Title

Annexin A2對於肺癌細胞生長及壓力刺激下的角色

Translated Titles

The Role of Annexin A2 on Lung Cancer Cell Growth and Stress Response

DOI

10.6844/NCKU.2012.02166

Authors

王琪芸

Key Words

ANXA2 ; 肺癌 ; 細胞週期 ; 細胞增生 ; 訊息傳遞 ; ANXA2 ; Lung cancer ; Cell cycle ; Proliferation ; Signal transduction

PublicationName

成功大學基礎醫學研究所學位論文

Volume or Term/Year and Month of Publication

2012年

Academic Degree Category

博士

Advisor

林秋烽

Content Language

英文

Chinese Abstract

ANXA2是一種鈣離子依賴性結合至細胞膜磷脂質的蛋白質,通常表現在細胞質中。當ANXA2和S100/A10形成複合體時則會表現在細胞膜表面。ANXA2參與在許多的細胞作用中,如細胞存活、生長、分裂及分化。缺乏ANXA2 表現會使細胞對於死亡刺激較為敏感。在許多種的癌症中,過度表現的ANXA2扮演促進腫瘤生成的角色,但是ANXA2在肺癌中的角色上不清楚。而且,關於本身ANXA2蛋白質表現調控及其對於細胞增生的調節作用並不清楚。本論文的第一部份將探討ANXA2在肺癌中的表現。將研究不同病程時期的臨床肺癌病人檢體中ANXA2蛋白質表現的程度差異,並將進一步探討ANXA2 在肺癌癌化機制上的可能作用以及對於肺癌病人預後的影響。研究結果發現,ANXA2會大量表現在肺癌上皮細胞上而且跟病人的預後有負相關。而且,在BALB/c裸鼠體內由A549所長成的腫瘤中,ANXA2 會持續表現在增生旺盛的腫瘤細胞膜周圍而非腫瘤中心的壞死的區域。本論文的第二部份將釐清ANXA2在肺癌細胞週期的進行及細胞增生機制上的可能作用。ANXA2在癌細胞增生扮演重要角色,然而ANXA2如何調控細胞週期機制尚不清楚。研究結果發現,當非小細胞肺癌細胞A549缺乏ANXA2並不會引起細胞毒殺死亡,但使活體內腫瘤生長及活體外細胞增生產生缺陷。降低ANXA2的表達會使細胞週期停滯於間期的G2 期。很意外地,降低ANXA2表達會使p53蛋白表達量增加,以及使p53下游基因表達隨之增加,並伴隨著p53相關的G2期停滯。在ANXA2缺乏的細胞中,JNK會去活化並伴隨著G2停滯以及細胞增生受到抑制。細胞內缺乏ANXA2會失去受JNK調控而穩定表現的c-Jun而使p53轉錄層級上的增加。這些結果證明一個ANXA2在肺癌細胞增生的新奇角色,ANXA2藉由維持JNK/c-Jun的訊號而抑制p53而促進細胞周期進行。本論文的第三部份將釐清ANXA2降解的調控機制及對肺癌細胞功能調節的可能影響。在此,我們證明了死亡刺激所誘導ANXA2裂解的可能的機制。研究證明,細胞內的ANXA2蛋白質會隨著死亡刺激時間增長而發生裂解。除了肺腺癌細胞,ANXA2蛋白裂解也發生在其他細胞中,包括類上皮細胞癌及子宮頸鱗狀上皮癌。在血清移除的模式下,Akt的活化被抑制接隨著GSK-3的活化,此過程中蛋白質去磷酸酶PP2A參與其中。我們發現 PP2A調節之GSK-3確實參與在ANXA2蛋白質裂解機制,但是如果只抑制PI3K/Akt的訊號卻不能造成ANXA2蛋白質裂解。這些結果顯示出PP2A的重要性。另外,我們發現serine 蛋白酶而非cathepsin可以造成ANXA2 蛋白質的裂解。進一步,我們發現PP2A和GSK-3 會透過調控Bax及Mcl-1在粒線體上的表現而導致ANXA2蛋白質的裂解。當粒線體膜完整性受破壞時,粒線體內的serine蛋白酶Omi/HtrA2就會被釋放到細胞質中因而導致ANXA2 的裂解。在生物功能方面,我們發現當抑制了GSK-3時,抗癌藥物cisplatin所引起的細胞死亡情形會被抑制。從這個計畫,我們發現在肺癌,ANXA2會過度表現。一旦降低ANXA2表現,會藉由調控JNK/c-Jun,導致p53所調節的G2期抑制。在壓力刺激之下,GSK-3及Omi/HtrA2協同性地造成ANXA2降解而使細胞走向死亡。

