Abstract
In the tumor microenvironment, inflammatory cells and molecules influence almost every process; among them, interleukin-23 (IL-23) is a pro-inflammatory molecule that exhibits pro- or anti-tumor properties, but both activities remain poorly understood. In this study, we investigated the effect of extracellular IL-23 in IL-23 receptor-positive (IL-23R+) esophageal squamous cell carcinoma (ESCC) and explored the mechanisms underlying this effect. We analyzed ESCC tumor tissues by immunohistochemical and immunofluorescence staining and found that IL-23, which was highly expressed, co-localized with Oct-4A in IL-23R+ ESCC cells. In addition, IL-23 treatment significantly increased the accumulation of CD133+ cells and activated the Wnt and Notch signaling pathways in CD133−IL-23R+ ESCC cell lines. Consistently, CD133−IL-23R+ cells pretreated with IL-23 showed stronger anti-apoptosis activity when exposed to radiation and higher survival than untreated groups. Moreover, the inhibition of Wnt/Notch signaling by a small-molecule inhibitor or siRNA abolished the effect of IL-23-induced dormancy and consequent radioresistance. Taken together, these results suggested that IL-23 facilitates radioresistance in ESCC by activating Wnt/Notch-mediated G0/1 phase arrest, and attenuating these detrimental changes by blocking the formation of dormancy may prove to be an effective pretreatment for radiotherapy.Key messagesIL-23/IL-23R is correlated with the acquisition of stem-like potential in ESCC.CD133−IL-23R+ ESCCs acquired dormancy via IL-23.Radioresistance depends on IL-23-mediated Wnt/Notch pathway activation in vitro and vivo.
Highlights
Diagnosing esophageal squamous cell carcinoma (ESCC) in the early stage is difficult because the clinical manifestations, such as esophageal obstruction and burning or aching with a concurrent dragging sensation, tend to be ignored or even misdiagnosed [1]
The results showed that high-intensity IL-23 clustered in the vessels, surrounding small lymph nodes, the edges of tumors, and areas infiltrated by cancer cells in the tumor tissues (Fig. 1a and Supplementary Fig. 1)
The data are presented as the mean ± SD from at least three independent experiments. **p < 0.01 we found that treating IL-23R+ ESCCs with extracellular IL23 stimulated the expression of Wnt3a (> 3.0-fold change, p < 0.01), Notch1 (> 1.9-fold change, p < 0.05), Cyclin D1(the mRNA level, p < 0.01), and Hes-1(p < 0.01), and this effect was attenuated by WHI-P154, while the pretreatment of anti-IL-23R blocked the phosphorylation cascades and activated Wnt/Notch that trigged by IL-23 (Fig. 2f, g)
Summary
Diagnosing esophageal squamous cell carcinoma (ESCC) in the early stage is difficult because the clinical manifestations, such as esophageal obstruction and burning or aching with a concurrent dragging sensation, tend to be ignored or even misdiagnosed [1]. Cancer cells with stem cell–like features like dormancy have been identified in hematological diseases and solid tumors widely [8, 9]. Accumulating evidence shows that cancer cells possessing stem-like properties exhibit an EMT phenotype that enables cells to survive and actively cause relapse, a better understanding of the causes of EMT could provide a foundation for tumor treatment [15, 16]. Tumorinfiltrating lymphocytes (TILs) and their associated cytokines, which are generally associated with better clinical outcomes, play an immune-editing role in cancer, in therapy resistance [10, 17, 18]. The tumor-promoting role of immune factors in the formation of cancer stem-like cells has rarely been reported
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