Hypoxia-inducible factor-1α expression correlates with focal macrophage infiltration, angiogenesis and unfavourable prognosis in urothelial carcinoma

Chai, Chee‐Yin; Chen, Wan‐Tzu; Hung, Wen‐Chun; Kang, Wan-Yi; Huang, Ya‐Chun; Su, Yue‐Chiu; Yang, Ching-Hsiu

doi:10.1136/jcp.2007.050666

Cited by 83 publications

(69 citation statements)

References 23 publications

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“…Our results are parallel to the studies in the literature regarding the correlation between HIF-1a and clinicopathologic parameters in urothelial carcinomas [9][10][11][12]. Eltz et al suggested that HIF-1a is significantly associated with the grade and pattern of growth in urothelial carcinomas of the upper urinary tract [11].…”

Section: Discussionsupporting

confidence: 92%

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Evaluation of relationship between HIF-1α immunoreactivity and stage, grade, angiogenic profile and proliferative index in bladder urothelial carcinomas

et al. 2009

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Hypoxia-inducible factor-1alpha (HIF-1alpha) is a critical regulatory protein of cellular response to hypoxia. In this study, we evaluated the relationship of HIF-1alpha with clinicopathologic parameters such as tumor stage and grade, as well as angiogenic profile and proliferation index. The immunoreactivity of HIF-1alpha was assessed in 70 cases of primary bladder urothelial carcinoma. Vascular endothelial growth factor (VEGF) and microvessel density (MVD) were used to evaluate the angiogenic profile. MVD was calculated by immunohistochemical staining of endothelial cells with CD34. Proliferation index was determined by the percentage of Ki-67 nuclear staining in tumor cells. There was a significant relationship between HIF-1alpha immunoreactivity and stage, as well as histologic grade of the tumor (P < 0.001). HIF-1alpha immunoreactivity was also closely related to VEGF expression (P < 0.001), MVD (P = 0.002) and proliferation index (P < 0.001). VEGF, MVD and proliferation index were found to be closely related to tumor stage and histologic grade. There was no correlation between HIF-1alpha immunoreactivity and lamina propria (P = 0.13), muscularis propria (P = 0.009) or vascular invasion (P = 0.1). In this study, HIF-1alpha expression was found to be closely related to prognostic parameters in bladder urothelial carcinoma. For this reason, it may be a useful marker to determine the prognosis and to choose the appropriate treatment modality.

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Section: Discussionsupporting

confidence: 92%

“…A strong relationship between HIF-1a immunoreactivity and the grade of the tumor in bladder urothelial carcinomas was claimed [9][10][11][12]. In our study the relation between HIF-1a immunoreactivity and the grade of the tumor was statistically significant (P = 0.002).…”

Section: Discussionsupporting

confidence: 42%

Evaluation of relationship between HIF-1α immunoreactivity and stage, grade, angiogenic profile and proliferative index in bladder urothelial carcinomas

et al. 2009

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“…BTCC is one of the common solid tumors with low oxygen tension because rapid tumor growth outstrips the capability of existing blood vessels to supply oxygen, and hyp oxic regions commonly occur. It has been reported that overexpression of HIF-1 ␣ is common in BTCC, and it is an independent prognostic factor for disease-free survival [10,21] . Thus, the blockade of HIF-1 ␣ appears to be a promising strategy for the treatment of metastatic BTCC.…”

Section: Discussionmentioning

confidence: 99%

Effects of YC-1 on Hypoxia-Inducible Factor 1 Alpha in Hypoxic Human Bladder Transitional Carcinoma Cell Line T24 Cells

Zhao

Tang

et al. 2011

Urol Int

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Objectives: It was the aim of this study to explore the effects of 3-(5′-hydroxymethyl-2′-furyl)-l-benzyl indazole (YC-1) on transcription activity, cell proliferation and apoptosis of hypoxic human bladder transitional carcinoma cells (BTCC), mediated by hypoxia-inducible factor 1α (HIF-1α). Methods: BTCC cell line T24 cells were incubated under normoxic or hypoxic conditions, adding different doses of YC-1. The protein expression of HIF-1α and HIF-1α-mediated genes was detected by Western blotting. RT-PCR was used to detect HIF-1α mRNA expression. Cell proliferation, apoptosis and migration activity were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry and transwell migration assay. The cells were pretreated by two ERK/p38 MAPK pathway-specific inhibitors, PD98059 or SB203580, and then incubated with YC-1 treatment under hypoxic condition. HIF-1α protein expression was detected by Western blotting. Results: Hypoxic T24 cells expressed a higher level of HIF-1α, vascular endothelial growth factor, matrix metalloproteinases-2, B-cell lymphoma/leukemia-2 protein and HIF-1α mRNA compared with normoxic controls, in which the above-mentioned expression was downregulated by YC-1 in a dose-dependent manner. Cell proliferation and migration activity were inhibited while apoptosis was induced by YC-1 under hypoxic condition. Moreover, YC-1-downregulated HIF-1α expression was reversed by PD98059 and SB203580, respectively. Conclusions: YC-1 inhibits HIF-1α and HIF-1α-mediated gene expression, cell proliferation and migration activity and induces apoptosis in hypoxic BTCC. The ERK/p38 MAPK pathway may be involved in YC-1-mediated inhibition of HIF-1α.

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“…Under normoxic conditions, HIF-1α mRNA is translated, but its protein is rapidly degraded (11 prevented, facilitating the regulation of the expression of a series of genes, which are involved in cell proliferation, differentiation, apoptosis, angiogenesis, migration and invasion (12). The overexpression of HIF-1α has been identified in patients with bladder carcinoma, and the expression of HIF-1α is correlated with the progression and recurrence of bladder carcinoma (13). Consequently, in addition to being a diagnostic biomarker, HIF-1α may be a novel therapeutic target in bladder carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia regulates the expression and localization of CCAAT/enhancer binding protein α by hypoxia inducible factor-1α in bladder transitional carcinoma cells

Xue

Chen

2015

Molecular Medicine Reports

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Abstract. Hypoxia inducible factor-1α (HIF-1α) is overexpressed in various types of solid tumor in humans, including bladder cancer. HIF-1α regulates the expression of a series of genes, which are involved in cell proliferation, differentiation, apoptosis, angiogenesis, migration and invasion and represents a potential therapeutic target for the treatment of human cancer. Despite extensive investigation of the effects of HIF-1α in the progression and metastasis of bladder cancer, the possible regulatory mechanisms underlying the effects of HIF-1α on bladder cancer cell proliferation and differentiation remain to be elucidated. It has been suggested that the transcription factor CCAAT/enhancer binding protein α (C/EBPα) acts as a tumor suppressor in several types of cancer cell, which are involved in regulating cell differentiation, proliferation and apoptosis. The present study confirmed that, in bladder cancer cells, the expression and localization of C/EBPα was regulated by hypoxia through an HIF-1α-dependent mechanism, which may be significant in bladder cancer cell proliferation and differentiation. The 5637 and T24 bladder cancer cell lines were incubated under normoxic and hypoxic conditions. The expression levels of HIF-1α and C/EBPα were detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence analysis. The results revealed that, under hypoxic conditions, the protein expression levels of HIF-1α were markedly upregulated, but the mRNA levels were not altered. However, the mRNA and protein levels of C/EBPα were significantly reduced. The present study further analyzed the subcellular localization of C/EBPα, which was markedly decreased in the nuclei under hypoxic conditions. Following HIF-1α small interference RNA silencing of HIF-1α, downregulation of C/EBPα was prevented in the bladder cancer cells cultured under hypoxic conditions. In addition, groups of cells treated with 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole, which inhibits the expression of HIF-1α in hypoxia, contributed to the inhibited expression of HIF-1α and enhanced expression of C/EBPα in hypoxic bladder cancer cells. These results suggested that C/EBPα was a downstream effector regulated by HIF-1α in hypoxic bladder cancer cells and that this regulatory pathway may represent a potential therapeutic target in the treatment of bladder cancer.

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Hypoxia-inducible factor-1α expression correlates with focal macrophage infiltration, angiogenesis and unfavourable prognosis in urothelial carcinoma

Abstract: Our results indicate that HIF-1alpha is a key regulator of the angiogenic cascade. We show that HIF-1alpha is an independent prognostic factor for disease-free survival.

Cited by 83 publications

References 23 publications

Evaluation of relationship between HIF-1α immunoreactivity and stage, grade, angiogenic profile and proliferative index in bladder urothelial carcinomas

Evaluation of relationship between HIF-1α immunoreactivity and stage, grade, angiogenic profile and proliferative index in bladder urothelial carcinomas

Effects of YC-1 on Hypoxia-Inducible Factor 1 Alpha in Hypoxic Human Bladder Transitional Carcinoma Cell Line T24 Cells

Hypoxia regulates the expression and localization of CCAAT/enhancer binding protein α by hypoxia inducible factor-1α in bladder transitional carcinoma cells

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