Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China; Department of Pathology, Yanbian University College of Medicine, Yanji, China.
Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji, China.
Exp Mol Pathol. 2019 Aug;109:104239. doi: 10.1016/j.yexmp.2019.03.007. Epub 2019 Mar 20.
Although tenascin-C (TNC), an extracellular matrix protein, has been shown to be widely expressed in stromal fibroblasts in various cancers, the role of its expression in esophageal squamous cell carcinoma (ESCC) cells remains unclear. Using immunohistochemistry, we investigated the expression of cancer stem-like cell (CSC) markers, epithelial-to-mesenchymal transition (EMT)-related genes, and the Akt/hypoxia-inducible factor-1α (HIF1α) signal pathway in ESCC tissue specimens from 154 patients. We further addressed the effects of TNC on the Akt/HIF1α axis and its putative association with cancer stemness in several ESCC cell lines by immunofluorescence imaging and western blot analysis. Our data suggest that TNC expression was positively correlated with the expression of the CSC marker SOX2 (p = .002), and TNC-expressing cancer cells expressed SOX2 in ESCC tissues. Moreover, TNC expression was strongly associated with EMT-related gene Snail (p = .022) and positively correlated with pAkt-Ser473 (p = .004) and HIF1α (p = .003). Furthermore, TNC-silencing down-regulated the expression of CSC marker SOX2 (p < .001) and EMT-related marker Snail (p < .001). The Akt inhibitor Perifosine inhibited the protein expression of pAkt-Ser473, Akt, HIF1α, and TNC in TE10 (an ESCC cell line) cells. Short-term exposure of TE10 cells to cobalt chloride caused an increase in protein expression of HIF1α, TNC, and SOX2 in a time-dependent manner. Taken together, these results suggest that TNC may enhance the cancer stem-like properties and promote EMT-like changes via the Akt/HIF1α axis.
尽管细胞外基质蛋白 tenascin-C（TNC）已被证实广泛表达于多种癌症的基质成纤维细胞中，但它在食管鳞状细胞癌（ESCC）细胞中的表达作用仍不清楚。我们通过免疫组织化学法，检测了 154 例 ESCC 组织标本中癌症干细胞（CSC）标志物、上皮间质转化（EMT）相关基因以及 Akt/缺氧诱导因子-1α（HIF1α）信号通路的表达情况。我们进一步通过免疫荧光成像和 Western blot 分析，研究了 TNC 对 Akt/HIF1α 轴的影响及其与 ESCC 细胞中癌症干性的潜在关联。我们的数据表明，TNC 表达与 CSC 标志物 SOX2 的表达呈正相关（p=0.002），且 TNC 表达的癌细胞在 ESCC 组织中表达 SOX2。此外，TNC 表达与 EMT 相关基因 Snail 呈强相关性（p=0.022），且与 pAkt-Ser473（p=0.004）和 HIF1α（p=0.003）呈正相关。此外，TNC 沉默下调了 CSC 标志物 SOX2（p<0.001）和 EMT 相关标志物 Snail（p<0.001）的表达。Akt 抑制剂 Perifosine 抑制了 TE10（一种 ESCC 细胞系）细胞中 pAkt-Ser473、Akt、HIF1α 和 TNC 的蛋白表达。TE10 细胞短期暴露于氯化钴可使 HIF1α、TNC 和 SOX2 的蛋白表达呈时间依赖性增加。综上所述，这些结果表明，TNC 可能通过 Akt/HIF1α 轴增强癌症干细胞样特性并促进 EMT 样改变。
