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標題: | 間質細胞衍生因子及其受體在人類喉癌和
下咽癌細胞移行/侵襲能力上所扮演的角色 The Role of SDF-1/CXCR4 on Human Laryngeal and Hypopharyngeal Cancer Cells Migration/Invasion Capability |
作者: | Ying-Chang Lu 呂盈璋 |
指導教授: | 郭明良(Min-Liang Kuo) |
關鍵字: | 間質細胞衍生因子,咽喉鱗狀上皮細胞癌, SDF-1,LHSCC, |
出版年 : | 2005 |
學位: | 碩士 |
摘要: | 喉癌及下咽癌(統稱咽喉癌)是常見的頭頸部癌症之一,它的組織病理學診斷百分之九十以上為鱗狀上皮細胞癌,雖然醫學逐漸進步,但此疾病患者的存活率在最近20年內並沒有增加的現象,對咽喉癌病患的治療而言,是否出現淋巴結及遠隔轉移對預後具有決定性的影響。眾所週知,癌症的轉移並非隨意發生的過程,不同的癌症會轉移到不同的部位,雖然有許多因子已知可能與癌症的轉移有關,但真正決定癌症細胞移動的方向,以及侵入特殊器官的機轉仍未被釐清。近年的研究顯示化學激活素(chemokine) CXC受體第4號( CXCR4 )及其配體間質細胞衍生因子第1號(SDF-1/ CXCL12),在某些實體腫瘤的轉移中扮演重要的角色,然而此一路徑在咽喉癌轉移的重要性仍不清楚。因此本計畫即在探討CXCL12/ CXCR4在咽喉癌的轉移中可能扮演的角色。
從免疫組織化學與反轉錄聚合酶連鎖反應結果顯示,由咽喉癌病患所採集的原位腫瘤組織中其CXCR4具有高度表現的現象。在咽喉癌細胞株中,利用反轉錄聚合酶連鎖反應與西方墨點法可分別觀察到CXCR4 mRNA與其蛋白質高度表現的情形,同時免疫組織化學法可於細胞表面偵測到CXCR4的表現。在本實驗中,我們證實CXCL12能促進細胞的化學趨化與侵襲的能力,而此特性可被CXCR4拮抗劑JM3100所阻斷。同時,我們研究能調節與CXCL12/ CXCR4此一路徑所誘發之咽喉癌細胞對細胞外基質進行細胞移行與侵襲的訊息傳遞機轉。由實驗結果得知,CXCL12所誘發活化的MMP-13能增加咽喉癌細胞的化學侵襲性,並且是透過活化AP-1與細胞外訊息調節激酶(ERK1/2)所完成。專一性的ERK1/2抑制劑(U0126)阻斷ERK1/2訊息傳遞分子則可有效抑制MMP-13的表現及減少LHSCC細胞的侵襲性。c-Jun antisense oligodeoxynucleotide (ODN)可有效抑制MMP-13的表現,但sense之ODN則無此反應。綜合上述結果,我們證實CXCL12/ CXCR4所誘發之咽喉癌細胞的趨化侵襲性與ERK1/2、AP-1與MMP-13活化有關,而此一路徑可能在咽喉癌的轉移上扮演著重要的角色。綜合以上實驗結果可使吾人更加了解咽喉癌轉移的機轉,而藉由對此一機制的進一步探討可能可以尋求新的輔助療法,以嘗試減少轉移,改善病人的存活率。 Cancer of the larynx and hypopharynx is one of the most common head and neck malignancy. Squamous cell carcinoma remains the most common pathologic type, accounting for more than 90% cases. Although therapeutic modality has improved gradually, there is no sign that the 5-year survival rate has improved during the past 20 years. The metastasis of tumor cells represents the primary source of clinical morbidity and mortality in the large majority of laryngeal and hypopharyngeal tumors. Cancer metastasis is not a random process and different cancer types have different metastatic sites. Though there are a number of molecules that have been shown to play a role in the metastatic process, the exact mechanisms determining the directional migration and invasion of tumor cells into specific organs have not been clearly established . Recent research has demonstrated the possible role of chemokine receptor, CXCR4, and its ligand stromal cell-derived factor-1 (SDF-1/ CXCL12) in the metastasis of some solid tumors. However, the role of /CXCR4 in metastasis of laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) is still unknown. Therefore, in this study we have investigated the role of CXCL12/ CXCR4 system in the metastasis of LHSCC. Immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) of primary tumor samples from LHSCC patients revealed high expression of CXCR4.RT-PCR and Western blot examination demonstrated CXCR4 mRNA and protein expression in LHSCC cell lines. Immunohistochemistry demonstrated CXCR4 surface expression. In the present study, we showed that CXCL12 enhanced the chemotaxis and chemoinvasion properties of cells, which could be blocked by CXCR4 antagonist (JM3100). We also examined the signaling mechanisms that regulate CXCL12-induced and CXCR4-mediated LHSCC cell motility and invasion to extracellular matrix. We found that CXCL12-induced MMP-13 activation which resulted in an increased chemoinvasion of LHSCC cells. This was mediated by extracellular signal-regulated kinase 1/2 activation. Blocking ERK1/2 pathway by specific ERK1,2 inhibitor U0126 resulted in suppression of MMP-13 expression and decreasing chemoinvasion of LHSCC cells. c-Jun antisense, but not sense, oligodeoxynucleotide (ODN ) also significantly decreases MMP-13 expression. We conclude that CXCL12/CXCR4-mediated chemotaxis and chemoinvasion is through activation of ERK1/2 AP-1 and MMP-13, and this pathway might play an important role in the metastasis of LHSCC. The results of this study will provide evidence for us to understand the mechanism of metastasis in laryngeal and hypopharyngeal SCC. Searching for a new therapeutic agent to block this pathway as an adjuvant therapy for laryngeal SCC, might reduce the metastasis rates and improve the survival rates. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/24263 |
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