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    Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/82797


    Title: ITPR2, an ER calcium channel, regulates ER stress and inflammatory response in pre-cancerous kidney tubule cells
    Authors: 黎怀北;Le, Hoai-Bac
    Contributors: 系統生物與生物資訊研究所
    Keywords: ITPR2;ccRCC;inflammation;ER stress;ITPR2;ccRCC;inflammation;ER stress
    Date: 2020-01-20
    Issue Date: 2020-06-05 17:13:18 (UTC+8)
    Publisher: 國立中央大學
    Abstract: 腎細胞癌 (Renal cell carcinoma, RCC) 是全球16大致死癌症之一。儘管腎細胞的診斷和偵測日益增強, RCC 仍是最致命的泌尿癌症之一。透明腎細胞癌 (Clear cell renal cell carcinoma, ccRCC)在所有RCC亞型中引起死亡人数最多。此外,超過 70% 的 ccRCC病人跟腫瘤抑制基因-VHL 的基因組或表觀基因的突變有關。在我們先前的研究中發現內質網 (Endoplasmic reticulum, ER)應激透過 IRE1α傳導訊號引起的發炎反應是透明細胞癌的發展中扮演重要調控因素之一。更有趣的是, DeLiSi研究團隊在2007年發現,與鄰近正常腎臟組織作相比,第二類別肌醇1,4,5-三磷酸受體 (Inositol 1,4,5-trisphosphate receptor, type 2, ITPR-2) 在RCC中有下調的表現。另一方面, 獨立全基因組關聯研究和其他最近的研究指出位於染色體12p11.23的 ITPR-2在ccRCC是一個敏感的位點,尤其12p區域是在VHL相關的 RCC病人中被發現會被放大。這些研究結果說明ITPR-2會透某一種機制在ccRCC的不同階段中會有不同的影響。因此我們提出一個假說,改變ITPR-2、內質網的膜蛋白,同時也是細胞內鈣釋放通道的第二傳到訊號、可以影響到內質網應激的反應,並且改變發炎反應及ccRCC的發展。在這份研究中,我們在近端腎小管上皮細胞 (HK-2) 有或沒有抑制VHL 表現細胞株中進行抑制 ITPR-2表現,然後利用鈣離子流動以監測 ITPR-2活性來研究 ITPR-2 在內質網應激和發炎中的功能。我們的結果表明抑制 ITPR-2的表現可以降低內質網應激的負擔及內質網應激引起的發炎反應。另外在巨噬細胞的外滲試驗(Extravasation assay)中,與單獨抑制VHL表現量對比,同時抑制ITPR-2和VHL表現量會降低巨噬細胞募集。綜合起來,這份研究在ccRCC發展提供新一中幾轉和潛在的新目標治療。;Renal cell carcinoma (RCC) is the 16th most common cause of cancer death worldwide. Although the diagnosis and observation for RCC has been improved, RCC still remains one of the most lethal urologic cancers. Among several subtypes of RCC, clear cell renal cell carcinoma (ccRCC) accounts for the most cancer-related deaths. Moreover, more than 70% of the ccRCC cases contain genomic and epigenetic defects in the VHL tumor suppressor gene. In the previous study, we reported that endoplasmic reticulum (ER) stress is one of the key regulators of VHL mutant ccRCC progression by inducing inflammatory responses via IRE1α signaling. Interestingly, DeLisi and his colleagues in 2007 revealed that inositol 1,4,5-triphosphate receptor type 2 (ITPR2) was declined in RCC tumors compared with normal kidney tissues. Nevertheless, results from independent genome-wide association study in 2011 and other recent studies pinpointed that the region 12p11.23, which contains ITPR2 gene is a susceptibility locus for ccRCC. Specifically, the 12p region was amplified among 14 regions of nonrandom copy-number change in VHL-related RCC. These outcomes indicate that ITPR2 somehow affects the ccRCC progression with various influences in different stages. That leads us to the hypothesis that the alteration of ITPR2—an ER membrane protein and a second messenger intracellular calcium release channel—could impact on the ER stress response, which in turn influences inflammation and ccRCC development. Here, we generated ITPR2 knockdown in proximal tubule epithelial cell line (HK-2) with or without VHL knockdown and used calcium flow as the reporter for ITPR2 activation to investigate the role of this gene in ER stress and inflammation. Our results showed that loss of ITPR2 expression reduces the ER stress burden and ER stress-induced inflammation. Besides, we also found that double knockdown ITPR2 and VHL in HK-2 diminishes macrophages recruitment compared with VHL single knockdown HK-2 in in vitro extravasation assay. Taken together, these findings provide the new mechanism of ccRCC development and identify a potential new target therapy for ccRCC or kidney cancer in general.
    Appears in Collections:[系統生物與生物資訊研究所] 博碩士論文

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