ITPR2, an ER calcium channel, regulates ER stress and inflammatory response in pre-cancerous kidney tubule cells

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黎怀北(Hoai-Bac Le) 查詢紙本館藏

畢業系所

系統生物與生物資訊研究所

論文名稱

(ITPR2, an ER calcium channel, regulates ER stress and inflammatory response in pre-cancerous kidney tubule cells)

相關論文

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★ VHL剔除模型之轉錄體差異以及台灣透明細胞腎細胞癌族群之特定基因體變異之研究	★ VHL knockdown HK-2 cells induce macrophage endothelial extravasation
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★ 應用大腸桿菌與酵母菌蛋白質體晶片系統性分析抗菌肽及抗生素作用之目標蛋白質	★ Analysis of Gene Expression of Chronic Obstructive Pulmonary Disease and Chronic Kidney Disease to Illuminate Chronic Inflammation Associated with Tumor Microenvironment and Potential Treatment

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摘要(中)

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。

摘要(英)

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.

關鍵字(中)

★ ITPR2
★ ccRCC
★ inflammation
★ ER stress

關鍵字(英)

★ ITPR2
★ ccRCC
★ inflammation
★ ER stress

論文目次

摘要 i
Abstract ii
Acknowledgement iii
List of contents iv
List of figures vi
List of tables vii
CHAPTER 1: INTRODUCTION 1
1-1. Renal cell carcinoma (RCC) 1
1-2. ccRCC and VHL deficiency. 1
1-3. Endoplasmic reticulum stress (ER stress) drives RCC 3
1-3-1. Endoplasmic reticulum stress (ER stress) 3
1-3-2. Ca2+ in ER Stress 4
1-3-3. ER stress and kidney disease 5
1-3-4. IRE1α-XBP1 signaling promotes inflammation and tumorigenesis 6
1-4. ITPR2 expression in RCC 9
1-4-1. ITPR2 overview 9
1-4-2. ITPR2 expression level in RCC 10
1-4-3. ITPR2’s role in ER stress 11
CHAPTER 2: MATERIAL AND METHOD 13
2-1. Cell culture 13
2-2. Vectors and gene transfer. 13
2-3. Double knockdown ITPR2 and VHL stable cell line generation 15
2-3-1. Construct shITPR2 plasmid with TRC vector containing Blasticidin resistant gene 15
2-3-2. Transfect shITPR2 plasmid into VHL loss-of-function stable cell line 15
2-4. Reverse transcription and real-time quantitative Polymerase chain reaction (qPCR. 15
2-5. Western blot analysis 16
2-6. Intracellular calcium measurement. 17
2-6-1. Staining cells 17
2-6-2. Measure calcium flux by flow cytometry 18
2-7. Macrophage recruitment assay 18
2-7-1. Co-culture by transwell system 18
2-7-2. Crystal violet staining 18
2-8. Paraffin immunohistochemistry and histological staining 20
2-9. Statistical Analysis 20
CHAPTER 3: RESULTS 21
3-1. Single knockdown ITPR2 and double knockdown VHL and ITPR2 HK-2 were established as experiments material 21
3-2. VHL deletion increases ITPR2 expression 23
3-3. Knockdown ITPR2 rescues ER stress 25
3-4. Measurement of intracellular Ca2+ concentration as an ITPR2 activation reporter 29
3-5. Lack of ITPR2 reduces inflammation via p-IRE1α-regulated cytokines production 31
3-6. ITPR2 ablation reduces macrophage recruitment 34
CHAPTER 4: DISCUSSION AND CONCLUSION 37
Reference 44

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指導教授

徐沺(Tien Hsu)

審核日期

2020-1-20

推文