Lee S H, Shin M S, Lee H S, Bae J H, Lee H K, Kim H S, Kim S Y, Jang J J, Joo M, Kang Y K, Park W S, Park J Y, Oh R R, Han S Y, Lee J H, Kim S H, Lee J Y, Yoo N J
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Hum Pathol. 2001 Mar;32(3):250-6. doi: 10.1053/hupa.2001.22769.
Many tumor cells, including hepatocellular carcinoma (HCC), express both Fas and its ligand on their surfaces, and it has remained a mystery why such cells do not spontaneously become apoptotic. In the current study, we analyzed the alterations of Fas structure and the expression of Fas and Fas ligand (FasL) and of Fas pathway inhibitors, including soluble Fas (sFas), Fas-associated phosphatase-1 (FAP-1), and bcl-2, in 50 cases of human HCC. Monoallelic loss of the Fas gene, as determined by loss of heterozygosity with intragenic polymorphisms, was observed in 5 of the 34 informative cases (15%), but none of the 50 cases showed Fas gene mutation. Expression of Fas and FasL was detected in 44 (88%) and 50 (100%) cases, respectively. sFas messenger RNA, as analyzed by in situ reverse-transcription polymerase chain reaction was expressed in 42 of the 50 cases (84%), and FAP-1 expression was observed in 40 of the 50 cases (80%). In contrast, none of the 50 cases showed bcl-2 expression. Our results showed that the majority of the HCCs (88%) coexpressed a death receptor, Fas and its cognate ligand, FasL, but all HCCs showed one or more alterations of the Fas pathway molecules known to inhibit Fas-mediated apoptosis. These findings suggest that the expression of sFas and FAP-1 and, in part, loss of Fas expression, rather than Fas gene alteration or bcl-2 expression, may be involved in the Fas resistance of HCC in vivo and that these mechanisms may play important roles in the pathogenesis of human HCC. HUM PATHOL 32:250-256.
许多肿瘤细胞，包括肝细胞癌（HCC），在其表面同时表达Fas及其配体，而这些细胞为何不会自发凋亡仍是一个谜。在本研究中，我们分析了50例人类HCC中Fas结构的改变、Fas和Fas配体（FasL）以及Fas途径抑制剂的表达，这些抑制剂包括可溶性Fas（sFas）、Fas相关磷酸酶-1（FAP-1）和bcl-2。通过基因内多态性的杂合性缺失确定，在34例信息充分的病例中有5例（15%）观察到Fas基因单等位基因缺失，但50例病例中均未显示Fas基因突变。分别在44例（88%）和50例（100%）病例中检测到Fas和FasL的表达。通过原位逆转录聚合酶链反应分析，50例病例中有42例（84%）表达sFas信使核糖核酸，50例病例中有40例（80%）观察到FAP-1表达。相比之下，50例病例中均未显示bcl-2表达。我们的结果表明，大多数HCC（88%）共表达死亡受体Fas及其同源配体FasL，但所有HCC均显示一种或多种已知可抑制Fas介导凋亡的Fas途径分子的改变。这些发现表明，sFas和FAP-1的表达以及部分Fas表达的缺失，而非Fas基因改变或bcl-2表达，可能参与了体内HCC对Fas的抵抗，并且这些机制可能在人类HCC的发病机制中起重要作用。《人类病理学》32:250 - 256。
