白血病抑制因子促進Gα12介導的鼻咽癌細胞遷移能力;Leukemia inhibitory factor promotes Gα12-mediated migration ability of NPC cells

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Title:	白血病抑制因子促進Gα12介導的鼻咽癌細胞遷移能力;Leukemia inhibitory factor promotes Gα12-mediated migration ability of NPC cells
Authors:	邵瑋如;Shao, Wei-Ru
Contributors:	系統生物與生物資訊研究所
Keywords:	鼻咽癌;白血病抑制因子;G蛋白偶聯受體;細胞遷移;Nasopharyngeal carcinoma;LIF;GPCR;cell migration
Date:	2022-09-20
Issue Date:	2022-10-04 11:16:14 (UTC+8)
Publisher:	國立中央大學
Abstract:	鼻咽癌是一種具有高度轉移性及侵襲性的頭頸部惡性腫瘤，與其他頭頸癌相比其遠處轉移的發生率最高，是影響鼻咽癌病人預後的關鍵因素。G蛋白偶聯受體(GPCR)的信號增強與多種癌症類型的腫瘤進展有關，Gα12活化small GTPase及其下游信號傳導，調控細胞骨架重組及血管新生促使癌細胞轉移。此外，在實驗室過去的研究中發現白血病抑制因子(LIF)會與鼻咽癌中較高的腫瘤復發率相關，並通過多種機制影響癌細胞遷移，然而Gα12與LIF之間的交互作用仍有待探討。在本研究結果顯示，過表達Gα12會造成鼻咽癌細胞轉化成細長的型態及細胞骨架聚集於細胞偽足的前端，進而促進細胞遷移，此外，qPCR的分析亦顯示Gα12會增加SNAI2表現量，免疫螢光染色結果也觀察到Gα12促使YAP1蛋白入核的表達量增加。LIF的刺激會活化鼻咽癌細胞STAT3，ERK1/2 與 mTOR訊息傳導路徑，而STAT3與 ERK1/2的活化在過表達Gα12的細胞組別中其表現量降低，但Gα12促使mTOR的活化型表達量增加。此外，LIF刺激亦會活化蛋白酶激活受體-1 (PAR1)及其下游信號因子的表達量，而此現象在過表達Gα12的細胞組別中受抑制，使用siRNA 降低 Gα12的表達量則會抑制鼻咽癌細胞的遷移及生長能力，而在LIF的刺激下細胞的生長能力有明顯的提升。綜合以上結果顯示，鼻咽癌細胞Gα12高表達對細胞遷移能力有所提升，在與LIF共同的下游信號途徑STAT3、ERK1/2、mTOR有相互影響的作用，並提高了Gα12介導的細胞遷移能力。;Nasopharyngeal carcinoma (NPC) is a highly metastatic and aggressive head and neck malignancy. NPC exhibits a highest rate of distant metastasis compared with other types of head and neck cancer. Metastasis is the most important prognostic factor associated with treatment failure in NPC patients. G protein-coupled receptors (GPCR) have been implicated in tumor progression in multiple types of cancer. The activation of Gα12 protein by GPCR triggers small GTPase and its downstream signaling that regulates cytoskeletal reorganization and angiogenesis to promote cancer cell migration ability. Previous studies reveal that higher level of leukemia inhibitor factor (LIF) in NPC tumors is correlated with local recurrence and distal metastasis through multiple mechanisms, however, the interplays between Gα12 and LIF remains largely unexplored. The main purpose of this study is to investigate the interacting network between LIF and Gα12 signaling. We found that overexpression of Gα12 could cause morphological changes and cytoskeleton redistribution in NPC cells, thereby promoting cell mobility. In addition, exogenous expression of Gα12 increased the mRNA expression of SNAI2. Results of immunofluorescence staining demonstrated that Gα12 enhanced nuclear translocation of YAP1 protein in NPC cells. Mechanistically, LIF stimulation activated multiple signaling, including STAT3 (Y705), ERK1/2(T202,Y204) and mTOR(S2448) signaling pathways in NPC cells. Overexpression of Gα12 decreased LIF-mediated activation of STAT3 and ERK1/2, but not mTOR. Further, LIF stimulation induced cleavage of protease-activated receptor-1 (PAR1) and increased expression of its downstream signaling molecules, including mTOR and ERK1/2. Depletion of Gα12 with siRNA inhibited NPC migration and growth ability, which were reversed by LIF stimulation. Collectively, these data demonstrate that PAR1-Gα12 axis plays a significant role in LIF-mediated NPC migration ability through activation of STAT3, ERK1/2 and mTOR signaling pathways.
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