Changes in angiogenesis and hypoxia‐inducible factor‐1α protein expression in relapsed/refractory indolent non‐Hodgkin lymphomas

Angiogenesis is involved in the pathogenesis and progression of non‐Hodgkin lymphomas (NHL), and hypoxia‐inducible factor‐1α (HIF‐1α, also termed HIF1A) might contribute to this process. Currently, there is no direct evidence that the clinical progression of indolent NHL is associated with angiogenesis, and the expression of HIF‐1α at recurrence is unknown. Matched lymph node biopsies at diagnosis and recurrence of relapsed/refractory indolent NHL patients were analysed by immunohistochemical and morphometric analysis. We observed an increased vascular network and HIF‐1α protein expression in the second biopsy, providing direct evidence that angiogenesis is an essential process for disease progression.     

Common single nucleotide polymorphism of hypoxia‐inducible factor‐1α and its impact on the clinicopathological features of esophageal squamous cell carcinoma

OBJECTIVE: Angiogenesis is one of the most important molecular events in solid tumor development and growth, in which hypoxia‐inducible factor (HIF)‐1α is a key regulator and plays an important role. Studies have shown that a single nucleotide polymorphism (C1772T) in the HIF‐1α gene exerts a large effect on the phenotype of human head and neck squamous cell carcinoma and renal cell carcinoma. But the impact of the C1772T polymorphism on the clinicopathological features of human esophageal squamous cell carcinoma (ESCC) remains unknown, and thus it is the main focus of our study. METHODS: The C1772T genotype of 95 ESCC patients and 104 healthy controls were studied by using the polymerase chain reaction and restriction fragment length polymorphism. Mutations were confirmed by direct DNA sequencing. The impact of C1772T on tumor size, invasive depth, lymph node metastasis, distant metastasis, histological grade and TNM stage was also studied. RESULTS: The genotype frequency observed in the patients and controls was 11.58% versus 10.58%, respectively, for genotype C/T (P > 0.05). Genotype T/T was not found in our study. Larger tumors and a higher rate of lymph node metastasis was found for the C/T group. CONCLUSIONS: Although there is no significant difference of genotype distribution between ESCC patients and healthy controls, genotype C/T is associated with larger tumor and higher rate of lymph node metastasis.     

Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia‐inducible factor and transforming growth factor‐β‐dependent mechanisms

Background/Aims: During development of liver fibrosis, an important source of myofibroblasts is hepatocytes, which differentiate into myofibroblasts by epithelial to mesenchymal transition (EMT). In epithelial tumours and kidney fibrosis, hypoxia, through activation of hypoxia‐inducible factors (HIFs), is an important stimulus of EMT. Our recent studies demonstrated that HIF‐1α is important for the development of liver fibrosis. Accordingly, the hypothesis was tested that hypoxia stimulates hepatocyte EMT by a HIF‐dependent mechanism. Methods: Primary mouse hepatocytes were exposed to room air or 1% oxygen and EMT evaluated. In addition, bile duct ligations (BDLs) were performed in control and HIF‐1α‐deficient mice and EMT quantified. Results: Exposure of hepatocytes to 1% oxygen increased expression of α‐smooth muscle actin, vimentin, Snail and fibroblast‐specific protein‐1 (FSP‐1). Levels of E‐cadherin and zona occludens‐1 were decreased. Upregulation of FSP‐1 and Snail by hypoxia was completely prevented in HIF‐1β‐deficient hepatocytes and by pretreatment with SB431542, a transforming growth factor‐β (TGF‐β) receptor inhibitor. HIFs promoted TGF‐β‐dependent EMT by stimulating activation of latent TGF‐β1. To determine whether HIF‐1α contributes to EMT in the liver during the development of fibrosis, control and HIF‐1α‐deficient mice were subjected to BDL. FSP‐1 was increased to a greater extent in the livers of control mice when compared with HIF‐1α‐deficient mice. Conclusions: Results from these studies demonstrate that hypoxia stimulates hepatocyte EMT by a HIF and TGF‐β‐dependent mechanism. Furthermore, these studies suggest that HIF‐1α is important for EMT in the liver during the development of fibrosis.     

