LaPierre David P, Lee Daniel Y, Li Sen-Zhu, Xie Yi-Zhen, Zhong Ling, Sheng Wang, Deng Zhaoqun, Yang Burton B
Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
Cancer Res. 2007 May 15;67(10):4742-50. doi: 10.1158/0008-5472.CAN-06-3610.
Expression of the extracellular matrix proteoglycan versican is associated with more than 10 types of cancers, often being secreted by stromal cells in response to tumor signals. Previous work in our lab has shown that overexpression of the V1 versican isoform in cultured fibroblasts (V1 cells) increases both proliferation and apoptotic resistance. We show here that V1 cells induced tumor formation in nude mice and that, in keeping with previously shown apoptotic resistance, V1 cells have down-regulated Fas mRNA and protein levels. Unexpectedly, however, V1 cells were found to be sensitized to a wide range of cytotoxic agents. This combination of selective apoptotic resistance and sensitivity is often seen in cancer cells. V1 cells were also shown to have high resting levels of p53 and murine double minute-2 proteins, correlating with apoptotic sensitivity. Treatment with UV radiation induced p21 expression in vector-transfected cells but not in V1 cells. As p21 induces cell cycle arrest and inhibits apoptosis, its loss in V1 cells, coupled with high resting levels of proapoptotic p53, may be at least partially involved in their premature death following cytotoxic treatment. This study further supports the importance of versican in cancer cell biology and the complexity of apoptosis regulation.
细胞外基质蛋白聚糖多功能蛋白聚糖的表达与10多种癌症相关，通常由基质细胞响应肿瘤信号而分泌。我们实验室之前的研究表明，在培养的成纤维细胞（V1细胞）中过表达V1多功能蛋白聚糖异构体可增加细胞增殖和抗凋亡能力。我们在此表明，V1细胞在裸鼠中诱导肿瘤形成，并且与之前显示的抗凋亡能力一致，V1细胞的Fas mRNA和蛋白水平下调。然而，出乎意料的是，V1细胞对多种细胞毒性药物敏感。这种选择性抗凋亡和敏感性的组合在癌细胞中经常可见。V1细胞还显示出高水平的p53和鼠双微体2蛋白，这与凋亡敏感性相关。紫外线辐射处理在载体转染细胞中诱导p21表达，但在V1细胞中未诱导。由于p21诱导细胞周期停滞并抑制凋亡，其在V1细胞中的缺失，加上促凋亡p53的高水平，可能至少部分参与了它们在细胞毒性处理后的过早死亡。这项研究进一步支持了多功能蛋白聚糖在癌细胞生物学中的重要性以及凋亡调控的复杂性。
