interleukin-8 and Small-Cell-Lung-Carcinoma

Small cell lung cancer (SCLC) is aggressive, with rapid growth and frequent bone metastasis; however, its detailed molecular mechanism remains poorly understood. Here, we report the critical role of early growth factor 4 (EGR4), a DNA-binding, zinc-finger transcription factor, in cell proliferation of SCLC. EGR4 overexpression in HEK293T cells conferred significant upregulation of specific splice variants of the parathyroid hormone-related protein (PTHrP) gene, resulting in enhancement of the secretion of PTHrP protein, a known mediator of osteolytic bone metastasis. More importantly, depletion of EGR4 expression by siRNA significantly suppressed growth of the SCLC cell lines, SBC-5, SBC-3 and NCI-H1048. On the other hand, introduction of EGR4 into NIH3T3 cells significantly enhanced cell growth. We identified four EGR4 target genes, SAMD5, RAB15, SYNPO and DLX5, which were the most significantly downregulated genes upon depletion of EGR4 expression in all of the SCLC cells examined, and demonstrated the direct recruitment of EGR4 to their promoters by ChIP and luciferase reporter analysis. Notably, knockdown of the expression of these genes by siRNA remarkably suppressed the growth of all the SCLC cells. Taken together, our findings suggest that EGR4 likely regulates the bone metastasis and proliferation of SCLC cells via transcriptional regulation of several target genes, and may therefore be a promising target for the development of anticancer drugs for SCLC patients.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Chromatin Immunoprecipitation; Early Growth Response Transcription Factors; HEK293 Cells; Homeodomain Proteins; Humans; Interleukin-6; Interleukin-8; Lung Neoplasms; Mice; Microfilament Proteins; NIH 3T3 Cells; Paracrine Communication; Parathyroid Hormone-Related Protein; rab GTP-Binding Proteins; RANK Ligand; Small Cell Lung Carcinoma; Transcription Factors; Transcriptional Activation; Up-Regulation

Thalidomide has potent anti-inflammatory and anti-angiogenic properties. It was evaluated in combination with chemotherapy in two randomised placebo-controlled trials in patients with small cell lung cancer (SCLC, n=724) and advanced non-small cell lung cancer (NSCLC, n=722). Neither study demonstrated an improvement in overall survival with the addition of thalidomide to chemotherapy. This study investigated circulating angiogenic biomarkers in a subset of these patients.. Serial plasma samples were collected in a cohort of patients enrolled in these two trials (n=95). Vascular endothelial growth factor (VEGF), soluble truncated form of VEGF receptor-2 (sVEGFR-2), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assays. Results were correlated with patient clinical data including stage, response rate and progression-free survival (PFS).. Baseline biomarker levels were not significantly different between SCLC and NSCLC. For pooled treatment groups, limited stage SCLC was associated with lower baseline VEGF (P=0.046), sICAM-1 (P=0.008) and IL-8 (P=0.070) than extensive stage disease. Low baseline IL-8 was associated with a significantly improved PFS in both SCLC and NSCLC (P=0.028), and a greater reduction in IL-8 was associated with a significantly improved tumour response (P=0.035). Baseline angiogenic factor levels, however, did not predict response to thalidomide.. Circulating angiogenic biomarkers did not identify patients who benefited from thalidomide treatment.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carboplatin; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Deoxycytidine; Etoposide; Female; Fibroblast Growth Factor 2; Gemcitabine; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Lung Neoplasms; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Neovascularization, Pathologic; Proportional Hazards Models; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma; Survival Analysis; Thalidomide; Treatment Outcome; Vascular Endothelial Growth Factor A