利用去整合蛋白抑制肝癌細胞黏附、遷移及侵犯能力

林庚酉

doi:10.6844/NCKU.2014.00832

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利用去整合蛋白抑制肝癌細胞黏附、遷移及侵犯能力

Inhibition of integrin-mediated adhesion, migration and invasion of hepatoma cells by disintegrins

林庚酉 , Masters　　Advisor：黃溫雅　　Co-advisor ：莊偉哲

繁體中文 DOI： 10.6844/NCKU.2014.00832

肝癌；轉移；整合蛋白；去整合蛋白； B型肝炎x蛋白； Hepatocellular carcinoma ； metastasis ； integrin ； disintegrin ； HBx

Abstract │ Reference (68) │ Times Cited (1) │ Altmetrics

Abstract 〈TOP〉

肝臟是富含微血管的器官，當肝臟出現癌化時，癌細胞容易侵犯血管並且轉移，這使得肝癌患者治療後出現復發的機會增加。研究顯示，肝癌細胞藉由大量表現整合蛋白(integrin)，促進細胞轉移、生長及血管新生的癌化作用。整合蛋白是由α及β次單元所形成的穿膜蛋白，它們負責調節細胞間、細胞與細胞外基質的交互作用。肝癌組織中發現，表現αv和β1相關的整合蛋白與癌症惡化有關，這類的整合蛋白可辨識RGD (arginine-glycine-aspartate)氨基酸序列結構，與細胞外基質黏附，誘發胞內外訊息傳遞。臨床實驗發現，抑制整合蛋白所調控的細胞活性可有效抑制癌化作用，而在肝病變的研究也指出，抑制αv和β1相關的整合蛋白可達到三點效果:第一，抑制整合蛋白調控的肝癌細胞黏附、遷移及侵犯能力；第二，抑制整合蛋白αv調控的肝纖維化；第三，抑制整合蛋白αvβ3、αvβ5及α5β1調控的血管新生。在本實驗中，我們試圖針對肝癌細胞表現的整合蛋白，抑制其生理活動。我們使用實驗室所開發的去整合蛋白(disintegrin) Rho、KG、KG-P和ARLDDL抑制肝癌細胞表現的整合蛋白。去整合蛋白源自於蛇毒蛋白，是天然的整合蛋白抑制劑，抑制強度為細胞外基質的1000倍以上，去整合蛋白含有RGD序列結構，利用此結構可與細胞外基質競爭整合蛋白的交互作用。目前已證實，去整合蛋白可抑制黑色素瘤的轉移及生長，同時也減緩腫瘤的血管新生。本實驗顯示，藉由去整合蛋白KG及KG-P針對整合蛋白αvβ3、αvβ5及α5β1，能有效抑制肝癌細胞對於細胞外基質(fibronectin、vitronectin)的黏附能力，其50%抑制濃度(IC50)介於15到80 nM；同時也具有抑制肝癌細胞遷移及侵犯能力，其IC50介於2到400 nM之間；然而單純針對整合蛋白αvβ3的ARLDDL則是較差的抑制效果。這些去整合蛋白對於肝癌細胞活性不具影響力。另外當肝癌細胞表現B型肝炎x蛋白(HBx)時，整合蛋白αvβ3及α5β1的表現量下降1.5倍以及3倍，同時減弱細胞的黏附能力並且增強細胞遷移及侵犯的趨勢，而這使得去整合蛋白無法有效抑制HBx蛋白誘發的細胞遷移能力。本篇證實整合蛋白αvβ3、αvβ5及α5β1參與肝癌細胞黏附、遷移及侵犯能力，且運用去整合蛋白可抑制肝癌細胞中整合蛋白調控的轉移能力，此結論可作為未來發展抑制肝癌轉移的藥物基礎。

Parallel Abstract 〈TOP〉

Hepatocellular carcinoma (HCC) is a vascularized tumor. The prognosis of HCC is poor due to blood vessel invasion. Integrins are major receptors mediating cancer cell motility, proliferation and angiogenesis which make them appealing for cancer treatments. Previous studies show that integrin α5β1 antagonists can inhibit VEGF-induced angiogenesis in hepatocellular carcinoma, and hepatitis B virus x protein (HBx) can modulate integrin signaling pathways in hepatoma cells. In this study, we evaluated integrin expression levels of liver cell lines, the regulation of HBx proteins in integrin-mediated cellular functions, and the biological functions of integrins on cell adhesion, migration, invasion, and proliferation. We also used integrin antagonists, mono-specific (αvβ3) and multi-specific (αvβx and α5β1) disintegrins, to inhibit integrin-related cellular functions. We found the HBx-expressing hepatoma cells with the down-regulation of integrins α5β1 and αvβ3 expression which led to the decreases in hepatoma cell adhesion to fibronectin and vitronectin, as well as the increases in hepatoma cell migration and invasion. In conclusion, our study demonstrates that integrins participate in hepatoma cell adhesion, migration, and invasion. These cellular processes can be impaired by integrins-specific disintegrins. The results of this study serve as the basis to develop the potent integrin-specific drugs for the treatment of hepatocellular carcinoma.

Reference ( 68 ) 〈TOP〉

1. Arnaout, M.A., Mahalingam, B., and Xiong, J.P. (2005). Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 21, 381-410.
連結：
2. Au, L.C., Huang, Y.B., Huang, T.F., Teh, G.W., Lin, H.H., and Choo, K.B. (1991). A common precursor for a putative hemorrhagic protein and rhodostomin, a platelet aggregation inhibitor of the venom of Calloselasma rhodostoma: molecular cloning and sequence analysis. Biochemical and biophysical research communications 181, 585-593.
連結：
4. Bandyopadhyay, A., and Raghavan, S. (2009). Defining the role of integrin alphavbeta6 in cancer. Current drug targets 10, 645-652.
連結：
5. Barczyk, M., Carracedo, S., and Gullberg, D. (2010). Integrins. Cell and tissue research 339, 269-280.
連結：
6. Bishayee, A., and Darvesh, A.S. (2012). Angiogenesis in hepatocellular carcinoma: a potential target for chemoprevention and therapy. Current cancer drug targets 12, 1095-1118.
連結：

Times Cited (1) 〈TOP〉

許雅穎(2015)。乙醯化轉移酶MORF調控姐妹染色體互換的機制。成功大學生命科學系學位論文。2015。1-54。

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