核轉錄因子NF-κB的活化與人類上泌尿道移行上皮癌之關聯性研究

The Study of the Association of Nuclear Factor-κB Activation and Human Upper Urinary Tract Transitional Cell Carcinoma

葉信志(Hsin-Chih Yeh)

指導教授 ： 黃俊雄

高雄醫學大學/醫學院/醫學研究所/碩士(2008年)

摘要

目的：侵犯性上泌尿道移行上皮癌的患者容易產生疾病的惡化而且死亡率高，所以能夠良好預測疾病預後的生物標誌相當重要，除了可以對病人做危險性的評估，也可以對不同病人做出最適當的治療。NF-κB是一個與細胞凋亡、侵犯、血管新生有關的轉錄因子，我們在本文檢視NF-κB在上泌尿道癌症的表現與對疾病預後的重要性。其他潛在可能為預後因子的臨床及病理變項也一併納入我們的分析當中。
材料與方法：從1991年7月到2005年4月間，我們收集了90位在本院接受手術治療的上泌尿道移行上皮癌患者做為研究的對象。他們的年齡介於24歲到84歲之間，平均歲數為64.5歲。我們利用每一位病人手術切取的標本，包括腫瘤組織和同一位病人正常的尿路上皮，來做NF-κB (p65)的免疫組織化學染色。經由單變項以及多變項的分析，我們檢視各個變項與病人存活率的相關性，除了NF-κB的表現以外，其他的參數包括發病年齡、性別、手術前的腎功能、是否有之前或同時存在的膀胱癌、腫瘤位置、組織分化程度、腫瘤分期、以及有無淋巴結轉移等。
結果：病人追蹤時間的中位數為40個月。有55位上泌尿道癌的病人(61.1%)其NF-κB在細胞質呈現過度表現，24位病人(26.7%)在細胞核中出現NF-κB的染色。雖然NF-κB出現在細胞核的染色，與其他的臨床及病理變項皆未呈現相關性，但NF-κB的核染對於疾病別存活率以及總存活率仍然具有顯著的預測性，造成死亡的相對危險比分別為2.87 倍(p = 0.025)及2.24 倍(p = 0.037)，而NF-κB在細胞質的過度表現對預後則沒有影響。另外，在多變項分析中，腫瘤位置、腫瘤分期、以及淋巴結轉移是預測疾病復發的獨立因子，而先前有膀胱癌的病史則是唯一可以預測膀胱腫瘤復發的參數。
結論：對於我們研究的這群上泌尿道癌症手術後的病人，不管在單變項或是多變項的分析中，NF-κB在細胞核內的染色對病人的存活率具有相當良好的預測性。這個結果支持了NF-κB的活化在上泌尿道癌症的形成與進展中扮演著一定的角色，並且可以將NF-κB的核染視為一個獨立的預後因子，除了幫助我們對這些病人做出最適當的輔助治療外，在日後也可以期待把NF-κB當成上泌尿道癌症治療的一個標的。

關鍵字

核轉錄因子NF-κB ； 免疫組織化學染色 ； 上泌尿道移行上皮癌 ； 預後

並列摘要

Purpose: Patients with advanced upper urinary tract transitional cell carcinoma (UUT-TCC) have a high risk for cancer progression and high mortality rate, emphasizing the need for prognostic biomarkers to stratify disease outcome for optimal patient management decisions. We examined the hypothesis that nuclear factor-κB (NF-κB), a transcription factor involved in apoptosis, invasion, and angiogenesis, plays a role in carcinogenesis of UUT-TCC and has prognostic value for survival. Other potential prognostic clinicopathologic parameters were also tested in this patient population.
Materials and methods: Ninety patients (mean age, 64.5 years; age range, 24–84 years) who underwent surgery in out institute from July 1991 to April 2005 were included in the present study. Clinicopathologic data were collected retrospectively. Using surgically resected specimens, we performed immunohistochemical staining for NF-κB (p65) on paraffin-embedded sections of the tumor and corresponding normal UUT tissue. The association between survival and possible prognostic factors, including NF-κB expression, age, gender, preoperative renal function, previous or concomitant bladder tumor, tumor side, tumor location, tumor grade, pathologic T stage, and presence of regional lymph node metastasis, was examined in univariate and multivariate analysis.
Results: Median follow-up of this population was 40 months. Fifty-five patients (61.1%) with UUT-TCC overexpressed cytoplasmic NF-κB, and positive nuclear NF-κB staining was recorded in 24 patients (26.7%). Nuclear staining of NF-κB did not correlate with other prognostic factors of UUT-TCC. Nuclear NF-κB was a significant predictor for disease specific survival (Cox regression hazard ratio, 2.87; p = 0.025) and overall survival (Cox regression hazard ratio, 2.24; p = 0.037), whereas cytoplasmic overexpression of NF-κB did not have prognostic significance. In multivariate model, tumor location, stage, and nodal status were independent prognostic factors for recurrence-free survival. Previous bladder tumor history was the only significant variable predicting subsequent bladder tumor recurrence.
Conclusions: In univariate and multivariate analysis, NF-κB nuclear expression was strongly predictive of cancer related death and overall mortality in patients with UUT-TCC after surgery. These results support a role for NF-κB activation in the tumorigenesis and progression of UUT-TCC. Nuclear NF-κB may serve as a useful independent molecular marker to facilitate proper adjuvant therapy strategy and may represent a promising therapeutic target for UUT-TCC patients.

並列關鍵字

NF-κB ； immunohistochemistry ； upper urinary tract ； transitional cell carcinoma ； prognosis

參考文獻

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