| 摘要: | 除了能夠引導白血球的趨化行為外，趨化激素與其受體也扮演了促使腫瘤生長與轉移的角色，如腫瘤細胞的增生、凋亡與不正常的血管增生。本篇研究在於探討趨化受體與表皮基底細胞癌化過程的相關性。研究顯示，CXCR4趨化受體在人類基底細胞癌株或患者病灶處所取下的基底細胞癌組織樣品內存有高度的表現量。此外，我們更假設在CXCR4趨化受體過度表現下將會促使表皮基底細胞的癌化。藉由反轉錄病毒載體轉染技術，CXCR4 受體蛋白基因被轉染至表皮基底細胞癌(CXCR4-BCC細胞)並經由體外細胞增殖實驗，顯示CXCR4-BCC細胞在低血清培養下以CXCR4受體接受分子CXCL12處理，會導致CXCR4-BCC細胞的增生。在細胞凋亡試驗下，CXCL12趨化激素也可以防止CXCR4-BCC細胞進行程序性死亡，但此現象卻受到專一性的CXCR4阻斷生肽，T22 peptide作拮抗性的中和而阻斷。在體外血管新生試驗方面，添加以CXCL12 趨化激素處理CXCR4-BCC細胞的培養液，能夠促使人類內皮細胞管狀形成，此現象亦可受到T22 peptide作拮抗性的阻斷。另外，我們將CXCR4-BCC細胞以皮下注射進入裸鼠進行異種移植而致腫瘤形成，然而T22的添加也確實能造成腫瘤的消減。 因此， CXCR4受體蛋白的表現或許與表皮基底細胞的癌化發生過程有關， 而阻斷CXCR4受體蛋白的活化或許可成為未來治療此類癌症的方向之一。; Beside the well-known capacity to regulate leukocyte trafficking, chemokines and their receptors also play important roles in the regulation of cell proliferation, apoptosis, and angiogenesis, which may enhance tumor growth or metastasis. Herein we investigated the possible involvements of chemokine receptors in the pathogenesis of cutaneous basal cell carcinoma (BCC), the most common human cancer. We found high expression of chemokine receptor CXCR4 in a human BCC cell line and a subset of tissue samples from BCC lesions. Furthermore, we addressed whether overexpression of CXCR4 may alter BCC tumor progression. By retroviral transduction, CXCR4 gene was transferred into BCC cells (CXCR4-BCC) and functionally expressed. In cell proliferation assay in vitro, CXCR4-BCC cells were cultured under low serum concentration and subject to treatments with the ligand for CXCR4, CXCL12. CXCL12 treatments resulted in significant increase of CXCR4-BCC proliferation, which could be neutralized by anti-CXCR4 monoclonal antibodies. In apoptosis-resistance assay in vitro, treatments with CXCL12 decreased apoptosis level in CXCR4-BCC, which could be negated by CXCR4-blocking peptide, T22. In angiogenesis assay in vitro, conditioned medium from CXCR4-BCC cells pre-incubated with CXCL12 could enhance tubule formation of human endothelial cells, which could be reversed by T22 addition. Moreover, xenograft tumor transplants by s.c. injections of CXCR4-BCC cells yielded significant tumor progression in nude mice, whereas additional serial injections of T22 resulted in significant tumor regression. Thus, CXCR4 expression may play critical roles in BCC tumorigenesis, and functional blockade of CXCR4 could be a potentially promising therapeutic strategy. |
