In addition, we found that the wild type SOCS-3 promoter construct has significantly greater activity in human non-small-cell lung cancer (NSCLC) cell lines than in normal cells in accordance with STAT3 deregulation in these cells.
Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor.
The strong expression of cytoplasmic inactive STAT3 in NSCLC and MM cases implies a major role for STAT3 in tumor motility, invasion, and metastasis via a nontranscriptional pathway.
We examined MUC1 expression in non-small cell lung cancer (NSCLC) cell lines and found high levels of MUC1 protein expression associated with higher levels of tyrosine phosphorylated STAT3.
Cyclins (D1, D2, D3, and E), p21, p27, EGFR, Snail, E-cadherin, beta-catenin, phosphatidylinositol-3' kinase, phosphatase and tensin homologue, phosphorylated Akt, and phosphorylated signal transducer, and activator of transcription-3 were analyzed by immunohistochemistry in 405 surgically resected NSCLC, using a standardized tissue microarray platform.
EGFR function is dysregulated in various malignancies including nonsmall cell lung cancer (NSCLC) leading to activation of several signal transduction pathways including K-RAS, PIK3, and STAT3 and STAT5, that promote cell cycle progression, proliferation, invasion, angiogenesis, and inhibit apoptosis.
We found that although the mitogen-activated protein kinase pathway is significantly downregulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho-epidermal growth factor receptor, and variable changes in phospho-Akt.
Consistent with these findings, human non-small cell lung cancer (NSCLC) cells in which Stat3 was silenced displayed an enhancement of proinflammatory chemokine production, reduced expression of MHC class I antigen, and increased susceptibility to NK cell-mediated cytotoxicity.
Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC.
The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC.
In this study we demonstrate that STAT3 is constitutively activated in human NSCLC samples and in a variety of NSCLC lines independent of activating KRAS or tyrosine kinase mutations.
Our results demonstrate that IL-27 stimulation in NSCLC resulted in 1) STAT1 and STAT3 activation in a JAK-dependent manner, 2) development of epithelial phenotypes, including a decrease in the expression of a transcriptional repressor for E-cadherin (SNAIL), and mesenchymal marker (vimentin) with a reciprocal increase in the expression of epithelial markers, 3) inhibition of cell migration, and 4) reduced production of pro-angiogenic factors.
Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.
Our results indicate a further level of complexity in the relationship between SRC, STAT3 and GJIC in NSCLC than what has been previously demonstrated.
Notably, enforcing expression of IKBKE induces chemoresistance, whereas knockdown of IKBKE not only sensitizes NSCLC cells to chemotherapy but also abrogates STAT3- and nicotine-induced cell survival.