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    請使用永久網址來引用或連結此文件: http://libir.tmu.edu.tw/handle/987654321/58550


    題名: PSMD3 (Proteasome Subunit Non-ATPase 3) Regulates Breast Cancer Tumorgenesis Through Stabilizing HER2 from Degradation
    作者: ABDULFATTAH SALAH ABDULFATTAH FARARJEH
    貢獻者: 癌症生物學與藥物研發博士學位學程
    何元順
    黃雯華
    關鍵詞: PSMD3;Breast cancer;HER2;Overall survival
    日期: 2018-12-28
    上傳時間: 2020-02-03 12:51:24 (UTC+8)
    摘要: Human epidermal growth factor receptor 2 (HER2) plays a central role in the pathogenesis of several human cancers including breast cancer (BC). It has a critical role in regulation of BC development and progression in-vitro and in-vivo. Several studies have revealed the role of proteasome system and its subunits in cancer. We examined in this study the PSMD3 mRNA and protein levels in BC using a panel of BC cell lines, human tissue samples from Taiwanese BC patients, and using TCGA and Oncomine databases. Immunohistochemistry (IHC) staining was used to detect PSMD3 immunostaining on Formalin fixed paraffin embedded (FFPE) and tissues microarray (TMA) sections from BC patients, Total (n=69). Furthermore, we investigated the functional role of PSMD3 in HER2 positive BC cell lines. We demonstrated that PSMD3 was upregulated in BC tissues (Group 2; tumor (T) > normal (N), n=153/176 (87%)) particularly, in HER2 positive human tumor tissues, HER2 positive cell lines and HER2 positive patients from TCGA and Oncomine databases. PSMD3 immunostaining was detected in cytoplasm and nuclear of BC tissue sections with high PSMD3 H-score (Histoscore) in tumor part (24/69, 35%). We detected a strong interaction between PSMD3 and HER2 at protein level by immunoprecipitation (IP) and Fluorescence Resonance Energy Transfer (FRET) assays. Loss of PSMD3 function by using two siRNAs significantly impaired the stability of HER2 and decreased the total amount of HER2 (185KD). Loss of PSMD3 function inhibited BC cells proliferation, colonies formation and induced cell apoptosis. Ubiquitination process was more intensely enhanced after silencing of PSMD3 with association with decrease HER2 protein level in BT474 and HCC-1419. Localizing of LAMP-1 with HER2 on cell membrane with association with decrease Immunofluorscent (IF) staining for HER2 after knockdown of PSMD3 in SKBR3 and BT474, normal IF staining for HER2 and LAMP-1 in the control groups. According to TCGA database, high PSMD3 expression associated with HER2 positive (p<0.001), tumor size (p<0.001) and clinical stage (p=0.036). Kaplan Meier survival database showed that high PSMD3 expression predict a worse Overall survival (OS), Relapse free survival (RFS) and Progression free survival (PFS) predominantly, for HER2 positive BC patients. In conclusion, we provide a novel finding for the role of PSMD3 in stabilizing HER2 from degradation and high PSMD3 expression predicts a worse clinical outcome for HER2 positive BC patients.
    描述: 博士
    指導教授：何元順
    共同指導教授：黃雯華
    委員：潘敏雄
    委員：王應然
    委員：楊沂淵
    資料類型: thesis
    顯示於類別:[癌症生物學與藥物研發博士學位學程] 博碩士論文

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