Lung Adenocarcinomas and Lung Cancer Cell Lines Show Association of MMP-1 Expression With STAT3 Activation

Abstract

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in the majority of lung cancer. This study aims at defining connections between STAT3 function and the malignant properties of non–small cell lung carcinoma (NSCLC) cells. To address possible mechanisms by which STAT3 influences invasiveness, the expression of matrix metalloproteinase-1 (MMP-1) was analyzed and correlated with the STAT3 activity status. Studies on both surgical biopsies and on lung cancer cell lines revealed a coincidence of STAT3 activation and strong expression of MMP-1. MMP-1 and tyrosine-phosphorylated activated STAT3 were found co-localized in cancer tissues, most pronounced in tumor fronts, and in particular in adenocarcinomas. STAT3 activity was constitutive, although to different degrees, in the lung cancer cell lines investigated. Three cell lines (BEN, KNS62, and A549) were identified in which STAT3 activitation was inducible by Interleukin-6 (IL-6). In A549 cells, STAT3 activity enhanced the level of MMP-1 mRNA and stimulated transcription from the MMP-1 promoter in IL-6–stimulated A549 cells. STAT3 specificity of this effect was confirmed by STAT3 knockdown through RNA interference. Our results link aberrant activity of STAT3 in lung cancer cells to malignant tumor progression through up-regulation of expression of invasiveness-associated MMPs.

Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor-1α Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium

“…This protein is frequently overexpressed in a large number of human cancers (19 -21) and is produced by various types of cells, including cancer cells, fibroblasts, and inflammatory cells (22)(23)(24). It has been reported that high MMP-1 level in patient lung tumor tissue is associated with metastasis of non-small cell lung cancer (25,26). MMP-1 knock-out mice exhibit reduced growth and angiogenesis of lung tumors (27).…”

Current mechanistic insights into the roles of matrix metalloproteinases in tumour invasion and metastasis

“…STAT3 is activated in lung cancer and is associated with expression of MMP1 (interstitial collagenase). STAT3 was inducible by interleukin 6, and STAT3 activation promoted transcriptional activation of MMP1, thus providing a link between STAT3 activation, increased MMP1 expression, and increased invasiveness in lung cancer .…”

Mitochondria‐mediated apoptosis was induced by oleuropein in H1299 cells involving activation of p38 MAP kinase

“…1,2 Lung cancer in human is divided into two categories: non-small cell lung cancer (NSCLC), which is dominant in all lung cancer, and small cell lung cancer (SCLC). 1,2 Lung cancer in human is divided into two categories: non-small cell lung cancer (NSCLC), which is dominant in all lung cancer, and small cell lung cancer (SCLC).…”