been explored.…”