Abstract. Neuroendocrine tumors (NETs) are a very heterogeneous group that are thought to originate from the cells of the endocrine and nervous systems. These tumors develop in a number of organs, predominantly in the gastrointestinal and pulmonary systems. Clinical detection and diagnosis are reliable at the late stages when metastatic spread has occurred. However, traditional conventional therapies such as radiation and chemotherapy are not effective. In the majority of cases even surgical resection at that stage is unlikely to produce promising reusults. NETs present a serious clinical challenge, as the survival rates remain low, and as these rare tumors are very difficult to study, novel approaches and therapies are required. This review will highlight the important points of accumulated knowledge covering the molecular aspects of the role of neuroendocrine cells, hormonal peptides, the reasons for ectopic hormone production in NET, neuropeptides and epigenetic regulation as well as the other challenging questions that require further understanding.
Abstract. Cytokines produced in the tumour microenvironment exert an important role in cancer pathogenesis and in the inhibition of disease progression. Cancer of the cartilage is termed metastatic chondrosarcoma; however, the signaling events resulting in mesenchymal cell transformation to sarcoma have yet to be fully elucidated. The present study aimed to characterize the cytokine expression profile in the human JJ012 chondrosarcoma cell line, as well as the effect of cytostatic proline-rich polypeptide-1 (PRP-1). Western blot experiments demonstrated that the levels of suppressor of cytokine signaling 3 (SOCS3) were upregulated in chondrocytes compared with chondrosarcoma cells. Addition of PRP-1 restored the expression of the tumor suppressors, SOCS3 and ten-eleven-translocation methylcytosine dioxygenase 1 and 2 (TET1/2), in a dose-responsive manner. It is known that methylation of histone H3K9 was eliminated from the promoters of the inflammation-associated genes. PRP-1 inhibited H3K9 demethylase activity with an IC 50 (concentration required to give half-maximal inhibition) value of 3.72 µg/ml in the chondrosarcoma cell line. Data obtained from ELISA experiments indicated that the expression of interleukin-6 (IL-6) in chondrosarcoma cells was 86-fold lower compared with that in C28 chondrocytes. In the present study, a 53-fold downregulation of IL-6 expression in co-culture of chondrosarcoma cells and C28 chondrocytes was identified as well. Downregulation of IL-6 expression has been documented in numerous other tumor types, although the reasons for this have not been fully established. In chondrosarcoma, IL-6 manifests itself as an anti-inflammatory agent and, possibly, as an anti-tumorigenic factor. To explore protein-DNA interactions leading to such differences, a gel-shift chemiluminescent assay was performed. Gel shifts were observed for chondrosarcoma and chondrocytes in the lanes that contained nuclear cell extract and oligo-IL-6 DNA. Notably, the DNA-protein complexes in C28 chondrocytes were markedly larger compared with those in chondrosarcoma cells. The mechanisms that underpin such differences, and characterization of the interacting proteins, remain to be fully elucidated.
Abstract. Neuropeptides act as neurohormones, neurotransmitters and/or neuromodulators. Neuropeptides maintain physiological homeostasis and are paramount in molecular mechanisms of disease progression and regulation, including in cancer. Neuropeptides, by their definition, originate and are secreted from the neuronal cells, they are able to signal to neighboring cells or are released into the blood flow, if they act as neurohormones. The majority of neuropeptides exert their functions through G protein-coupled receptors, with certain exceptions. Although previous studies indicate that neuropeptides function in supporting proliferation of malignant cells in many types of solid tumor, the antitumorigenic action of the neuropeptides and their receptors, for example, in gastric cancers and chondrosarcoma, were also reported. It is known that epigenetically modified chromatin regulates molecular mechanisms involved in gene expression and malignant progression. The epigenetic modifications are genetically heritable, although they do not cause changes in DNA sequence. DNA methylation, histone modifications and miRNA expression are subject to those modifications. While there is substantial data on epigenetic regulation of neuropeptides, the epigenetic control of cancer by neuropeptides is considered to be uncharted territory. The aim of the current review is to describe the involvement of neuropeptides in the epigenetic machinery of cancer based on data obtained from our laboratory and from other authors.
Abstract. Cytokines produced in the tumour microenvironment serve important roles in cancer pathogenesis or in the supression of disease progression. Metastatic chondrosarcoma is a cancer of the cartilage, and our group previously reported from a human ELISA assay that interleukin 6 (IL6) expression in JJ012 chondrosarcoma cells was 86-fold lower than that in C28 chondrocytes, indicating its role as an anti-inflammatory and anti-tumorigenic factor. Additionally, to the best of our knowledge, the study was the first to demonstrate downregulation of IL6 in a human chondrosarcoma cell line. To fully elucidate the effect of this IL6 downregulation, it is important to identify protein complexes and components that bind IL6 and potentially affect its gene expression directly or indirectly. To investigate IL6-protein interactions leading to these differences in IL6 expression, the current study performed a gel retardation electrophoretic mobility shift assay (EMSA), followed by 2D gel phoresis, in-gel trypsin digestion and proteomic mass spectral analysis. The results indicated a presence of ubiquitination enzymes in C28 chondrocytes, while none were identified in JJ012 chondrosarcoma cells. While it seems counterintuitive, it may be that the absence of ubiquitination of certain factors leads to the downregulation of IL6 expression in human chondrosarcoma. Therefore, dysregulated ubiquitination may be among the possible mechanisms for the markedly reduced IL6 expression in chondrosarcoma.
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