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Interleukin-23 receptor signaling mediates cancer dormancy and radioresistance in human esophageal squamous carcinoma cells via the Wnt/Notch pathway.

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 MESSAGES: IL-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.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC6348073 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Interleukin-23 receptor signaling mediates cancer dormancy and radioresistance in human esophageal squamous carcinoma cells via the Wnt/Notch pathway.

Zhou Yuepeng Y Su Yuting Y Zhu Haitao H Wang Xuefeng X Li Xiaoqin X Dai Chunhua C Xu Chengcheng C Zheng Tingting T Mao Chaoming C Chen Deyu D

Journal of molecular medicine (Berlin, Germany) 20181127 2

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<sup>+</sup>) esophageal squamous cell carcinoma (ESCC) and explored the mechanisms underlying this effect. We analyzed ESCC tumor tissues by immuno ...[more]

PMID: 30483821

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer in East Asia, with approximately half of ESCC cases occurring in China. ESCC poses a serious threat to the quality of life of patients. MicroRNAs (miRNAs) are extremely important in the occurrence and development of ESCC. Current studies have shown that miR-212-3p is expressed at low levels in esophageal adenocarcinoma tumor tissues; however, its function and mechanism in ESCC have not been studied.MethodsThe expression levels of miR-212-3p and SOX4 were detected by quantitative polymerase chain reaction (qPCR) in ESCC tissues and adjacent tissues, and ESCC cell lines from 60 patients. The interaction of miR-212-3p and SOX4 was determined using a dual-luciferase reporter gene system. EC9706 Cells were transfected with miR-212-3p mimic, NC mimic, si-NC and si-SOX4 and miR-212-3p mimic + overexpressing-SOX4, and the effects on miR-212-3p and SOX4 expression were observed, respectively. An MTT assay was carried out to detect the proliferation ability of ESCC. The invasion ability and apoptosis level of the cells were determined by Transwell assay and flow cytometry, respectively. qPCR was used to detect expression of miR-212-3p and SOX4. Western blot was performed to observe the expression of SOX4, Wnt1, β-catenin, c-Myc, and Cyclin D1.ResultsmiR-212-3P was observed to be down-regulated in ESCC tissues and cells, while SOX4 expression was up-regulated; the two were negatively correlated. The dual-luciferase reporter gene further confirmed that miR-212-3p targeted SOX4. miR-212-3p overexpression and interference with SOX4 significantly inhibited the proliferation and invasion of ESCC EC970 cells, and promoted apoptosis. Furthermore, the results of Western blot confirmed that miR-212-3p overexpression and interference with SOX4 down-regulated the expression of Wnt1, β-catenin, c-Myc, and Cyclin D1. Meanwhile, SOX4 overexpression reversed the effect of up-regulation of miR-212-3p on EC970 function.ConclusionsmiR-212-3p mediates the apoptosis and invasion of ESCC cells through inhibiting the Wnt/β-catenin signal pathway by targeting SOX4.

Dataset Information

Interleukin-23 receptor signaling mediates cancer dormancy and radioresistance in human esophageal squamous carcinoma cells via the Wnt/Notch pathway.

Publications

Interleukin-23 receptor signaling mediates cancer dormancy and radioresistance in human esophageal squamous carcinoma cells via the Wnt/Notch pathway.

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