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Item CCL5 promotes the proliferation and metastasis of bladder cancer via the JAK2/STAT3 signaling pathway(AME, 2023) Shen, Jie; Chen, Cheng; Chen, Zhen; Gong, Pengfeng; Lee, Lui Shiong; Schmeusser, Benjamin N.; Zhuang, Qianfeng; Sun, Yangyang; Xue, Dong; He, Xiaozhou; Urology, School of MedicineBackground: Non-muscle invasive bladder cancer (NMIBC) is one of the most common malignant tumors of the urinary system. There is an urgent need for further studies to elucidate the underlying mechanisms of bladder cancer (BC) progression. It has been observed that C-C chemokine ligand 5 (CCL5) and its receptor C-C chemokine receptor type 5 (CCR5) are expressed abnormally and activated in solid tumors and hematological malignancies, which is gaining increasing attention. However, the underlying mechanism of CCL5 in BC remains unclear. Methods: The expression levels of CCL5 were analyzed by real-time polymerase chain reaction (RT-PCR) and western blot. Proliferation analysis of cells was carried out using Cell Counting Kit-8 (CCK-8). The assessment of the migration was conducted using a wound-healing assay. A Matrigel-coated transwell chamber was used to test cell invasiveness. A subcutaneous transplantation tumor model and tail vein injection pulmonary metastasis tumor model were used to evaluate the proliferation and metastasis of BC cell in vivo. Results: This study showed that CCL5 promotes proliferative, migratory, and tumor-growing BC cells in vitro and tumor metastasizing BC cells in vivo. Moreover, we found that the tumor-promotive role of CCL5 is dependent on activation of the JAK2/STAT3 signaling pathway. Conclusions: CCL5 may play an oncogenic role in BC and may also serve as a potential diagnostic and prognostic biomarker.Item JAK2 regulates mismatch repair protein‐mediated epigenetic alterations in response to oxidative damage(Wiley, 2019) Ding, Ning; Miller, Sam A.; Savant, Sudha S.; O'Hagan, Heather M.; Medicine, School of MedicineAt sites of chronic inflammation epithelial cells undergo aberrant DNA methylation that contributes to tumorigenesis. Inflammation is associated with an increase in reactive oxygen species (ROS) that cause oxidative DNA damage, which has also been linked to epigenetic alterations. We previously demonstrated that in response to ROS, mismatch repair proteins MSH2 and MSH6 recruit epigenetic silencing proteins DNA methyltransferase 1 (DNMT1) and polycomb repressive complex 2 (PRC2) members to sites of DNA damage, resulting in transcriptional repression of tumor suppressor genes (TSGs). However, it was unclear what signal is unique to ROS that results in the chromatin binding of MSH2 and MSH6. Herein, we demonstrate that in response to hydrogen peroxide (H2O2), JAK2 localizes to the nucleus and interacts with MSH2 and MSH6. Inhibition or knockdown of JAK2 reduces the H2O2‐induced chromatin interaction of MSH2, MSH6, DNMT1, and PRC2 members, reduces H2O2‐induced global increase in trimethylation of lysine 27 of histone H3 (H3K27me3), and abrogates oxidative damage‐induced transcriptional repression of candidate TSGs. Moreover, JAK2 mRNA expression is associated with CpG island methylator phenotype (CIMP) status in human colorectal cancer. Our findings provide novel insight into the connection between kinase activation and epigenetic alterations during oxidative damage and inflammation. Environ. Mol. Mutagen. 2018. © 2018 Wiley Periodicals, Inc.