白血病抑制因子活化蛋白酶激活受體1進而促進鼻咽癌細胞的遷移

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蔡承翰(Cheng-Han Cai) 查詢紙本館藏

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系統生物與生物資訊研究所

論文名稱

白血病抑制因子活化蛋白酶激活受體1進而促進鼻咽癌細胞的遷移
(Leukemia inhibitory factor activates protease activated receptor 1 to promote NPC cell migration)

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至系統瀏覽論文 (2027-8-1以後開放)

摘要(中)

白血病抑制因子(LIF)和凝血酶受體(PAR1)與鼻咽癌的惡化有關。已經有文獻報導
LIF、 PAR1這兩者的過表現會促使鼻咽癌癌細胞的生長、侵犯以及轉移，鼻咽癌病人血
清與腫瘤組織中LIF的高表現量與較差的預後有關。由次世代定序的分析結果顯示LIF影
響PAR1訊息傳導路徑。本研究目的是要瞭解這LIF與PAR1相互關係以及對細胞功能上
的影響。在此研究中，我們發現LIF透過LIFR去活化PAR1與其下游訊號分子，包含mTOR、
SRC、 p70S6k以及活化型YAP1的表現量，而LIF的刺激促使鼻咽癌細胞型態上轉化成梭
狀細長型且細胞爬行能力增強。利用PAR1抑制劑Vorapaxar抑制受LIF刺激而活化的
PAR1及YAP1訊息傳導路徑，而其導致的生物效應包含細胞的萎縮及細胞爬行能力低落，
證明了PAR1會參與LIF對YAP1刺激的訊息傳遞。
綜合以上結果，本研究闡明在鼻咽癌腫瘤細胞中LIF透過刺激PAR1進而促進細胞移
動的能力並影響YAP1訊息傳導，說明LIF除了透過LIFR影響下游分子外，亦會透過PAR1
執行複雜生物效應，進一步瞭解LIF於鼻咽癌的惡性化的分子機轉與對鼻咽癌細胞功能
的影響。

摘要(英)

Leukemia inhibitory factor (LIF) and Protease activated receptor 1 (PAR1) are associated
with nasopharyngeal carcinoma (NPC) progression. It has been reported that overexpression of
LIF and PAR1 can enhance NPC tumor growth, invasion, and metastasis. Further, higher levels
of LIF in the serum and tumor tissues of NPC patients are correlated with poorer prognosis.
Our previous next-generation sequencing (NGS) data revealed that LIF induced expressions of
a gene set involved in PAR1 signaling pathway. The main purpose of this study is to investigate
the regulatory network between LIF and PAR1. We found that LIF stimulation activated PAR1
and its downstream signaling molecules, including mTOR, SRC, p70S6K, and YAP1 through
LIF receptor (LIFR). Functionally, LIF stimulation in NPC cells induced a spindle-like
appearance and an enhanced cell mobility. Usage of a PAR1 antagonist, Vorapaxar, suppressed
LIF-mediated effects on the activation of PAR1 and YAP1 signaling pathways, resulting in cell
shrinkage and reduced cell mobility. These data showed that PAR1 plays a role in LIF-mediated
biological effects in NPC.
Together, this study reveals that LIF activates PAR1 signaling through LIFR and further
clarifies the LIF-mediated regulatory network in NPC progression.

關鍵字(中)

★ 白血病抑制因子
★ 蛋白酶激活受體 1
★ 鼻咽癌

關鍵字(英)

★ Leukemia inhibitory factor
★ protease activated receptor 1
★ NPC
★ LIF
★ PAR1

論文目次

目錄
頁次
中文摘要 i
英文摘要 ii
誌謝 iii
目錄 iv
圖目錄 v
符號說明 vi
一、 Introduction 1
1-1 Nasopharyngeal Carcinoma Cell (NPC) 1
1-2 Leukemia Inhibitory Factor (LIF) 2
1-2-1 Role of LIF in NPC 3
1-3 Protease Activated Receptor 1 (PAR1) 3
1-3-1 Relationship of PAR1 in NPC 4
1-3-2 PAR1 antagonist – Vorapaxar (SCH 530348) 5
1-4 Yes-associated-protein 1 (YAP1) 5
1-4-1 Role of YAP1 in NPC 6
二、 Method 7
2-1 Cell culture 7
2-2 xCELLigence Real Time Cell Analyzer (RTCA) 7
2-3 Protein lysis and Western blot 8
2-4 Immunofluorescence 9
2-5 Transfection 10
2-6 Wound healing assay 10
2-7 Reagent 10
2-8 Statistic 10
三、Results 11
3-1 PAR1 and LIF are positively correlated in head and neck squamous cell carcinoma (HNSC)dataset. 11
3-2 Stimulation enhances activation of PAR1 and its downstream signaling molecules through LIFR in NPC cell 11
3-3 The binding of LIF to LIFR enhances activation of PAR1 signaling in NPC cells. 11
3-4 Vorapaxar inhibits LIF signaling through PAR1 11
3-5LIF promotes YAP activation and YAP nuclear translocation via PAR1 12
3-6Vorapaxar decreases the effect of LIF on cell migration 13

四、 Discussions 14
五、 Figures 17
參考文獻 33

參考文獻

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指導教授

劉淑貞(Shu-Chen Liu)

審核日期

2022-7-25

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