Up-regulation of osteopontin expression by aryl hydrocarbon receptor via both ligand-dependent and ligand-independent pathways in lung cancer.
The secreted glycol-phosphoprotein OPN not only plays important roles in immune responses and tissue remodeling but is also intimately involved in tumorigenesis. It is up-regulated in various cancers and correlated with poor prognosis. It is evident by enhancing growth and migration of cancer cells. However, the mechanisms that participate in up-regulation of OPN in lung cancer are largely unknown. Up-regulation of aryl hydrocarbon receptor (AhR), a transcription factor activated by xenobiotics, has been observed in lung cancer as well as premalignant lesions. In this study we demonstrated that AhR positively regulates OPN expression in lung cancer. We observed positive correlation of OPN and AhR expression in lung cancer specimen. Knockdown or overexpression of AhR exhibited down- or up-regulation of OPN expression in lung cancer cells. We identified an OPN promoter region between positions -268 and +435 that was activated by both ligand-independent and ligand-activated AhR. However, this region does not contain AhR response element/dioxin response element (DRE/XRE). Further truncations and internal deletions of the promoter revealed that the ligand-independent and ligand-activated AhR function through different regions of OPN promoter. The region between -268 and -100 was required for ligand-independent AhR activity. This region contains several cis-elements including AP2, C/EBP, SP1 and AP1 sites. On the other hand, the ligand-activated AhR up-regulates OPN activity through two regions of OPN promoter; one contains NFκB site at +137 and the other is between positions -100 and +126. This study suggested that both overexpression of un-induced AhR (in cases of non-smokers with high level of AhR) and ligand-activated AhR (such as smokers) contribute to up-regulation of OPN that in turn leads to lung tumorigenesis.
Institute of Medicine, Chung Shan Medical University, and Division of Thoracic Surgery, Department of Education & Research, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.
Cheng-Yen
CY
Chuang
Han
H
Chang
Pinpin
P
Lin
Shih-Jung
SJ
Sun
Po-Hung
PH
Chen
Yu-Ying
YY
Lin
Gwo-Tarng
GT
Sheu
Jiunn-Liang
JL
Ko
Shih-Lan
SL
Hsu
Jinghua Tsai
JT
Chang
D045744:Cell Line, Tumor; D004147:Dioxins; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics*; D053495:Osteopontin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
D004147:Dioxins; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D053495:Osteopontin