Stat3 downstream genes serve as biomarkers in human lung carcinomas and chronic obstructive pulmonary disease

Abstract

Smoking causes lung cancer and chronic obstructive pulmonary disease (COPD) that impose severe health problem to humans. Both diseases are related to each other and can be induced by chronic inflammation in the lung. To identify the molecular mechanism for lung cancer formation, a CCSP-rtTA/(Teto)7Stat3C bitransgenic model was generated recently. In this model, persistent activation of the Stat3 signaling pathway induced pulmonary inflammation and adenocarcinoma formation in the lung. A group of Stat3 downstream genes were identified by Affymetrix GeneChip microarray analysis that can be used as biomarkers for lung cancer diagnosis and prognosis. To determine which human lung cancers are related to the Stat3 pathway, multiple Stat3 downstream genes were screened in human lung cancers (adenocarcinomas and squamous cell carcinomas) and lung tissue with COPD. In both cancer and COPD, the Stat3 gene was up-regulated. A panel of Stat3-up-regulated downstream genes in mice was up-regulated in human adenocarcinomas, but not in human squamous cell carcinomas. This panel of genes was also modestly up-regulated in lung tissue with COPD from patients with a history of smoking and not up-regulated in those without histories of smoking. Several Stat3-down-regulated downstream genes also showed differential expression patterns in carcinoma and COPD. These studies support a concept that Stat3 is a potent oncogenic molecule that plays a role in formation of lung adenocarcinomas in both mice and humans. The carcinogenesis of adenocarcinoma and squamous cell carcinoma is mediated by different molecular mechanisms and pathways in vivo. Stat3 and its downstream genes can serve as biomarkers for lung adenocarcinoma and COPD diagnosis and prognosis in mice and humans.

Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling

“…For example, in hepatocellular adenoma, somatic mutations coding for constitutively activated gp130 have been detected (107), while elevated IL-6 levels in patients with breast, lung, and hematopoietic tumors correlate with poor clinical outcome (108,109). Biomarkers of STAT3 activity also represent reliable diagnostic/prognostic factors for patients with colorectal neoplasia and non-small cell lung carcinoma (100,(110)(111)(112). Furthermore, ADAM17, which mediates the ectodomain shedding (and activation) of some EGFR ligands, Notch and IL-6R, is also upregulated in various cancers (113) and is considered a novel anticancer drug target (114).…”

“…The regulation of STAT3 by IL-6 has received considerable attention in the study of both cancer biology and (auto)immunity, and pathway signatures that reflect altered STAT3 activity have prognostic value in certain cancers (4,(110)(111)(112). Furthermore, pharmacogenomic approaches have identified genetic links between STAT3 and chronic disease.…”

Analysis of protein-protein interaction network in chronic obstructive pulmonary disease

“…Other researchers showed that the Stat3 pathway also relates to COPD. Stat3 upregulation is observed in lung tissue with COPD from both smokers and non-smokers, indicating that it serves as biomarker for COPD diagnosis and prognosis in mice and humans (Qu et al, 2009).…”

Signal Transducer and Activator of Transcription 3 (Stat3C) Promotes Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Lung Tumorigenesis

“…In a clinical setting, the expression of Stat3 and the genes it induces are increased in human lung adenocarcinoma and in chronic obstructive pulmonary disease, a disease similar in pulmonary impairment to lung cancer. 5 Both diseases are common in human smokers. A knockin mouse model also shows the enhanced tumorigenic power of the Stat3C molecule in mammary tumors.…”