研究部公告：12月10日(周四)下午12：30-13：30於3樓和氣會議室舉辦「109年12月研究發想會」，由共同實驗室 郭展延博士 主講「研究在腎臟透明細胞癌化的過程中VHL抑癌基因突變 透過LCN2-ROS訊息傳遞路徑對於發炎反應的影響」，歡迎有興趣同仁前往參加。
主題摘要：Objective: Kidney disease and cancer are serious health problems in Taiwan. Accumulating evidence has demonstrated that cancer is a systemic disease and that tissue inflammation is an early promoter of cancer formation. Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) are a major cause of clear-cell renal cell carcinoma (ccRCC) that may result from chronic inflammation-induced reactive oxygen species (ROS) overproduction. However, due to the complex cellular functions of VHL, this speculation has not been confirmed.
Materials and Methods: To further study the role of VHL in ccRCC formation, we developed a novel conditional knockout mouse model that recapitulates features of kidney inflammation and fibrosis (kidney disease), leading to cyst formation and metastatic kidney cancer. Additionally, we also used VHL mutant HK-2 and mouse primary renal tubule cells (mRTCs) as cell models to speculate the effects and underlying molecular mechanisms of ROS accumulation. We also study the role of Lipocalin 2 (LCN2) in regulation of recruitment of macrophages in VHL mutant HK-2 cells.
Results: To elucidate the effect of vhl on ROS production in a LCN2-dependent manner, we detected the level of ROS in vhl mutant HK-2 cells in presence or absence of LCN2. Results showed that vhl mutation caused ROS overproduction in HK-2 cells, and that of reversed in LCN2 knockdown. On the other hand, data demonstrated that VHL mediated the expression and secretion of LCN2 in vitro and in vivo. Therefore, we proposed that vhl mutant induced ROS production via LCN2-dependent manner. Our findings also suggested that LCN2 sensitizes inflammation of HK-2 cells and chemotaxis abilities of macrophage cells, RAW 264.7.
Conclusions: In this study, we aimed to elucidate the regulatory effect of VHL on chronic inflammation in the progress of ccRCCC via LCN2-ROS pathway, and our results offer novel insights into the therapeutic target and strategy to attenuate the development of ccRCC.