Nuclear factor‐kappa B as a promising target for selenium chemoprevention in rat hepatocarcinogenesis

Background and Aims: Selenium's molecular mechanism for cancer chemoprevention remains unknown. We aimed to study the gene expression of nuclear factor‐κB (NF‐κB), tumor growth factor‐α (TGF‐α) and cyclin D1 and the effects of sodium selenite using preventive and therapeutic approaches in chemically‐induced hepatocarcinogenesis in rats. Methods: Rats were divided randomly into six groups: negative control, positive control (diethyl nitrosamine [DEN] + 2‐acetylaminofluorene [2‐AAF]), preventive group, preventive control (respective control for preventive group), therapeutic group and therapeutic control (respective control for therapeutic group). The relative gene expression of NF‐κB, TGF‐α and cyclin D1 in liver tissues were measured using real‐time polymerase chain reaction. Results: The findings showed that the gene expression of NF‐κB in the preventive group and its respective control was significantly lower (P < 0.05) when compared with both the negative and positive controls. However, the expression of NF‐κB in the positive controls and therapeutic group was significantly higher (P < 0.05) when compared with the negative controls. The expression of TGF‐α and cyclin D1 was insignificant in all groups. Conclusion: The inhibition of the NF‐κB pathway in the initiation phase of hepatocarcinogenesis could be a promising target for selenium chemoprevention. However, further studies are required.     

Prognostic value of hypoxia inducible factor 1α in esophageal squamous cell carcinoma

Hypoxia inducible factor 1α (HIF 1α) plays a major role in the pleitropic response observed secondary to hypoxic conditions in tumors. Its expression in the tumor cells has been correlated to tumor aggressiveness and prognosis in squamous cell carcinoma (SCC) of the esophagus in Far Eastern population, but limited information is available on the prognostic role of HIF 1α in SCC of esophagus in European population. This information may help in choosing appropriate therapeutic strategies and possibly developing a monoclonal antibody with therapeutic potential targeting the HIF 1α. Tumor samples from 36 patients diagnosed with SCC of the esophagus were collected. Prepared tissue sections were stained with validated and specific monoclonal antibodies for HIF 1α and the expression was correlated with the disease pattern and survival. Out of 36 patients, 17 patients showed low and 19 high expression of HIF 1α. There was no difference in the disease‐free and overall survival between these two groups (P > 0.05, log rank test). Regression analysis showed that HIF 1α was not an independent prognostic factor for survival (P > 0.05). HIF 1α did not show prognostic value in SCC of the esophagus in our study on European population, in agreement with previous studies. Novel strategies on the therapeutic manipulation of HIF 1α in cancer are to be explored further and may have a role to play in improving treatment outcome.     

Nuclear factor‐κB as a potential therapeutic target for the novel cytotoxic agent LC‐1 in acute myeloid leukaemia

Nuclear factor‐κB (NF‐κB) has been implicated in a number of malignancies and has been suggested to be a potential molecular target in the treatment of leukaemia. This study demonstrated the constitutive activation of NF‐κB in human myeloid blasts and a clear correlation between NF‐κB expression and in vitro cytoprotection. High NF‐κB expression was found in many of the poor prognostic acute myeloid leukaemia (AML) subtypes, such as French‐American‐British classification M0 and M7, and the poor cytogenetic risk group. The in vitro effects of LC‐1, a novel dimethylamino‐parthenolide analogue, were assessed in 62 primary untreated AML samples. LC‐1 was found to be cytotoxic to AML cells in a dose‐dependent manner, mediated through the induction of apoptosis. The median drug concentration necessary to kill 50% of the cells was 4·5 μmol/l for AML cells, compared with 12·8 μmol/l for normal marrow cells. LC‐1 was shown to reduce the five individual human NF‐κB Rel proteins in a dose‐dependent manner. The subsequent inhibition of many NF‐κB‐regulated cytokines was also demonstrated. Importantly, sensitivity to LC‐1 was correlated with the basal NF‐κB activity. Consequently, LC‐1 treatment provides a proof of principle for the use of NF‐κB inhibitors in the treatment of AML.