| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 102 === Lung cancer is the most common malignant tumors in the world. The high mortality rate in patients with lung cancer is due to cancer metastasis and therapeutic resistance. Many evidences indicate that cancer metastasis and therapeutic resistance are mediated by cancer stem-like cells (CSCs), a small population of cancer cells, which may require for cancer initiation and development. Targeting CSCs may provide effective therapy for human cancers. α-Catulin is an oncoprotein that helps sustain proliferation by preventing cellular senescence. Recent studies have shown that the expression level of α-catulin is positive correlated with epithelial-mesenchymal transition. Increasing evidence suggests that CSCs can be enriched when cancer cells undergo EMT. We also found that several lung cancer stemness genes were upregulated in α-catulin-overexpressing cells. Therefore, the expression of α-catulin may correlate with CSC formation. Here, we found that α-catulin interacted with ILK and KLF5 separately. ILK is a serine/threonine protein kinase and mediates the signaling functions in cell proliferation, anti-apoptosis, migration/invasion and angiogenesis. We found that overexpression of α-catulin promoted lung cancer metastasis through NFB-ILK dependent pathway and increased expression of integrin αVβ3 and fibronectin. On the other hand, KLF5 is a member of the Kruppel-like transcription factor family and has been shown to play important role in maintenance of stem cell self-renewnal. We found that α-catulin enhanced CSC formation through antagonizes the E3 ubiquitin ligase WWP1 mediated KLF5 degradation and activated KLF5 downstream genes Oct4 and Nanog expression. Attenuation of KLF5 or α-catulin reciprocally decreased CSC proterties induced by the other protein. Taken together, our study shows that α-catulin plays a critical role in lung cancer metastasis and CSC formation by activating ILK and KLF5 signaling axes. Targeting α-catulin may be an effective therapy for lung cancer.
|
|---|
