芳香烴受體可在肺癌中藉由有或無配體的不同路徑活化骨橋蛋白的表現

已知骨橋蛋白(Osteopontin;OPN)在肺癌中表現量會增加且在肺癌形成的過程中扮演重要的角色。然而，OPN在肺癌中表現量增加的原因和參與的機制仍然不是十分清楚。本研究顯示於肺癌中芳香烴受體(aryl hydrocarbon receptor;AhR)對OPN表現量增加的現象扮演重要的角色。AhR在肺癌中已被證實表現量會增加，並且在肺癌形成的過程中扮演重要的角色。我們證實在肺癌的組織檢體裡，OPN表現量高時AhR的表現量也高，兩者呈現正相關的關係。並在細胞株中利用OPN-Luciferase promoter reporter assay來證明此正相關性。在證實兩者呈正相關後，我們試圖釐清AhR調控OPN的機制。利用 AhR-Luciferase reporter assay分析系統發現，OPN啟動子-268到+435區域為AhR在不需配體的狀態下或是AhR經由配體活化後調控OPN啟動子活性的位置。然而，此區域缺乏DRE或XRE (dioxin- or xenobiotics-responsive elements)。接著縮短或剔除OPN的啟動子區域-268到-100，發現此片段是AhR在不需配體的狀況下調控OPN啟動子的區域，此區包含許多個cis-elements，AP2、C/EBP、SP1和AP1的結合位置。此外，AhR經配體活化後調控OPN啟動子活性的區域有兩處，一個是+126到+435的區域，此區域包含了位於+137的NFkB結合位，另一個是在-100和+126之間。既然AhR在肺癌形成的過程中扮演重要的角色，我們推測AhR在無配體活化或經配體活化後，皆能由不同路徑增加 OPN 的表現量，進而促使肺癌的生成。

Osteopontin (OPN) up-regulates in human lung cancer and plays an important role in lung tumorigenesis. However, the mechanism that participates in up-regulation of OPN in lung cancer remains to be uncovered. This study showed that the expression of OPN and AhR proteins are positively correlated in lung cancer specimens. We identified an OPN promoter region between positions -268 and +435 that was activated by both ligand-independent and ligand-activated AhR in human lung cancer cell lines. 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 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. 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. Since AhR plays an important role in lung tumorigenesis, we speculate that both overexpressed un-induced AhR and ligand-activated AhR contribute to up-regulation of OPN that in turn leads to lung tumorigenesis.