VHL基因突變在癌前期的組織發炎機制;The Mechanism of VHL Mutant-induced Precancerous Tissue Inflammation

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Title:	VHL基因突變在癌前期的組織發炎機制;The Mechanism of VHL Mutant-induced Precancerous Tissue Inflammation
Authors:	方韋程;Fang,Wei-Cheng
Contributors:	系統生物與生物資訊研究所
Keywords:	透明細胞腎細胞癌;癌前期組織發炎;發炎;內質網壓力;腎臟癌
Date:	2016-08-31
Issue Date:	2016-10-13 13:25:18 (UTC+8)
Publisher:	國立中央大學
Abstract:	VHL是一個抑癌基因，當此基因突變會造成透明細胞腎細胞癌。在VHL剔除的老鼠模式中，我們發現VHL的突變會在腎小管造成發炎跟纖維化的現象。因此，我們希望釐清發炎跟癌症之間的關聯性。VHL的突變會穩定HIF蛋白質，而使得過氧化物的產生以及蛋白大量合成，最終導致內質網壓力。UPR是為了適應與調適內質網壓力所產生的機制。在我們的數據中，我們發現人類腎小管上皮细胞中IRE1α路徑的下游蛋白質XBP1隨VHL的表現降低而提高，這個結果得知VHL突變會引起內質網壓力。另外也發現內質網壓力的增加會導致發炎相關的蛋白質在VHL突變的腎細胞中提高，如p-JNK和核中NF-κB 亞基p65。內質網壓力會活化IRE1α路徑造成JNK的活化，因此我們利用IRE1α抑制劑APY29，來分析p-JNK表現跟NF-κB/p65的移位，藉此釐清VHL突變調控IRE1α路徑的分子機制。結果顯示使用APY29可以有效在VHL突變的細胞中降低p-JNK表現跟NF-κB/p65的移位。最後我們推測，VHL突變會透過內質網壓力造成慢性發炎最後導致透明細胞腎細胞癌。;Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) lead to clear-cell renal cell carcinoma (ccRCC). We found that VHL mutation in kidney tubules caused tissue inflammation and fibrosis in VHL knockout mouse model. We wanted to figure out the causal relationship between inflammation and cancer. VHL mutation stabilizes hypoxia inducible factor (HIF) which leads to reactive oxygen species (ROS) production and excessive protein synthesis then causing endoplasmic reticulum (ER) stress. ER stress initiates a series of adaptive mechanisms that together are known as the unfolded protein response (UPR). Our results showed that the level of XBP1, downstream of IRE1α, was increased in VHL knockdown HK-2 cells. It proved that VHL mutation caused ER stress. ER stress was also increased in VHL mutant kidney cells, and that inflammation-related proteins such as p-JNK and nuclearly-localized NF-κB subunit p65 were also increased. To further investigate the molecular mechanisms of VHL mutation-mediated IRE1α pathways, we used APY29, an inhibitor of IRE1α autophosphorylation, to analyze the p-JNK expression and NF-κB/p65 translocation. Results showed that APY29 reversed p-JNK expression and NF-κB/p65 translocation to nucleus in VHL mutant cells. In summary, we suggest that VHL mutation causes chronic inflammation via ER stress in the development of ccRCC.
Appears in Collections:	[Institute of Systems Biology and Bioinformatics] Electronic Thesis & Dissertation

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