Non-canonical Targets of HIF1a Impair Oligodendrocyte Progenitor Cell Function

1. Download : Download high-res image (180KB)
2. Download : Download full-size image

     

Visfatin in adipocytes is upregulated by hypoxia through HIF1alpha-dependent mechanism

Obesity is associated with metabolic disorders, such as insulin resistance. Visfatin is an adipose-derived secretory factor to exert insulin-mimetic effects. Plasma visfatin levels and mRNA levels of visfatin in adipose tissues are increased in obesity. However, the mechanism that mediates induction of visfatin mRNA in adipose tissue of obesity remains unknown. Recent studies have reported that fat tissue is hypoxia in obesity. In this study, we investigated the effects of hypoxia on mRNA expression of visfatin in adipocytes. Hypoxia increased visfatin mRNA expression. Desferoxamine and Cobaltous chloride, two hypoxia mimetic compounds, also increased visfatin mRNA levels. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1alpha (HIF1alpha), mimicked the hypoxia-mediated upregulation of visfatin, and YC1, an inhibitor of HIF1 cancelled the hypoxia-induced upregulation of visfatin mRNA. We identified two functional hypoxia responsive elements (HRE) in mouse visfatin promoter. Hypoxic treatment and overexpression of HIF1alpha increased the promoter activity, and mutation of the HRE blunted hypoxia-induced activation of visfatin promoter. Our results suggest that visfatin mRNA expression is upregulated in the fat tissue of obesity through the activation of HIF1alpha pathway due to hypoxia.     

HIF-1alpha在乳腺癌中的表达及临床意义

目的：分析乳腺癌患者HIF-1alpha的表达水平与临床病理的关系,探讨HIF-1alpha表达水平对于乳腺癌诊治的意义。方法：选取我 院收治的乳腺癌患者共46 例作为实验组,随机选取同期收治的42 例乳腺良性病变患者作为对照组,所有患者均采取手术治疗, 手术中留取病变的乳腺组织,应用免疫组织化学法对乳腺组织中的HIF-1alpha表达水平进行检测,同时分析HIF-1alpha表达水平与乳 腺癌临床病理特征的相关性,并应用统计学软件对结果进行分析。结果：①实验组患者病变乳腺组织中HIF-1alpha表达水平（95.65 %）显著高于对照组（2.50 %）,差异具有显著性（P<0.05）;②HIF-1alpha表达水平与乳腺癌的患者的年龄、肿瘤直径以及雌激素受体状 态无显著相关（P＞0.05）;③HIF-1alpha表达水平与乳腺癌的临床分期、组织学分级以及淋巴结转移情况具有显著相关性（P<0.05）。结 论：乳腺癌患者的HIF-1alpha表达异常升高,其表达水平与癌组织分级、分期以及淋巴结转移情况密切相关,对预后不良具有一定的 提示作用,值得临床深入探讨。     

HIF1A-AS2 predicts poor prognosis and regulates cell migration and invasion in triple-negative breast cancer

The aberrant expression of hypoxia-inducible factor 1 alpha (HIF1A)-antisense RNA 2 (HIF1A-AS2) was found in various human cancers including breast cancer. The aim of this study was to present more evidence about the role HIF1A-AS2 on triple-negative breast cancer (TNBC). In our results, HIF1A-AS2 was also found to be upregulated in TNBC tissues compared with non-TNBC tissues or adjacent normal tissues. Besides, HIF1A-AS2 expression was also elevated in TNBC cell lines compared with the normal breast epithelial cell line. Moreover, high expression of HIF1A-AS2 was associated with lymph node metastasis, distant metastasis and unfavorable histological grade in TNBC patients. Survival analysis showed a TNBC patient with high HIF1A-AS2 expression had shorter overall survival than patients with low HIF1A-AS2 expression, and HIF1A-AS2 high expression acted as an independent poor prognostic factor for overall survival in TNBC patients. The cell migration and invasion assays suggested inhibition of HIF1A-AS2 obviously depressed TNBC cell migration and invasion. In conclusion, HIF1A-AS2 serves as a novel biomarker for predicting clinical progression and prognosis in TNBC.     

The real face of HIF1α in the tumor process

It is well known that the hypoxia-inducible factor 1 α (HIF1α) is detectable as adaptive metabolic response to hypoxia. However, HIF1/HIF1α is detectable even under normoxic conditions, if the metabolism is altered, e.g., high proliferation index. Importantly, both hypoxic metabolism and the Warburg effect have in common a decrease of the intracellular pH value. In our interpretation, HIF1α is not directly accumulated by hypoxia, but by a process which occurs always under hypoxic conditions, a decrease of the intracellular pH value because of metabolic imbalances. We assume that HIF1α is a sensitive controller of the intracellular pH value independently of the oxygen concentration. Moreover, HIF1α has its major role in activating genes to eliminate toxic metabolic waste products (e.g., NH₃/NH₄+) generated by the tumor-specific metabolism called glutaminolysis, which occur during hypoxia, or the Warburg effect. For that reason, HIF1α appears as a potential target for tumor therapy to disturb the pH balance and to inhibit the elimination of toxic metabolic waste products in the tumor cells.     

Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity

1. Download : Download high-res image (245KB)
2. Download : Download full-size image