Friess H, Lu Z, Andrén-Sandberg A, Berberat P, Zimmermann A, Adler G, Schmid R, Büchler M W
Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Switzerland.
Ann Surg. 1998 Dec;228(6):780-7. doi: 10.1097/00000658-199812000-00009.
To analyze the expression of the antiapoptotic gene bcl-xL in human pancreatic cancer and to correlate the results with clinical patient parameters.
Bcl-xL belongs to the bcl-2-related gene family and acts as a broad antiapoptotic factor to extend both normal and tumor cell survival. Recent findings indicate that tumor cell death induced by chemotherapy and radiotherapy is mediated by the activation of apoptosis. The fact that pancreatic cancer has an extremely malignant potential and that it is resistant to most anticancer treatment modalities suggests that mechanisms are activated that increase the viability of pancreatic cancer cells.
Seventy-four pancreatic cancer tissue samples were obtained from 32 female and 42 male patients undergoing surgery for exocrine pancreatic cancer. Normal human pancreatic tissue samples were available from 11 organ donors and 4 patients without pancreatic disease. The levels of bcl-xL mRNA expression were analyzed by Northern blot analysis. The exact site of bcl-xL mRNA transcription was determined by nonradioactive in situ hybridization. In addition, immunohistochemistry using specific polyclonal antibodies was used to localize the protein.
Northern blot analysis indicated that, in comparison with the normal pancreas, bcl-xL mRNA was markedly overexpressed in 54% of the pancreatic cancer samples. Densitometric analysis revealed that pancreatic adenocarcinomas exhibited a mean 3.4-fold increase (p < 0.01) in bcl-xL mRNA levels in comparison with normal controls. With in situ hybridization, bcl-xL mRNA was found to be highly expressed in the cancer cells of tumor samples that exhibited increased mRNA expression by Northern blot analysis. Immunohistochemical analysis revealed bcl-x immunostaining in 88% of the cancer samples. Correlation of the molecular data with clinical patient parameters revealed that patients whose tumors exhibited no, faint, or weak bcl-xL expression lived significantly longer after tumor resection (median 12 months) than patients whose tumors exhibited moderate bcl-xL mRNA expression (median 5 months) (p < 0.05). However, 5 patients whose tumors exhibited intense bcl-xL mRNA expression tended to live longer (median 14 months).
Enhanced expression of the antiapoptotic gene bcl-xL in pancreatic cancer and its association with shorter patient survival suggests that this factor may enhance the viability of pancreatic cancer cells in vivo. Inhibition of apoptotic pathways might be one of the reasons why pancreatic cancer shows only limited sensitivity to anticancer treatment.
分析抗凋亡基因bcl-xL在人胰腺癌中的表达情况，并将结果与临床患者参数相关联。
Bcl-xL属于bcl-2相关基因家族，作为一种广泛的抗凋亡因子，可延长正常细胞和肿瘤细胞的存活时间。最近的研究结果表明，化疗和放疗诱导的肿瘤细胞死亡是由凋亡激活介导的。胰腺癌具有极高的恶性潜能且对大多数抗癌治疗方式具有抗性，这一事实表明激活了一些机制来提高胰腺癌细胞的存活率。
从32名女性和42名男性接受外分泌性胰腺癌手术的患者中获取74份胰腺癌组织样本。从11名器官捐赠者和4名无胰腺疾病的患者中获取正常人胰腺组织样本。通过Northern印迹分析来分析bcl-xL mRNA的表达水平。通过非放射性原位杂交确定bcl-xL mRNA转录的确切位点。此外，使用特异性多克隆抗体的免疫组织化学方法来定位该蛋白。
Northern印迹分析表明，与正常胰腺相比，54%的胰腺癌样本中bcl-xL mRNA明显过度表达。光密度分析显示，与正常对照相比，胰腺腺癌的bcl-xL mRNA水平平均增加了3.4倍（p < 0.01）。通过原位杂交发现，在Northern印迹分析中显示mRNA表达增加的肿瘤样本的癌细胞中，bcl-xL mRNA高度表达。免疫组织化学分析显示88%的癌症样本中有bcl-x免疫染色。分子数据与临床患者参数的相关性显示，肿瘤未表现出、微弱或弱bcl-xL表达的患者在肿瘤切除后存活时间（中位数12个月）明显长于肿瘤表现出中度bcl-xL mRNA表达的患者（中位数5个月）（p < 0.05）。然而，5名肿瘤表现出强烈bcl-xL mRNA表达的患者往往存活时间更长（中位数14个月）。
抗凋亡基因bcl-xL在胰腺癌中的表达增强及其与患者较短生存期的关联表明，该因子可能在体内提高胰腺癌细胞的存活率。凋亡途径的抑制可能是胰腺癌对抗癌治疗仅表现出有限敏感性的原因之一。
