Aggressiveness of HNSCC tumors depends on expression levels of cortactin, a gene in the 11q13 amplicon.
Aggressiveness of HNSCC tumors depends on expression levels of cortactin, a gene in the 11q13 amplicon.
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DOI：
10.1038/onc.2008.389
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发表时间：
2009-01-22
期刊：
影响因子：
8
通讯作者：
Weaver, A. M.
中科院分区：
文献类型：
--
作者：
Clark, E. S.;Brown, B.;Whigham, A. S.;Kochaishvili, A.;Yarbrough, W. G.;Weaver, A. M.
11q13扩增是几种癌症的晚期事件，通常与预后不良有关。在11q13扩增基因中，肌动蛋白组装蛋白接触蛋白/CTTN被认为是直接参与肿瘤进展的可能候选基因，因为它具有增强细胞活力的功能。我们调节了头颈部鳞状细胞癌（HNSCC）细胞系中皮质蛋白的表达。在原位HNSCC体内模型中，皮质蛋白的表达水平与肿瘤大小、血管形成和细胞增殖直接相关。相比之下，在正常体外培养条件下，接触蛋白的表达水平对细胞增殖没有影响。然而，在生长因子剥夺、锚定不依赖性和空间约束的恶劣条件下，通过敲低（KD）降低相关性表达的细胞系在体外生长不良。相反，在同样恶劣的条件下，过表达的接触蛋白促进了体外生长。令人惊讶的是，通过与表达接触蛋白的细胞共培养，接触蛋白kd细胞的生长因子非依赖性增殖缺陷得以修复。由于共培养细胞被渗透性过滤器分离，表达接触蛋白的细胞必须分泌支持生长的自分泌因子来拯救接触蛋白kd细胞。总的来说，联系蛋白的表达调节了多种细胞特性，这些特性可能允许肿瘤环境中的生存，这表明肿瘤中联系蛋白的频繁过表达不是一种附带现象，而是促进了肿瘤的侵袭性。
11q13 amplification is a late-stage event in several cancers that is often associated with poor prognosis. Among 11q13-amplified genes, the actin assembly protein cortactin/CTTN is considered a likely candidate for direct involvement in tumor progression, because of its cell motility-enhancing functions. We modulated cortactin expression in head and neck squamous cell carcinoma (HNSCC) lines. Cortactin expression levels directly correlated with tumor size, vascularization, and cell proliferation in an orthotopic HNSCC in vivo model. In contrast, under normal in vitro culture conditions, cortactin expression levels had no effect on cell proliferation. However, cell lines in which cortactin expression was reduced by knockdown (KD) grew poorly in vitro under harsh conditions of growth-factor deprivation, anchorage independence, and space constraint. Conversely, overexpression of cortactin enhanced in vitro growth under the same harsh conditions. Surprisingly, defects in growth factor-independent proliferation of cortactin-KD cells were rescued by co-culture with cortactin-expressing cells. Since the co-cultured cells are separated by permeable filters, cortactin-expressing cells must secrete growth-supporting autocrine factors to rescue the cortactin-KD cells. Overall, cortactin expression modulates multiple cellular traits that may allow survival in a tumor environment, suggesting that the frequent overexpression of cortactin in tumors is not an epiphenomenon but rather promotes tumor aggressiveness.
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