8 research outputs found
Expression of liver X receptors in normal and refractory carcinoma tissues of the human lung and pancreas
Liver X receptors (LXRs) participate not
only in maintaining cholesterol homeostasis but also in
controlling cellular growth in many types of normal and
tumor cells. We previously reported that LXRĪ± was
aberrantly expressed in human oral squamous cell
carcinoma (HOSCC) tissues and cell lines, and that LXR
stimulation led to significant reduction of proliferation
of HOSCC cells via accelerating cholesterol efflux.
Since LXRs and downstream proteins involved in
cholesterol metabolism could be also applied as
therapeutic targets in small cell lung carcinoma (SCLC)
and pancreatic ductal adenocarcinoma (PDAC), we
herein analyzed the distribution of LXR proteins in these
refractory cancers as well as in normal human lung and
pancreatic tissues. LXRĪ² was observed in ciliated
epithelial cells, bronchial gland epithelia, type II alveolar
epithelia and alveolar macrophages of the lung, and was
less expressed in bronchial basal cells and type I alveolar
epithelia. In addition, LXRĪ² was detected in epithelium
of the pancreatic duct and acinar cells of the pancreas,
and was weakly expressed in pancreatic islet cells. By
contrast, LXRĪ± expression was restricted to alveolar
macrophages, and was not evident in any types of
epithelial cells in the lung and pancreas. We also
demonstrated that LXRĪ² but not LXRĪ± was abundantly
expressed in nine cases of SCLC and twenty cases of
PDAC tissues. These findings provide basic information
for evaluating the efficacy of LXR-targeted treatment in
SCLC and PDA
Neuroendocrine Cancer-Specific Up-Regulating Mechanism of Insulin-Like Growth Factor Binding Protein-2 in Small Cell Lung Cancer
Small cell lung cancer (SCLC) exhibits insulin-like growth factor-dependent growth. SCLC is the most aggressive among known in vivo lung cancers, whereas in vitro growth of SCLC is paradoxically slow as compared with that of non-SCLC (NSCLC). In this study, we demonstrate that SCLC cells overexpress insulin-like growth factor binding protein (IGFBP)-2 via NeuroD, a neuroendocrine cell-specific transcription factor. Chromatin immunoprecipitation, electrophoretic mobility shift, and IGFBP-2 promoter assays all revealed that NeuroD binds to the E-box in the 5ā²-untranslated region of IGFBP-2. A NeuroD transgene in both airway epithelial and NSCLC cells up-regulated the transcription of IGFBP-2 and retarded cell growth. Recombinant IGFBP-2 repressed the growth of both airway epithelial and NSCLC cells in a dose-dependent manner. A NeuroD-specific small interfering RNA repressed IGFBP-2 expression in SCLC, and neutralization of IGFBP-2 and an IGFBP-2-specific small interfering RNA increased SCLC cell growth. Pathological samples of SCLC also expressed IGFBP-2 abundantly, as compared with NSCLC, and showed only rare (8%) IGFBP-2 promoter methylation, whereas the IGFBP-2 promoter was methylated in 71% of adenocarcinomas and 29% of squamous cell carcinomas. These findings suggest that 1) SCLC has an IGFBP-2 overexpression mechanism distinct from NSCLC, 2) secreted IGFBP-2 contributes to the slow growth of SCLC in vitro, and 3) the epigenetic alterations in the IGFBP-2 promoter contribute to the striking differences in IGFBP-2 expression between SCLC and NSCLC in vivo
Early Growth Response-1 Induces and Enhances Vascular Endothelial Growth Factor-A Expression in Lung Cancer Cells
Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signalāregulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1āinducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1Ī± (HIF-1Ī±)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1Ī± and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1Ī± expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression