探討pVHL-HIF-1α-CXCR4途徑和乳癌的相關性

The Association of pVHL-HIF-1α-CXCR4 Pathway and Breast Cancer

蘇月秋(Yue-Chiu Su)

指導教授 ： 蔡志仁

高雄醫學大學/醫學院/醫學研究所/碩士(2005年)

摘要

背景: 早期乳癌病人的腋窩淋巴結是否有轉移對病人的影響不僅在於其術式的選擇和是否增加術後輔助治療，更在於它也是具有當作一預後的參數的能力。近日的研究發現CXCR4這個趨化激素受體在許多的癌症中常有高度表現且被它被認為和癌症轉移有關。另外，文獻中亦提及CXCR4需經由缺氧誘導因子-1α (HIF-1α)和von Hippel-Lindau蛋白質(pVHL)所調控，所以，我們認為有必要了解在早期乳癌病人中，pVHL-HIF-1α-CXCR4這一個途徑和其腋窩淋巴結轉移或是遠端器官轉移的關係，以便提供一些有益的訊息供臨床運用。

原料和方法: 85個早期乳癌的樣本依他們的腋窩淋巴結的狀態被分成3組：第一組為無淋巴結轉移，第二組為有1-3顆淋巴結轉移，第三組為有大於3顆以上的淋巴結轉移。之後我們以免疫組織化學染色的方法偵測CXCR4、HIF-1α、pVHL等因子在早期乳癌細胞中的表現，再利用統計方法評估它們個別和腋窩淋巴結狀態或是遠端器官轉移的相互關係以及它們三者彼此的相互關係。

結果: CXCR4在細胞核的表達和淋巴結轉移的數目在統計學上是呈現負相關(P=0.0345)；然而，CXCR4在細胞質的表達和淋巴結轉移的數目在統計學上並沒有顯著相關(P=0.2782)。其他因素，包括年齡、停經狀態、左右側、腫瘤大小、病理型態、組織惡性等級、淋巴或血管是否浸潤、賀爾蒙受器ER、PR的有無、致癌基因HER-2的有無、遠端器官轉移等和CXCR4在細胞核或細胞質的表達在統計學上沒有顯著相關。
HIF-1α的表達和腫瘤大小，組織惡性等級在統計學上是呈現正相關(P=0.0094；P=0.0272)；然而，HIF-1α的表達和其他的因素，包括年齡、停經狀態、左右側、病理型態、淋巴或血管是否浸潤、賀爾蒙受器ER、PR的有無、致癌基因HER-2的有無、遠端器官轉移等和淋巴結轉移的數目在統計學上並沒有相關。
pVHL在細胞質的表達和年齡、停經狀態、左右側、腫瘤大小、病理型態、組織惡性等級、淋巴或血管是否浸潤、賀爾蒙受器ER、PR的有無、致癌基因HER-2的有無、遠端器官轉移等和淋巴結轉移的數目在統計學上沒有相關。
進一步我們分析CXCR4、HIF-1及pVHL三者的關係，得知CXCR4在細胞核的表達和pVHL的表現情形在統計學上具有顯著的正相關(P<0.001)，CXCR4在細胞質的表達和HIF-1α的表現情形在統計學上有接近顯著相關(P=0.0611)，但是，CXCR4在細胞核的表達和HIF-1α的表現量不具有統計學上相關；CXCR4在細胞質的表達和pVHL的表現情形也不具有統計學上相關。

結論:我們的研究是想了解在早期乳癌病人pVHL- HIF-1α-CXCR4這一個途徑和其腋窩淋巴結轉移或是遠端器官轉移的關係，以便提供一些有益的訊息供臨床運用。在此研究中，雖然沒有如預期地闡明這條途徑在乳癌轉移所扮演的角色，但至少藉此了解了pVHL、HIF-1α、CXCR4個別和早期乳癌的關係。

關鍵字

免疫組織化學染色 ； 乳癌 ； 缺氧誘導因子-1α ； von Hippel-Lindau蛋白質 ； 趨化激素受器分子CXCR4

並列摘要

Background: The axillary lymph node status of early breast cancer patient affects not only types of surgery and adjuvant therapeutic planning but it has also been regarded as a prognostic parameter for these patients. Recent studies discovered that CXCR4 was highly expressed in many cancers and associated with tumor progression or metastasis. In addition, it is reported that CXCR4 was regulated by HIF-1α and pVHL.It is worth to understand the association between the CXCR4 expression and axillary lymph node involvement and distant metastasis in early breast cancer in order to provide valuable information for clinical application.

Materials and methods: Eighty-five patients with early breast cancers were divided into three groups based on their axillary lymph node status. We assessed the expression of CXCR4、HIF-1α、pVHL in all cases by immunohistochemistry and then evaluated their correlation with the axillary lymph node involvement and distant metastasis. Furthermore, we also determine the association between CXCR4、HIF-1α and pVHL.

Results: There was a significant difference in nuclear CXCR4 expression between these three groups and high nuclear expression of CXCR4 was significantly associated with cases without lymph node involvement (P=0.0345). However, cytoplasmic expression of CXCR4 was not significantly associated with axillary lymph node involvement (P=0.2782). Other factors, including patient’s age、menopausal status、tumor location、tumor size、pathologic type、histologic grade、lymphovascular invasion、ER、PR、HER-2, and distant metastasis had no significant association with the nuclear or cytoplasmic expression of CXCR4.
There was a significant association between HIF-1αexpression and tumor size and histologic grade (P=0.0094；P=0.0272)；however other factors, including patient’s age、menopausal status、tumor location、pathologic type、lymphovascular invasion、ER、PR、HER-2, and distant metastasis had no significant association with the expression of HIF-1α.
There was no significant association between cytoplasmic pVHL expression and patient’s age、menopausal status、tumor location、tumor size、pathologic type、histologic grade、lymphovascular invasion、ER、PR、HER-2、and distant metastasis.
Furthermore, the expression of unclear CXCR4 had a significant association with pVHL (P<0.001), and the expression of cytoplasmic CXCR4 also had a marginally significant association with HIF-1α (P=0.0611). However, there was no significant association between expression of nuclear CXCR4 and HIF-1α；there was no significant association between expression of cytoplasmic CXCR4 and pVHL.

Conclusions: In this study, we attempt to determine the association between pVHL-HIF-1α-CXCR4 pathway and the metastastic potential of early breast cancer. Although we didn’t confirm the hypothesis that pVHL-HIF-1α-CXCR4 pathway might play an critical role in metastastic potential in early breast carcinoma, we determined the association between the expression of pVHL、HIF-1αand CXCR4 independently and early breast cancer.

並列關鍵字

breast cancer ； immunohistochemistry ； HIF-1α ； von Hippel-Lindau protein ； CXCR4

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