Radiotherapy for treating breast cancer is associated with cardiac damage. This study aimed to investigate the role of the interleukin (IL)-33/soluble receptor ST2 (sST2) axis in radiation-induced cardiac injury. Expressions of IL-33 and sST2 were detected in breast cancer patients following radiotherapy, radiation-induced cardiac damaged mice model, and cardiomyocytes using quantitative real-time PCR (qRT-PCR) and immunohistochemical assay. Cardiac injury was evaluated through an ultrasound imaging system and hematoxylin & eosin staining. The transcriptional factor was assessed using dual-luciferase reporter assay and chromatin immunoprecipitation. The results indicated that IL-33 and sST2 were highly expressed in breast cancer patients, which further elevated post-6 months but reduced after 12 months of radiotherapy. Radiation induces cardiac dysfunction and elevated IL-33 and sST2 levels in a time-dependent manner. However, silencing of IL-33 decreased sST2 expression to alleviate radiation-induced cardiac dysfunction. The IL-33 could be transcriptional activated by TCF7L2 by binding to IL33 promoter sites, which mutation alleviated cardiomyocyte injury caused by radiation. Additionally, radiation treatment resulted in higher levels of TCF7L2, IL-33, and sST2 in cardiomyocytes, and TCF7L2 knockdown reduced IL-33 and sST2 expression. In conclusion, TCF7L2 transcriptional-activated IL-33 mediated sST2 to regulate radiation-induced cardiac damage, providing novel insights into radiotherapy-induced cardiac damage.
Graphical abstract
Chao Weng,Man Ding,Shanghua Fan,Qian Cao,Zuneng Lu
Transcription factor 7 like 2 (TCF7L2, also termed TCF4), is a Wnt effector induced transiently in the oligodendroglial lineage. The current well accepted hypothesis is that TCF7L2 inhibits oligodendrocyte differentiation and remyelination through canonical Wnt/β‑catenin signaling. However, recent studies indicated that TCF7L2 activity is required during oligodendrocyte differentiation and remyelination. In order to clarify this, in situ hybridization, immunofluorescence and western blot analysis using in vivo TCF7L2 conditional knockout mice, were performed and it was found that TCF7L2 promotes oligodendrocyte differentiation during myelin formation and remyelination. Furthermore, it was established that TCF7L2 does not affect oligodendrocyte precursor cells during remyelination. These data are of important clinical significance to develop novel therapeutic targets to overcome multiple sclerosis and other demyelinating diseases.
Peng He,Guoguang Xiong,Wei Guo,Guanjun Jiang,Yun Li,Hao Li
Long non‑coding RNA colon cancer associated transcript 2 (CCAT2) is dysregulated in a number of different types of human cancer, and affects cancer progression via the Wnt/β‑catenin signaling pathway. However, the roles of CCAT2 and the Wnt/β‑catenin signaling pathway in prostate cancer (PCa) are not completely understood. The present study aimed to investigate the potential mechanism of CCAT2 in PCa. In the present study, the reverse transcription‑quantitative PCR (RT‑qPCR) results indicated that CCAT2 expression was significantly upregulated in PCa tissues, and DU145 and PC3 cell lines compared with normal prostate tissues and the epithelial RWPE‑1 cell line, respectively. Functional assays indicated that CCAT2 downregulation inhibited DU145 and PC3 cell proliferation, cell cycle, migration and invasion. In addition, the luciferase reporter assay, RT‑qPCR and western blotting results indicated that CCAT2 regulated transcription factor 7 like 2 (TCF7L2) expression by binding to microRNA‑217. Further western blotting and TOPFlash assays indicated that CCAT2‑knockdown inhibited the Wnt/β‑catenin signaling pathway in DU145 and PC3 cell lines by inhibiting the expression of TCF7L2. However, CCAT2‑knockdown‑mediated effects were reversed by the Wnt/β‑catenin signaling pathway activator lithium chloride (LiCl). Further cell experiments suggested that LiCl treatment reversed CCAT2‑knockdown‑mediated inhibition of PCa cell proliferation, cell cycle, epithelial‑mesenchymal transition, migration and invasion. Overall, the results indicated that CCAT2 regulated PCa via the Wnt/β‑catenin signaling pathway; therefore, CCAT2 may exhibit key role during the progression of PCa and may serve as a therapeutic target for the disease.
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