Tenascin-C is involved in promotion of cancer stemness via the Akt/HIF1ɑ axis in esophageal squamous cell carcinoma

Abstract

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.