Tropomyosin-related kinase B and brain-derived neurotrophic factor in ovarian cancer

Introduction: Ovarian epithelial tumors are common tumours in women and contribute to the highest mortality among all gynecological cancers. Studies have been carried out on drugs targeting at different signaling pathways during the progression of cancers especially those activated by the growth factors. Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family which comprises a group of related polypeptide growth factor. It preferentially binds and activates Tropomyosin-related kinase B(TrkB). There are three forms of TrkB in human: a full-length form (TrkB-fl)and two truncated isoforms (TrkB-Shc and TrkB-T1). The TrkB-fl contains a cytoplasmic kinase domain that can trigger downstream signals while the other two isoforms lack the kinase activity. It has been shown that activation of TrkB by BDNF promotes cell survival and invasion in some cancers. However, their role in ovarian cancer has not been fully understood. Aim: We planned to explore the role of trkB in ovarian cancer by studying its differential expression at different stages of tumor progression in ovarian epithelial tumors and correlate it with clinicopathological parameters as well as to investigate the in vitro effect of the TrkB-BDNF pathway on the ovarian cancer cell growth. Method: Immunohistochemistry was carried out on the archival paraffin sections of ovarian tumors including 57 carcinomas, 17 borderline tumors and 4 cystadenomas. The mRNA and protein expression levels of TrkB in three "immortalized"human ovarian surface epithelium (OSE) cell lines and five ovarian carcinoma cell lines were analyzed by quantitative real time PCR and Western Blotting using an antibody specific to the cytoplasmic terminus of TrkB-fl respectively. To study the effect of BDNF stimulation on cell growth, different doses of BDNF was administered to a TrkB-expressing ovarian cancer cell line, OVCAR420, followed by cell proliferation assessment by MTT assay. Result: By immunohistochemistry, there was no TrkB expression in benign cystadenomas. Significantly higher TrkB expression was found in ovarian carcinomas when compared with borderline tumor (p=0.02). It was discovered that TrkB was predominantly expressed in the cytoplasm. Higher TrkB mRNA and protein expression was further confirmed in ovarian carcinoma cell lines when compared with normal ovarian epithelium cell lines. The in vitro study showed that exogenous BDNF could stimulate the growth of OVCAR420 after a 48-hour culture with BDNFat the doses of 50 or 100 ng/mL. Conclusion: The higher TrkB expression in borderline tumors and carcinoma compared to the cystadenoma implicated that TrkB may play a crucial role in ovarian carcinogenesis. The proliferation-stimulating effect of BDNF on the cancer cell line showed that the TrkB-BDNF pathway may be important regulators for the progression of ovarian cancer, with potential impacts on the development of targeted anticancer therapies

Follicle stimulating hormone can act on receptors of other growth hormone [2]

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Emerging issues in traditional Chinese medicine

Traditional Chinese medicine (TCM) has many beneficial effects and has been practiced for several thousand years. It is known to treat the cause of a disease rather than to alleviate its symptoms. Based on a belief that TCM is natural, safe, and of lower cost, consumers worldwide are spending more out-of-pocket money on this form of therapy. This increased spending, and reports of adverse reactions, has drawn the attention of many regulatory agencies. Scientists have called for more evidence-based and scientific research on the risks and benefits of TCM. In Canada, the Natural Health Product Regulations came into effect January 2004. TCM herbal product manufacturers will need to provide products of reputable quality to the market. Many will apply modern technology and good science to support their products. The issues facing producers, scientists, and consumers alike are quality control and assessment, standardization of bioactive components, mechanisms of actions, and integration of the evolved modern Chinese medicine into the healthcare system. Solid science, better regulation of the final product, and better education of consumers are necessary to extract the best of TCM to complement existing conventional medicine to deliver the best healthcare. © 2005 NRC Canada.link_to_subscribed_fulltex

Hyperhomocysteinemia Activates Nuclear Factor-κB in Endothelial Cells via Oxidative Stress

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated an important interaction between nuclear factor-κB (NF-κB) activation and homocysteine (Hcy)-induced chemokine expression in vascular smooth muscle cells and macrophages. The objective of the present study was to investigate the in vivo effect of hyperhomocysteinemia on NF-κB activation and the underlying mechanism of Hcy-induced NF-κB activation in endothelial cells. Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. The activated form of NF-κB and increased level of superoxide anions were detected in the endothelium of aortas isolated from hyperhomocysteinemic rats. The underlying mechanism of Hcy-induced NF-κB activation was investigated in human umbilical cord vein endothelial cells and in human aortic endothelial cells. Incubation of cells with Hcy (100 μmol/L) activated IκB kinases (IKKα and IKKβ), leading to phosphorylation and subsequent degradation of IκBα. As a consequence, NF-κB nuclear translocation, enhanced NF-κB/DNA binding activity, and increased transcriptional activity occurred. Additional analysis revealed a marked elevation of superoxide anion levels in Hcy-treated cells. Treatment of cells with a superoxide anion scavenger (polyethylene glycol-superoxide dismutase) or IκB kinase inhibitor (prostaglandin A 1) could prevent Hcy-induced activation of IKK kinases and NF-κB in endothelial cells. In conclusion, these results suggest that Hcy-induced superoxide anion production may play a potential role for NF-κB activation in the early stages of atherosclerosis in the vascular wall via activation of IκB kinases.link_to_subscribed_fulltex

Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor-κB activation

Hyperhomocysteinemia, or an elevation of blood homocysteine (Hcy) levels, is associated with cardiovascular disorders. Although kidney dysfunction is an important risk factor causing hyperhomocysteinemia, the direct effect of Hcy on the kidney is not well documented. There is a positive association between an elevation of blood Hcy levels and the development of chronic kidney disease. Inflammatory response such as increased chemokine expression has been implicated as one of the mechanisms for renal disease. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that is involved in the inflammatory response in renal disease. Nuclear factor-κB (NF-κB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism underling such an effect in rat kidneys as well as in proximal tubular cells. Hyperhomocysteinemia was induced in rats fed a high-methionine diet for 12 wk. The MCP-1 mRNA expression and MCP-1 protein levels were significantly increased in kidneys isolated from hyperhomocysteinemic rats. The NF-κB activity was significantly increased in the same kidneys. Pretreatment of hyperhomocysteinemic rats with a NF-κB inhibitor abolished hyperhomocysteinemia-induced MCP-1 expression in the kidney. To confirm the causative role of NF-κB activation in MCP-1 expression, human kidney proximal tubular cells were transfected with decoy NF-κB oligodeoxynucleotide to inhibit NF-κB activation. Such a treatment prevented Hcy-induced MCP-1 mRNA expression in tubular cells. Our results suggest that hyperhomocysteinemia stimulates MCP-1 expression in the kidney via NF-κB activation. Such an inflammatory response may contribute to renal injury associated with hyperhomocysteinemia. Copyright © 2008 the American Physiological Society.link_to_subscribed_fulltex

Aberrant activation of hedgehog signaling pathway in ovarian cancers: Effect on prognosis, cell invasion and differentiation

Aberrant activation of hedgehog (HH) pathway has been implicated in the development of human malignancies. This study aimed at investigating the role of HH molecules in human ovarian carcinogenesis. The expression profiles of HH molecules were examined in ovarian tumor samples and ovarian cancer cell lines and the in vitro effects of HH molecules on cell proliferation, apoptosis, migration, invasion and cell differentiation as well as related downstream target genes were assessed. Overexpression of Patched and Gli1 protein in ovarian cancers correlated with poor survival of the patients (P = 0.008; P = 0.004). Significantly elevated expression of Sonic hedgehog messenger RNA was observed in ovarian cancers compared with normal tissues and benign ovarian tumors and such differential expression was specific to histological types (P < 0.05). Ectopic Gli1 overexpression in ovarian cancer cells conferred increased cell proliferation, cell mobility, invasiveness and change in differentiation in association with increased expression of E-cadherin, vimentin, Bcl-2, caspases as well as β1 integrin, membrane type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF). Treatment with 3-keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl)-cyclopamine induced cancer cell apoptosis, suppressed cell growth, mobility and invasiveness and induced cancer cell dedifferentiation with decreased expression of E-cadherin, cytokeratin 7, Snail, calretinin, vimentin, Bcl-2, caspases, β1 integrin, MT1-MMP and VEGF. Our data suggested that abnormal HH signaling activation plays important roles in the development and progression of ovarian cancers. Gli1 expression is an independent prognostic marker. Inhibition of the HH pathway molecules might be a valid therapeutic strategy for ovarian cancers. © The Author 2008. Published by Oxford University Press. All rights reserved.link_to_OA_fulltex

Tyrosine kinase B receptor and BDNF expression in ovarian cancers - Effect on cell migration, angiogenesis and clinical outcome

In this report, we demonstrated that overexpression of tropomyosin-related kinase B (TrkB) was associated with shorter survival in ovarian cancer patients. Brain-derived neurotrophic factor (BDNF), the TrkB ligand, induced activation (phosphorylation) of TrkB in a dose dependent manner. Besides demonstrating the effect of BDNF/TrkB pathway in enhancing cancer cell migration and invasion but inhibiting apoptosis, we also report for the first time that exogenous hepatocyte growth factor induced TrkB expression at both mRNA and protein levels as well as phosphorylation. Our findings suggest that BDNF/TrkB pathway is important in ovarian carcinogenesis and TrkB may be a potential therapeutic target for ovarian cancer. © 2009 Elsevier Ireland Ltd. All rights reserved.link_to_subscribed_fulltex

Aberrant activation of hedgehog signaling pathway contributes to endometrial carcinogenesis through Β-catenin

The hedgehog and Wnt signaling pathways play important roles in human cancers with possible interaction. This study aimed at analysis and correlation of the expression of Gli1, a transcriptional factor and target gene of hedgehog signaling pathway, with clinicopathological parameters and expression of Β-catenin, an important member of the Wnt pathway, in normal, hyperplastic and malignant endometrium. Immunohistochemical study on 15 normal endometrium, 14 simple and complex hyperplasia without atypia, 37 atypical complex hyperplasia and 80 endometrial cancers showed significant Gli1 overexpression and Β-catenin nuclear immunoreactivity in endometrial cancers and atypical endometrial hyperplasia when compared with normal endometrium (P0.05). Overexpression of Gli1 in endometrial cancers correlated with well-differentiated histological grade (P0.001), non-myometrial invasion (P0.004) and superficial myometrial invasion (P0.041). Β-Catenin nuclear immunoreactivity was also associated with well-differentiated histology (P0.013). Gli1 overexpression positively correlated with Β-catenin nuclear immunoreactivity in atypical complex hyperplasia (P0.013) and endometrial carcinoma (P0.017). Similar Gli1 and Β-catenin protein expression pattern was observed in normal and endometrial cancer cell lines by western blotting. We further showed a complex formation between Gli1 and Β-catenin protein in endometrial cancer cell lines in an immunoprecipitation study. Ectopic overexpression of Gli1 into endometrial cancer cells led to reduced expression of Β-catenin in cell cytoplasm and increased expression of Β-catenin in the nuclei. In summary, overexpression of Gli1 was an early event in endometrial carcinogenesis. Aberrant activation of hedgehog pathway may play important roles in endometrial cancer through Β-catenin nuclear accumulation. © 2009 USCAP, Inc. All rights reserved.link_to_OA_fulltex