Recent efforts have been aimed at targeting the hypoxia inducible factor (HIF)-mediated hypoxia-induced gene pathway for renal cell carcinomas (RCC) therapy. Among the various genes induced by HIF, vascular endothelial growth factor (VEGF) is one of the critical mediators in angiogenesis, tumor growth and metastasis. To date, however, limited information is available on the functional differences regarding VEGF transcription between the HIF subunits, namely HIF-1alpha and HIF-2alpha. To investigate the HIF-1alpha and HIF-2alpha-dependent effect on VEGF gene induction in RCC, a panel of human RCC cell lines was analyzed. We found that a loss of HIF-1alpha protein expression was a common event in RCC cell lines, which was associated not only with truncated HIF-1alpha mRNA transcripts but also with transcriptional silencing. Since the CpG rich promoter region of the HIF-1alpha gene contained a similar frequency of methylated CpG dinucleotides in RCC cell lines, a complex and non-uniform mechanism may be involved in this phenomenon. In these HIF-1alpha defective cell lines, the knockdown of the HIF-2alpha gene demonstrated that HIF-2alpha regulated the VEGF production, irrespective of the VHL gene mutation status. In contrast, HIF-1alpha played a predominant role in VEGF secretion in the cells expressing both wild-type HIF-1alpha and HIF-2alpha proteins. HIF-1alpha may therefore represent an important target molecule for RCC therapy; however, HIF-2alpha should be targeted in HIF-1alpha defective renal cancer cells.
These results suggest that the decreased acetylation of histone H3 is a common alteration in a malignant phenotype of renal cell carcinoma. Increasing the amount of acetylated histone H3 might be a therapeutic option for renal cell carcinoma.
Elevated monocyte counts were associated with aggressive tumor features and poor survival outcomes of patients with CRPC treated with docetaxel chemotherapy.
Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through MatrigelTM were then examined. AhR was predominantly expressed in the nuclei of high‐grade clear cell RCC (ccRCC) and tumor‐infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease‐specific survival. AhR ligands up‐regulated the expression of AhR and CYPs and promoted invasion by up‐regulating MMPs. Furthermore, siRNA for AhR down‐regulated CYPs, and inhibited cancer cell invasion together with the down‐regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.
BackgroundNo previous study has addressed the efficacy of NF-κB blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κB activation and therapeutic impact of NF-κB blockade by the novel NF-κB inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells.MethodsTwo human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro.ResultsIntranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively.ConclusionThere was a distinct change in the activation level of NF-κB between T24 and T24PR cells, suggesting strong nuclear localization of NF-κB could be a promising target after developing acquired platinum-resistance in bladder cancer.
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