The hypoxia-regulated transcription factor DEC1 (Stra13, SHARP-2) and its expression in human tissues and tumours

DEC1, also known as SHARP-2 or Stra13, is an important molecule in embryonic differentiation and has recently been identified to be strongly inducible by hypoxia. Its distribution in normal human tissues and most tumour types is unknown. In the present study, a polyclonal antiserum to a 10-amino acid peptide from DEC1 has been raised. Using this antiserum, DEC1 was shown to be widely expressed in most normal human tissues, but usually only in a proportion of cells and typically with a nuclear localization. In tumours, expression was either augmented (the commonest pattern) or occasionally decreased. Similarly, in most normal tissues, low or absent expression was observed in endothelial cells, whereas in many tumour samples endothelium was usually strongly positive. In tumours, there was a striking pattern of staining seen in connection with areas of necrosis, with absence of DEC1 expression within a zone of morphologically viable cells immediately adjacent to the necrotic zone. This suggests that while DEC1 may be up-regulated by hypoxia in cancer, in more extreme hypoxia it may have a role in cell death. Its interrelationship with other hypoxically regulated molecules, such as the hypoxia-inducible factors or carbonic anhydrase IX, and differentiation of tumours now requires further investigation.     

HIF1α-siRNA and gemcitabine combination-based GE-11 peptide antibody-targeted nanomedicine for enhanced therapeutic efficacy in pancreatic cancers

Abstract

Pancreatic cancer is one of the deadliest cancers across the world with an average 5-year survival rate of less than <6%. In this study, gemcitabine (GEM) and HIF1α-siRNA loaded GE-11 peptide conjugated liposome was successfully prepared and evaluated for its antitumor efficacy in pancreatic cancer cells. The GE11 increased the targeting specificity of liposome carrier and increased the intracellular concentrations in the cancer cells. Furthermore, synergistic combination of GEM and HIF1a-siRNA exhibited remarkable improvement in the declining of cancer cell proliferations. siRNA could effectively decrease the expression of HIF1a gene in the cancer cells. Importantly, GE-11 peptide-conjugated GEM/siRNA-loaded liposomes (GE-GML/siRNA) increased the total amount of apoptosis cells with higher proportion of cells in late apoptosis phase. GE-GML induced remarkable apoptosis of cancer cells and induced chromatin condensation and nuclear fragmentation which are considered to be typical features of apoptosis and cell death. GE-GML/siRNA showed a significant reduction in the tumour burden suggesting the superior anticancer efficacy of this formulation. GE-GML/siRNA showed four-fold reduction in tumour compared to control and two-fold reduction compared to GE-GML, respectively. Overall, present work lays foundation for the combination of GEM and HIF1a-siRNA loaded in a targeted nanocarrier system as a unique therapeutic option in pancreatic cancer treatment.     

MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth

FGF2 and VEGFA are the two most potent angiogenic factors. Here we report that miR-503 can simultaneously down-regulate FGF2 and VEGFA. The expression of miR-503 is repressed in HCC cells and primary tumors due to a potential epigenetic mechanism. Overexpression of miR-503 reduced tumor angiogenesis in vitro and in vivo. We also found that miR-503 expression was down-regulated by hypoxia through HIF1α. These results identify a miRNA that targets both FGF2 and VEGFA in cancers, demonstrate the anti-angiogenesis role of miR-503 in tumorigenesis, and provide a novel mechanism for hypoxia-induced FGF2 and VEGFA through HIF1α-mediated inhibition of miR-503.     

Hypoxic inactivation of glycogen synthase kinase‐3β promotes gastric tumor growth and angiogenesis by facilitating hypoxia‐inducible factor‐1 signaling

Since the molecular mechanism of hypoxic adaptation in cancer cells is cell‐type specific, we investigated whether glycogen synthase kinase‐3β (GSK‐3β) activation is involved in hypoxia‐induced gastric tumor promotion. Stable gastric cancer cell lines (SNU‐638, SNU‐484, MKN1, and MKN45) were cultured under hypoxic conditions. Cells overexpressing wild‐type GSK‐3β (WT‐GSK‐3β) or kinase‐dead mutant of GSK‐3β (KD‐GSK‐3β) were generated and used for cell culture and animal studies. In cell culture experiments, hypoxia decreased GSK‐3β activation in gastric cancer cells. Cell viability and the expressions of HIF‐1α protein and VEGF mRNA in gastric cancer cells were higher in KD‐GSK‐3β transfectants than in WT‐GSK‐3β transfectants under hypoxic conditions, but not under normoxic conditions. Gastric cancer xenografts showed that tumor growth, microvessel area, HIF‐1α activation, and VEGF expression were higher in KD‐GSK‐3β tumors than in WT‐GSK‐3β tumors in vivo. In addition, the expression of hypoxia‐induced HIF‐1α protein was regulated by GSK‐3β at the translational level. Our data suggest that GSK‐3β is involved in hypoxic adaptation of gastric cancer cells as an inhibitory upstream regulator of the HIF‐1α/VEGF signaling pathway.     

Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF‐1α‐VEGF pathway in oxygen‐induced retinopathy mice

Retinopathy of prematurity (ROP) is a retinopathy characterized by retinal neovascularization (RNV) occurring in preterm infants treated with high concentrations of oxygen and may lead to blindness in severe cases. Currently, anti‐VEGF therapy is a major treatment for ROP, but it is costly and may cause serious complications. The previous study has demonstrated that melatonin exerted neuroprotective effect against retinal ganglion cell death induced by hypoxia in neonatal rats. However, whether melatonin is anti‐angiogenic and neuroglial protective in the progression of ROP remains unknown. Thus, this study was to investigate the effect of melatonin on RNV and neuroglia in the retina of oxygen‐induced retinopathy (OIR) mice. The results showed a reduction in retinal vascular leakage in OIR mice after melatonin treatment. Besides, the size of retinal neovascular and avascular areas, the number of preretinal neovascular cell nuclei, and the number of proliferative vascular endothelial cells within the neovascular area were significantly decreased in mice treated with melatonin. After oxygen‐induced injury, the density of astrocytes was decreased, accompanied by morphologic and functional changes of astrocytes. Besides, retinal microglia were also activated. Meanwhile, the levels of inflammatory factors were elevated. However, these pathologic processes were all hindered by melatonin treatment. Furthermore, HIF‐1α‐VEGF pathway was activated in the retina of OIR mice, yet was suppressed in melatonin‐treated OIR mice retinas. In conclusion, melatonin prevented pathologic neovascularization, protected neuroglial cells, and exerts anti‐inflammation effect via inhibition of HIF‐1α‐VEGF pathway in OIR retinas, suggesting that melatonin could be a promising therapeutic agent for ROP.     

Apparent diffusion coefficients in prostate cancer: correlation with molecular markers Ki‐67, HIF‐1α and VEGF

Prostate cancer (PCa) is the second most common cancer in men. The Gleason score (GS) and biomarkers play important roles in the diagnosis and treatment of patients with PCa. The purpose of this study was to investigate the relationship between the apparent diffusion coefficient (ADC) and the molecular markers Ki‐67, hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF) in PCa. Thirty‐nine patients with 39 lesions, who had been diagnosed with PCa, were enrolled in this study. All patients underwent diffusion‐weighted magnetic resonance imaging (DW‐MRI) (b = 800 s/mm²). The expression of Ki‐67, HIF‐1α and VEGF was assessed by immunohistochemistry. Statistical analysis was applied to analyze the association between ADC and prostate‐specific antigen (PSA), GS and the expression of Ki‐67, HIF‐1α and VEGF. The group differences in ADC among different grades of Ki‐67, HIF‐1α and VEGF were also analyzed. The mean ± standard deviation of ADC was (0.76 ± 0.27) × 10^?3 mm²/s. ADC correlated negatively with PSA and GS (p < 0.05). The Ki‐67 staining index (SI), HIF‐1α expression and VEGF expression in PCa were correlated inversely with ADC, controlling for age (r = –0.332, p < 0.05; r = ?0.662, p < 0.0005; and r = ?0.714, p < 0.0005, respectively). ADC showed a significant difference among different grades of Ki‐67 (F = 9.164, p = 0.005), HIF‐1α (F = 40.333, p < 0.0005) and VEGF (F = 22.048, p < 0.0005). In conclusion, ADC was correlated with PSA, GS, and Ki‐67, HIF‐1α and VEGF expression in patients with PCa. ADC may be used to evaluate tumor proliferation, hypoxia and angiogenesis in PCa.     

p-STAT3与缺氧诱导因子在结肠癌组织中的表达及其临床意义

目的检测信号转导和转录激活子3(STAT3)的活化形式-p-STAT3及缺氧诱导因子-1α(HIF-1α)在结肠癌及癌旁组织中的表达,探究p-STAT3和HIF在结肠癌诊断中的临床意义。方法采用免疫组织化学SABC法检测40例结肠癌及癌旁组织中p-STAT3和HIF-1α的表达情况及二者的相关性。结果在40例结肠癌组织中p-STAT3阳性表达率为92.5%,HIF-1α的阳性表达率为87.5%,两者呈正相关,p-STAT3和HIF-1α的表达在结肠癌组织均明显高于癌旁组织(P<0.05)。结论 p-STAT3和HIF-1α的过度表达在结肠癌的诊断中具有重要价值,p-STAT3可能通过HIF的转录共同促进结肠癌的发生和发展。