Gas6/Axl途徑在肝細胞癌中經由Slug調控腫瘤侵犯

Abstract

肝細胞癌（HCC）是台灣最普遍的致命癌症之一，截至目前為止除了蕾莎瓦（Sorafenib）以外，尚未找到其他有效的治療方法。而在癌症的標靶治療中，最常見的就是針對受器酪胺酸激脢（RTK）的抑制，因此，在肝細胞癌的受器酪胺酸激脢中找出標靶治療的新標的就顯得更為重要了。經由受器酪胺酸激脢陣列試驗（RTK array），我們發現Axl在肝癌細胞中是常被活化的受器酪胺酸激脢之一，而在之前的報導都提到過在許多的癌症中Axl的活化會增加腫瘤侵犯能力，然而其中的機制尚未完全被瞭解。在本篇實驗中，Axl的基因敲減會抑制肝細胞癌細胞侵犯能力，而給予Axl的配體Gas6會提高細胞的侵犯能力。此外，我們發現促進上皮間質轉化的轉錄因子Slug，會被Gas6/Axl誘導表現，Gas6會活化PI3K/Akt 和 MAPK路徑。在肝細胞癌細胞株中給予MAPK 路徑的抑制劑PD98059會抑制Gas6引起的Slug的表現，Axl的抑制物Bosutinib會抑制肝細胞癌細胞株的侵犯能力，這證實了Gas6/Axl是經由MAPK 路徑增加Slug轉錄來調控癌細胞侵犯能力。

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers in Taiwan. Until now, no effective systemic therapy is available, except for the sorafenib treatment. Most targets of molecularly targeted therapy for cancer are receptor tyrosine kinases (RTKs). Therefore, identification of activated RTKs in cancer is of ultimate importance in identifying new targets for molecularly targeted therapy. Using RTK array, we found that Axl is one of the most frequently activated RTKs in liver cancer cell lines. Activation of Axl has been reported to enhance tumor invasion in several types of human cancer; however, the mechanism is still unknown. The results in this study showed that knockdown of Axl by RNA interference significantly reduced cell invasion in HCC cell lines HA22T and Mahlavu. On the other hand, treating cells with Axl ligand Gas6 enhanced tumor invasion. We identified epithelial-mesenchymal transition (EMT)-inducing transcription factor Slug as one of the targets of Gas6/Axl pathway. PI3K/Akt pathway and MAPK pathway were activated by Gas6 treatment. Treating HCC cell line HA22T with the MAPK pathway inhibitor PD98059 suppressed the induction of Slug by Gas6. Axl inhibitor Bosutinib decreased the invasiveness of HCC cell lines. These results suggest that Gas6/Axl regulates tumor invasion via transcriptional activation of Slug by MAPK pathway.