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// Chun-Te Wu 1,2 , Wei-Yu Lin 2,3 , Ying-Hsu Chang 2,4 , Paul-Yang Lin 2,5 , Wen-Cheng Chen 2,6 and Miao-Fen Chen 2,6 1 Department of Urology, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan 2 Chang Gung University, College of Medicine, Taoyuan City, Taiwan 3 Department of Urology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan 4 Department of Urology, Chang Gung Memorial Hospital at Linko, Taoyuan City, Taiwan 5 Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan 6 Department of Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan Correspondence to: Miao-Fen Chen, email: // Keywords : bladder cancer, miR424, DNMT1, EGFR Received : March 16, 2015 Accepted : May 30, 2015 Published : June 10, 2015 Abstract The aim of this study was to examine the role of miRNAs regulation by DNMT1 and its underlying mechanisms in bladder cancer. The choice of target miRNAs was based on the analysis of a TaqMan MicroRNA Panel assay. The role of target miRNA in tumor behavior and the related signaling pathways were assessed using the human bladder cancer cell lines. We also evaluated the predictive power of the target miRNA and its link to DNMT1 from 124 clinical bladder cancer specimens. Our results revealed that the miR-424 level is significantly increased when blocking DNMT1 in bladder cancer cells. From the clinical specimen analysis, the staining of miR-424 was inversely correlated with DNMT1 immunoreactivity. The lack of miR-424 expression was significantly linked to aggressive tumor growth, advanced clinical stage and poor prognosis in bladder cancer. Increased miR-424 suppressed the tumor growth rate and invasion ability determined in vitro and in vivo . Furthermore, the EGFR pathway plays a role in the transmission of the miR-424 signal that regulates cell growth and the epithelial-to-mesenchymal transition. These results highlight a potential role for miR-424 as a molecular predictor and therapeutic target in bladder cancer.

The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non-malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL-6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival. As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC.

// Miao-Fen Chen 1,2 , Feng-Che Kuan 2,3 , Tzu-Chen Yen 4,5 , Ming-Shian Lu 6 , Paul-Yang Lin 7 , Yi-Hsiu Chung 5 , Wen-Cheng Chen 1,2 and Kuan-Der Lee 2,3 1 Department of Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, Taiwan 2 Chang Gung University, College of Medicine, Taiwan 3 Hematology and Oncology, Chang Gung Memorial Hospital at Chiayi, Taiwan 4 Nuclear Medicine Department, Chang Gung Memorial Hospital at Linko, Taiwan 5 Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, at Linko, Taiwan 6 Thoracic & Cardiovascular Surgery, Chang Gung Memorial Hospital at Chiayi, Taiwan 7 Pathology, Chang Gung Memorial Hospital at Chiayi, Taiwan Correspondence: Miao-Fen Chen , email: // Keywords : IL-6; esophageal SCC; MDSC Received : July 07, 2014 Accepted : August 18, 2014 Published : August 19, 2014 Abstract The aim of this study was to assess the significance of myeloid-derived suppressor cells (MDSCs) and their association with IL-6 in esophageal squamous cell carcinoma (SCC). We examined the percentage of CD11b+CD14 + HLA-DR − myeloid cells and the levels of IL-6 in the peripheral blood of 50 patients with esophageal SCC and 12 healthy controls. Moreover, we evaluated the relationship between MDSC recruitment, IL-6 levels, and tumor progression by adding 4-nitroquinoline 1-oxide (4-NQO) to the drinking water of mice to induce esophageal tumors. Here we demonstrated that circulating CD11b+CD14 + HLA-DR − cells were significantly increased in esophageal SCC patients compared with healthy people, and this was associated with the clinical stage, treatment response and circulating IL-6 levels. In a 4-NQO-induced esophageal tumor animal model, MDSC recruitment was associated with invasive esophageal tumors and with increased IL-6 levels. IL-6 stimulated reactive oxygen species, arginase 1 and p-STAT3 in MDSCs. Blockade of IL-6 prevented induction of MDSCs and the incidence of 4-NQO- induced invasive tumors. In conclusion, the levels of MDSCs and IL-6 predicted the prognosis of patients with esophageal SCC. Moreover, we suggest inhibition of IL-6 as a potential strategy for the treatment of esophageal SCC.