English Abstract

ANXA2, a calcium-dependent phospholipid binding protein, is widely expressed in cytoplasm and on the cell surface membrane while complexed with S100/A10. ANXA2 is involved in multiple cellular processes, including cell survival, growth, division, and differentiation. A lack of ANXA2 makes cells more sensitive to apoptotic stimuli. ANXA2 is overexpressed in many kinds of cancer and promotes tumorigenesis; however, the role of ANXA2 in lung cancer tumorigenesis has not been determined. This thesis is aimed at understanding the expression level of ANXA2 and the role of ANXA2 in lung tumorigenesis and further the regulatory mechanism of ANXA2 under stress. In the first part of this thesis, the expression of ANXA2 in patients with non-small cell lung cancer (NSCLC) was detected. Results show that ANXA2 is richly expressed in non-small cell lung cancer (NSCLC) and is positively correlated with poor prognosis. The survival time of patients with lower-ANXA2-expressed lung cancer is longer than whom with higher-ANXA2-expressed lung cancer. Moreover, ANXA2 is persistently expressed around the proliferative but not the necrotic region in BALB/c nude mice with human lung epithelial carcinoma A549 cell-derived tumor. In the second part of this thesis, the regulatory role of ANXA2 on cell cycle progression and cell proliferation was clarified. ANXA2 plays an important role in cancer cell proliferation, whereas the molecular mechanisms underlying the ANXA2-regulated cell cycle are still unknown. Results show that NSCLC A549 cells lacking ANXA2 exhibits defects in tumor growth in vivo and cell proliferation in vitro without cytotoxicity. ANXA2 knockdown induces cell cycle arrest at the G2 phase of interphase. Unexpectedly, ANXA2 silencing increases the expression of p53 and its downstream genes followed by a partial p53-mediated G2 arrest. Aberrant c-Jun N-terminal kinase (JNK) inactivation, which is observed in ANXA2 deficient cells, causes cell proliferation inhibition following G2 arrest. A lack of ANXA2 causes a loss of JNK-regulated c-Jun expression followed by a p53 transcriptional increase. These results demonstrate a novel role of ANXA2 in NSCLC cell proliferation by facilitating the cell cycle through the maintenance of JNK/c-Jun-inhibited p53. Further, the regulation of ANXA2 expression is still unclear. In the final part of this thesis, the regulation of ANXA2 expression was clarified under apoptotic stimuli. Here, we demonstrate a potential mechanism for apoptotic stimuli-induced ANXA2 cleavage. Results show that, under apoptotic stimuli, ANXA2 is cleaved via a time-dependent manner. Mechanistic studies have shown that protein phosphatase 2A (PP2A)-activated GSK-3 is essential for this process. Therefore, inhibiting GSK-3 reverses serum withdrawal-induced cell cycle inhibition or cisplatin-induced apoptosis. Furthermore, inhibiting serine proteases blocks apoptotic stimuli-induced ANXA2 cleavage. Bax activation and Mcl-1 destabilization, which is regulated by PP2A and GSK-3, causes ANXA2 cleavage via an Omi/HtrA2-dependent pathway. These results demonstrate that GSK-3 and Omi/HtrA2 synergistically cause ANXA2 cleavage and then cell cycle inhibition or apoptosis. Taken together, ANXA2 is overexpressed in lung cancer and loss of ANXA2 mediates p53 suppression of G2/M progression by targeting JNK/c-Jun. Under stress, GSK-3 and Omi/HtrA2 synergistically cause ANXA2 downregulation following cell apoptosis.

Topic Category 醫藥衛生 > 基礎醫學
醫學院 > 基礎醫學研究所
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