VCAM-1 (CD106) 是一個穿膜的醣蛋白，參與許多病理性的發炎反應，並且透過結合細胞表面上的integrinVLA-1的激活作用，影響白血球黏著及穿透的能力。在我們之前的研究結果中，我們發現VCAM-1在卵巢癌的類似癌幹細胞的side-population中的表現，約有2至3倍的增加。此外，我們也發現在許多乳腺癌上皮细胞受到發炎性細胞激素刺激後會增加VCAM-1蛋白的表達並與乳癌腫瘤的發展有直接的關聯; 但是VCAM-1蛋白在腫瘤生物學中所扮演的角色仍然未知。因此，首先我們運用小鼠正常乳腺上皮細胞株來分析VCAM-1大量表現後對乳房上皮細胞的影響。我們將VCAM-1過度表達在NMuMG乳房上皮细胞株中，我們發現VCAM-1會增加細胞的轉移能力並對於Doxorubicin和Cisplatin兩種化療藥物產生抗藥性。同樣的，在高侵略性的乳腺癌細胞株 MDA-MB231中，我們發現經由small interfering RNA或shRNA knockdown的技術去抑制住內生性VCAM-1的表達後會降低細胞轉移能力。此外，從體內異體移植的SCID老鼠動物模式中我們也發現將MDA-MB231細胞株中內生性VCAM-1的表現抑制住後會降低異體移植的SCID老鼠腫瘤形成。總而言之，從我們的研究結果發現，當VCAM-1過度表現時會藉由提高乳腺癌細胞轉移及抗藥性，進而促進乳腺癌腫瘤的發展並且得知VCAM-1是可當作治療乳癌的新目標。

VCAM-1 (CD106) is a transmembrane glycoprotein and involved in many pathological inflammatory processes. VCAM-1 plays an important role in leukocyte adhesion, leukocyte transendothelial migration and cell activation by binding to integrin VLA-1 (α4β1). In our preliminary data, we observed 2-3 fold increase in the expression of VCAM-1 in the side population of ovarian cancer, which exhibits stem cell-like properties in ovarian cancer. In addition, we have also found VCAM-1 is upregulated in many breast cancer epithelial cells and directly correlated with breast tumor progression; however, its mechanism of action in tumor biology remains unknown. Here, we describe the establishment and use of breast cancer cell line model systems to dissect the functional roles of VCAM-1 activation in the manifestation of malignant phenotype of human breast cancer. We show that VCAM-1 overexpression in the NMuMG breast epithelial cells increase cell motility rates and chemoresistance to doxorubicin and cisplatin in vitro, conversely, in an established metastatic breast cancer cell line, MDAMB231, we find that knockdown endogenous VCAM-1 expression by small interfering RNA reduced the migration rate . Furthermore, we also demonstrated that knockdown endogenous VCAM-1 expression in MDAMB231 cells reduced the tumor formation in SCID xenograft mouse model. In conclusion, our findings are consistent with the hypothesis that overexpression of VCAM-1 facilitates breast cancer progression by enhancing the malignant properties of breast cancer cells and suggests that targeting of VCAM-1 induced pathways are attractive strategies for therapeutic intervention.

中文摘要-----------------------------------------------------5
英文摘要-----------------------------------------------------6
緒論-----------------------------------------------------------7
研究目的----------------------------------------------------13
實驗方法與材料-------------------------------------------14
實驗結果----------------------------------------------------32
討論----------------------------------------------------------51
參考文獻----------------------------------------------------57

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