Fukuchi Minoru, Nakajima Masanobu, Fukai Yasuyuki, Miyazaki Tatsuya, Masuda Norihiro, Sohda Makoto, Manda Ryokuhei, Tsukada Katsuhiko, Kato Hiroyuki, Kuwano Hiroyuki
Department of Surgery I, Gunma University Faculty of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Int J Cancer. 2004 Mar 1;108(6):818-24. doi: 10.1002/ijc.11651.
Transforming growth factor-beta (TGF-beta) regulates cell growth inhibition, and inactivation of the TGF-beta signaling pathway contributes to tumor development. In our previous study, altered expression of TGF-beta, TGF-beta-specific receptors and Smad4 was shown to correlate with tumor progression in esophageal squamous cell carcinoma (SCC). These components, however, were maintained normally in some patients with esophageal SCC. In our study, the mechanism by which aggressive esophageal SCC maintains these components was investigated, with particular emphasis on the participation of c-Ski and SnoN as transcriptional co-repressors in TGF-beta signaling. Immunohistochemistry for c-Ski and SnoN was carried out on surgical specimens obtained from 80 patients with esophageal SCC. The expression of c-Ski and SnoN was also studied in 6 established cell lines derived from esophageal SCC and compared to an immortalized human esophageal cell line by Western blotting. High levels of expression of c-Ski, detected immunohistologically, were found to correlate with depth of invasion (p = 0.0080) and pathologic stage (p = 0.0447). There was, however, no significant correlation between expression of SnoN and clinicopathologic characteristics. A significant correlation between c-Ski and TGF-beta expression was observed. Moreover, in patients with TGF-beta negative expression, the survival rates of patients with c-Ski positive expression were significantly lower than those of patients with c-Ski negative expression (p = 0.0486). c-Ski was expressed at a high level in 5 of 6 cell lines derived from esophageal SCC compared to immortalized esophageal keratinocytes. Furthermore, the cyclin-dependent kinase (CDK) inhibitor, p21 that was up-regulated by TGF-beta signaling was expressed at a low level in the 5 cell lines. The expression of c-Ski protein as a transcriptional co-repressor in TGF-beta signaling seems to be correlated with tumor progression of esophageal SCC.
转化生长因子-β（TGF-β）调节细胞生长抑制，TGF-β信号通路的失活有助于肿瘤发展。在我们之前的研究中，TGF-β、TGF-β特异性受体和Smad4的表达改变与食管鳞状细胞癌（SCC）的肿瘤进展相关。然而，在一些食管SCC患者中，这些成分保持正常。在我们的研究中，研究了侵袭性食管SCC维持这些成分的机制，特别强调了c-Ski和SnoN作为TGF-β信号传导中的转录共抑制因子的参与情况。对80例食管SCC患者的手术标本进行了c-Ski和SnoN的免疫组织化学检测。还在6个源自食管SCC的已建立细胞系中研究了c-Ski和SnoN的表达，并通过蛋白质免疫印迹法与永生化人食管细胞系进行了比较。免疫组织化学检测发现，c-Ski的高表达水平与浸润深度（p = 0.0080）和病理分期（p = 0.0447）相关。然而，SnoN的表达与临床病理特征之间没有显著相关性。观察到c-Ski与TGF-β表达之间存在显著相关性。此外，在TGF-β阴性表达的患者中，c-Ski阳性表达患者的生存率显著低于c-Ski阴性表达患者（p = 0.0486）。与永生化食管角质形成细胞相比，在6个源自食管SCC的细胞系中有5个细胞系中c-Ski高水平表达。此外，TGF-β信号传导上调的细胞周期蛋白依赖性激酶（CDK）抑制剂p21在这5个细胞系中低水平表达。c-Ski蛋白作为TGF-β信号传导中的转录共抑制因子的表达似乎与食管SCC的肿瘤进展相关。
