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http://hdl.handle.net/11375/26129
Title: | The examination of OIP5 expression in renal cell carcinoma(RCC) and during RCC progression |
Authors: | Chow, Mathilda |
Advisor: | Tang, Damu |
Department: | Medical Sciences |
Publication Date: | 2020 |
Abstract: | Renal Cell Carcinoma (RCC) is the most lethal kidney cancer and accounts for approximate 2%-3% adult malignant neoplasm. The current risk assessment on which treatment decisions are formulated largely relies on clinical criteria. Improvement in predicting prognosis requires the use of molecular events or biomarkers. OIP5 (Mis18β) is accumulated in telophase-G1 centromere and plays a critical role in centromere formation. Mis18β forms Mis18 heterotetramer with Mis18α and the complex is involved in the deposition of new centromeric protein A (CENP-A) nucleosomes, which is essential for centromere/kinetochore structure and functions. In normal individual, OIP5 is intensively expressed in testis, while recent studies have demonstrated that OIP5 promotes the initiation and progression of several cancers. However, its function in RCC remains unclear. This thesis thus aims to examine the hypothesis that OIP5 plays in RCC pathogenesis. In vitro studies demonstrated that overexpression of OIP5 promoted cell growth, proliferation, and invasion in ACHN pRCC cells. In comparison to ACHN cells stably expressing an empty vector (EV), ACHN OIP5 cells produced xenografts with a significantly enhanced ability with concurrent upregulation of PLK1 and other factors that are likely contribute to cell cycle progression. PLK1 plays important roles in promoting M phase progression, which is in accordance with an important role of OIP5 in centromere formation. Importantly, the PLK1 inhibitor BI2536 led to significantly more cells arrested in M phase compared to OIP5 EV cells, implying a reliance of PLK1 function to drive ACHN OIP5 cells progression through M phase. This property suggests an appealing scenario to treat pRCCs with OIP5 upregulation. Intriguingly, this possibility is supported by our clinical investigation. In our analysis of OIP5 expression in primary RCC (n=57), OIP5 upregulation was found in both ccRCC and pRCC tumors compared to their adjacent non-tumor tissues. The upregulation is associated with ccRCC and pRCC progression as well as prognosis. Both ccRCC and pRCC tumors with elevated OIP5 expression are correlated with poor overall survival compared to those without the upregulation. Collectively, this thesis reveals a novel and important contribution of OIP5 in RCC, particularly pRCC; targeting PLK1 might be an option in treating pRCCs expressing high levels of OIP5. |
URI: | http://hdl.handle.net/11375/26129 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Mathilda_Chow_Thesis_Revised.pdf | 2.31 MB | Adobe PDF | View/Open |
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