第二型轉麩胺酶對肺癌細胞存活和侵入的影響

Effect of transglutaminase 2 on survival and invasion of lung cancer cells

陳宛君(Wuan-Chun Chen)

指導教授 ： 李宜儒

中山醫學大學/醫學院/微生物免疫研究所/碩士(2012年)

摘要

肺癌是全世界因癌症而死亡的首要因素。基於造成癌症病患死亡之主因為癌細胞轉移，我們希望能進一步了解肺癌轉移之機制。第二型轉麩胺酶（transglutaminase 2）為轉麩胺酶家族中的一員，廣泛分佈於各組織。它在細胞中主要是位於細胞質，但亦存在於細胞核、細胞膜、細胞表面，且可以分泌到細胞外。第二型轉麩胺酶是一個多功能的蛋白，具有多重酵素活性，像是最為熟知的轉麩胺酶活性以及GTP水解酶（GTPase）、蛋白質激酶（protein kinase）和雙硫鍵異構酶（protein disulphide isomerase）活性。不僅於此，第二型轉麩胺酶還可與integrin作用進而促進細胞對fibronectin的黏附。近來的文獻更進一步指出第二型轉麩胺酶與乳癌細胞的抗藥性以及轉移有關。在此，我們探討第二型轉麩胺酶在肺癌細胞轉移中所扮演的角色。我們發現高侵入性的肺癌細胞株CL1-5比其同源低侵入性的肺癌細胞株CL1-0表現更高量的第二型轉麩胺酶。此外，CL1-5也較能抵抗脫離基質所誘發的細胞凋亡，又稱為失巢凋亡，以及化療藥物doxorubicin所引發的死亡。在CL1-0表現野生型的第二型轉麩胺酶可以提高細胞移動和侵入的能力，但卻不影響對失巢凋亡及doxorubicin的抗性。另外，我們發現細胞內的第二型轉麩胺酶表現量愈高其胞外含量也愈高；而外加重組第二型轉麩胺酶於CL1-0時能有效地增進細胞的移動和侵入。總結而言，第二型轉麩胺酶能促進細胞的移動和侵入，所以它在肺癌轉移過程中應扮演一重要的角色。

關鍵字

肺癌 ； 第二型轉麩胺酶

並列摘要

Lung cancer is the leading cause of cancer death worldwide. Given that the major threat of cancer to life is distant metastasis, we aimed to delineate the molecular mechanism underlying lung cancer metastasis. Transglutaminase 2 (TG2), belonging to the transglutaminase superfamily, is ubiquitously expressed. It localizes mainly in the cytosol, but also appears in the nucleus, plasma membrane, cell surface and extracellular space. TG2 possesses multiple enzymatic activities, including the most well-known transglutaminase as well as GTPase, protein kinase and protein disulphide isomerase activities. Nevertheless, it can associate with integrin on the cell surface, thereby facilitating cell adhesion to fibronectin. Recent findings further reveal its involvement in drug resistance and tumor metastasis of breast cancer cells. Here we explore the role of TG2 in metastasis of lung cancer cells. Our results show that the highly invasive lung cancer cell line CL1-5 display higher levels of TG2 than its parental line CL1-0, which shows low extent of invasion. CL1-5 is also more resistant to anoikis, a type of apoptosis induced by cell detachment, and the treatment of doxorubicin, a drug used in chemotherapy. Overexpression of TG2 in CL1-0 enhances cell migration and invasion, but exerts no effect on the anoikis resistance and drug resistance. Cells with higher TG2 expression also have greater levels of external TG2. Application of recombinant TG2 into CL1-0 substantially enhances the extents of migration and invasion. Thus, TG2 plays a positive role in cell migration and invasion, and this might confer the metastatic capacity of lung cancer cells.

並列關鍵字

Lung cancer ； TG2

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