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Bladder cancer, the most common malignancy of the urinary tract, has a poor overall survival rate when the tumor becomes muscle invasive. The discovery and evaluation of new alternative medications targeting high-grade muscle invasive bladder cancer (MIBC) are of tremendous importance in reducing bladder cancer mortality. Isorhapontigenin (ISO), a stilbene derivative from the Chinese herb Gnetum cleistostachyum, exhibits a strong anti-cancer effect on MIBCs. Here, we report the whole transcriptome profiling of ISO-treated human bladder cancer T24 cells. A total of 1047 differentially expressed genes (DEGs) were identified, including 596 downregulated and 451 upregulated genes. Functional annotation and pathway analysis revealed that ISO treatment induced massive changes in gene expression associated with cell movement, migration, invasion, metabolism, proliferation, and angiogenesis. Additionally, ISO treatment-activated genes involved in the inflammatory response but repressed genes involved in hypoxia signaling, glycolysis, the actin cytoskeleton, and the tumor microenvironment. In summary, our whole transcriptome analysis demonstrated a shift in metabolism and altered actin cytoskeleton in ISO-treated T24 cells, which subsequently contribute to tumor microenvironment remodeling that suppresses tumor growth and progression. [ABSTRACT FROM AUTHOR]

Our recent studies demonstrate that X‐linked inhibitor of apoptosis protein (XIAP) is essential for regulating colorectal cancer invasion. Here, we discovered that RhoGDIβ was a key XIAP downstream effector mediating bladder cancer (BC) invasion in vitro and in vivo. We found that both XIAP and RhoGDIβ expressions were consistently elevated in BCs of N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine (BBN)‐treated mice in comparison to bladder tissues from vehicle‐treated mice and human BCs in comparison to the paired adjacent normal bladder tissues. Knockdown of XIAP attenuated RhoGDIβ expression and reduced cancer cell invasion, whereas RhoGDIβ expression was attenuated in BBN‐treated urothelium of RING‐deletion knockin mice. Mechanistically, XIAP stabilized RhoGDIβ mRNA by its positively regulating nucleolin mRNA stability via Erks‐dependent manner. Moreover, ectopic expression of GFP‐RhoGDIβ in T24T(shXIAP) cells restored its lung metastasis in nude mice. Our results demonstrate that XIAP‐regulated Erks/nucleolin/RhoGDIβ axis promoted BC invasion and lung metastasis. [ABSTRACT FROM AUTHOR]

Our most recent studies demonstrate that Rho GDIβ 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 Rho GDIβ 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 Rho GDIβ inhibited MMP-2 protein expression accompanied by a reduction of invasion in human BC cells, whereas ectopic expression of Rho GDIβ upregulated MMP-2 protein expression and promoted invasion as well. The mechanistic studies indicated that MMP-2 was upregulated by Rho GDIβ at the transcriptional level by increased specific binding of the transcription factor Sp1 to the mmp-2 promoter region. Further investigation revealed that Rho GDIβ 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 Rho GDIβ 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 Rho GDIβ and mmp-2, reveal the nature of the MMP-2 regulatory network, which leads to MMP-2 overexpression and BC invasion. [ABSTRACT FROM AUTHOR]

(C) The invasion abilities of BECN1 knockdown in UMUC3 cells were evaluated in comparison to their vector transfectants using a BD BioCoatTM MatrigelTM Invasion Chamber applied with the matrigel. ATG7 Promotes Bladder Cancer Invasion via Autophagy-Mediated Increased ARHGDIB mRNA Stability A) The invasion abilities of the indicated cells were evaluated. gl GLO:I6Z7/17nov21:advs202104365-fig-0003.jpg PHOTO (COLOR): S1 (A) The potential microRNAs binding sites in ATG7 mRNA 3'-UTR were analyzed using the TargetScan, PicTar, and miRanda databases. [Extracted from the article]

Since invasive bladder cancer (BC) can progress to life threatening metastases, understanding the molecular mechanisms underlying BC invasion is crucial for potentially decreasing the mortality of this disease. Herein, it is discovered that autophagy‐related gene 7 (ATG7) is remarkably overexpressed in human invasive BC tissues. The knockdown of ATG7 in human BC cells dramatically inhibits cancer cell invasion, revealing that ATG7 is a key player in regulating BC invasion. Mechanistic studies indicate that MIR190A is responsible for ATG7 mRNA stability and protein overexpression by directly binding to ATG7 mRNA 3′‐UTR. Furthermore, ATG7‐mediated autophagy promotes HNRNPD (ARE/poly(U)‐binding/degradation factor 1) protein degradation, and in turn reduces HNRNPD interaction with ARHGDIB mRNA, resulting in the elevation of ARHGDIB mRNA stability, and subsequently leading to BC cell invasion. The identification of the MIR190A/ATG7 autophagic mechanism regulation of HNRNPD/ARHGDIB expression provides an important insight into understanding the nature of BC invasion and suggests that autophagy may represent a potential therapeutic strategy for the treatment of human BC patients. [ABSTRACT FROM AUTHOR]

Epithelial mesenchymal transition (EMT) is highly correlated with metastasis during cancer development. Although previous studies have revealed that ISO is able to inhibit cancer cell invasion and stem-cell properties, little is known about the effects of ISO on EMT markers. The present study explores the potential regulation of ISO on EMT, leading to the inhibition of migration and invasion of bladder cancer cells. We found that ISO inhibited Vimentin, one of the EMT markers, in the invasive bladder cancer cell lines U5637 and T24T. ISO reduced Vimentin protein level by increasing the expression of METTL14. On the other hand, ISO upregulated the METTL14 mRNA by activating the transcription factor FOXO3a. The results demonstrate that ISO inhibits invasion by affecting the EMT marker and offer a novel insight into understanding the upregulation of METTL14 by ISO. • The effect on EMT and its potential mechanisms of ISO is first explored. • ISO treatment significantly upregulated the protein expression of METTL14 via activating its promoter. • ISO treatment inhibited the Vimentin expression by increasing the expression of METTL14. • The study of the effect on anti-cancer by ISO provides novel insight against BC. [ABSTRACT FROM AUTHOR]

Recent studies show p85α up-regulates epidermal growth factor (EGF) receptor, thereby promoting malignant cell transformation and migration in normal mouse embryonic fibroblasts (MEFs). However, the potential role of p85α in human bladder cancer (BC) remains unknown. Here, we show that p85α is down-regulated in BC tumor tissues. Ectopic expression of p85α inhibited cell invasion, but not migration, whereas p85α knockdown promoted invasion in BC cells, revealing that p85α inhibits BC invasion. Overexpression of kinase-deficient p110 in T24 T(p85α) cells inhibited BC cell migration, but not invasion, suggesting that the inhibition of p85α on invasion is independent of PI3K activity. The effect of p85α on inhibiting BC invasion was mediated by the inactivation of MMP-2 concomitant with the up-regulation of TIMP-2 and down-regulation of MMP-14. Mechanistic studies revealed c-Jun inactivation was associated with p85α knockdown-induced MMP-14 expression, and down-regulated miR-190, leading to ATG7 mRNA degradation. This suppressed the autophagy-dependent removal of TIMP-2 in human BC cells. The present results identify a novel function of p85α and clarify the mechanisms underlying its inhibition of BC invasion, providing insight into the role of p85α in normal and cancer cells. [ABSTRACT FROM AUTHOR]