In addition, regorafenib significantly inhibited tumor growth, NF-κB, p38, ERK activation and expression of tumor progression-associated proteins in bladder cancer in vitro and in vivo.
We demonstrated that RAB14-promoted BC cancer development and progression were associated with activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase signaling through upregulation of MAPK1/MAPK8 and downregulation of dual-specificity protein phosphatase 6/Src homology 2 domain containing transforming protein/Fos proto-oncogene, AP-1 transcription factor subunit (FOS).
Importantly, we provide evidence that <i>PPP2R2A</i> represents a new miR-21 direct target and regulator of the ERK pathway and bladder cancer cell growth.Furthermore, i.v. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A-ERK network in mice.<i></i>.
We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates <i>MYC</i> mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates <i>FGFR3</i> expression by binding to active enhancers upstream from <i>FGFR3</i> Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing <i>MYC</i> transcription decreased cell viability <i>in vitro</i> and tumor growth <i>in vivo</i> A relevance of this loop to human bladder tumors was supported by the positive correlation between <i>FGFR3</i> and <i>MYC</i> levels in tumors bearing <i>FGFR3</i> mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an <i>FGFR3</i> mutation.
Further statistical analysis shows that low-expression of MAPK1 or Snail is an independent prognostic factor for a better overall survival in patients with BCa (n = 401).
In conclusion, our study demonstrated that Derlin-1 is overexpressed in bladder cancer and promotes malignant phenotype through ERK/MMP and PI3K/AKT/Bcl-2 signaling pathway.
Signaling activity in the PI3K and MAPK pathways was assessed by measuring intracellular levels of p-AKT and p-ERK at baseline and in response to pathway modulation; 66% (N = 19) of BC samples and 27% (N = 4) of NC samples met the "evaluable" criteria, i.e., at least 400,000 total cells available upon sample receipt with >2% of cells showing an epithelial phenotype.
The AKT and ERK pathways may reciprocally regulate, which are responsible for in vitro and in vivo epithelial to mesenchymal transition (EMT) process of bladder cancer.
Signaling mediated by p38 and JNK has well-established importance in cancer, yet the contribution of this pathway in urothelial bladder cancer is not understood.
The present study suggests that VEGF-C can enhance the proliferation and invasiveness of bladder cancer T24 cells, which is due to suppression of apoptosis and facilitation of migration, accompanied with upregulation of p38 MAPK and Akt phosphorylation.
In examining the role and function of ALKBH8 in human bladder cancer development in vitro, we found that silencing of ALKBH8 through small interfering RNA transfection reduced reactive oxygen species (ROS) production via down-regulation of NAD(P)H oxidase-1 (NOX-1) and induced apoptosis through subsequent activation of c-jun NH(2)-terminal kinase (JNK) and p38.