Xin Zhang1,2, Bo Hu1,2, Yun-Fan Sun1,2, Xiao-Wu Huang1,2, Jian-Wen Cheng1,2, Ao Huang1,2, Hai-Ying Zeng3, Shuang-Jian Qiu1,2, Ya Cao4, Jia Fan1,5, Jian Zhou1,2,5,6,7, Xin-Rong Yang1,2. 1. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. 2. Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China. 3. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China. 4. Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China. 5. Institutes of Biomedical Sciences, Fudan University, Shanghai, China. 6. Shanghai Key Laboratory of Organ Transplantation, Shanghai, China. 7. State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
Abstract
OBJECTIVE: Differentiation-inducing therapy for tumors is a strategy that aims to induce the differentiation and maturation of cancer stem cells (CSCs). The differentiation-inducing capacity of arsenic trioxide (ATO) in hepatocellular carcinoma (HCC) and the underlying mechanism were previously unknown. METHODS: In the present study, we explored the ATO-induced differentiation of CSCs in HCC by detecting the expression of CSC-related markers and tumorigenicity variation in vivo and in vitro. We developed a combined chemotherapeutic approach to HCC by characterizing the effects of combinatorial treatment with 5-fluorouracil (5-FU)/cisplatin and ATO in vitro and in patient-derived xenograft models. Changes in gene expression patterns were investigated by gene microarray analysis. RESULTS: ATO effectively induced differentiation of CSCs by downregulation of CSC-related genes and suppression of tumorigenicity capability. Combinatorial treatment with ATO and 5-FU/cisplatin significantly enhanced therapeutic effects in HCC cells compared with the treatment with 5-FU/cisplatin alone. Synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways by ATO and 5-FU/cisplatin is a potential molecular mechanism underlying the differentiation effect. CONCLUSIONS: ATO induced the differentiation of HCC CSCs and potentiated the cytotoxic effects of 5-FU/cisplatin through synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways. These results offer new insights for the clinical treatment of HCC.
OBJECTIVE: Differentiation-inducing therapy for tumors is a strategy that aims to induce the differentiation and maturation of cancer stem cells (CSCs). The differentiation-inducing capacity of arsenic trioxide (ATO) in hepatocellular carcinoma (HCC) and the underlying mechanism were previously unknown. METHODS: In the present study, we explored the ATO-induced differentiation of CSCs in HCC by detecting the expression of CSC-related markers and tumorigenicity variation in vivo and in vitro. We developed a combined chemotherapeutic approach to HCC by characterizing the effects of combinatorial treatment with 5-fluorouracil (5-FU)/cisplatin and ATO in vitro and in patient-derived xenograft models. Changes in gene expression patterns were investigated by gene microarray analysis. RESULTS: ATO effectively induced differentiation of CSCs by downregulation of CSC-related genes and suppression of tumorigenicity capability. Combinatorial treatment with ATO and 5-FU/cisplatin significantly enhanced therapeutic effects in HCC cells compared with the treatment with 5-FU/cisplatin alone. Synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways by ATO and 5-FU/cisplatin is a potential molecular mechanism underlying the differentiation effect. CONCLUSIONS: ATO induced the differentiation of HCC CSCs and potentiated the cytotoxic effects of 5-FU/cisplatin through synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways. These results offer new insights for the clinical treatment of HCC.
Authors: E Lengfelder; F Lo-Coco; L Ades; P Montesinos; D Grimwade; B Kishore; S M Ramadan; M Pagoni; M Breccia; A J G Huerta; A M Nloga; J D González-Sanmiguel; A Schmidt; J-F Lambert; S Lehmann; E Di Bona; B Cassinat; W-K Hofmann; D Görlich; M-C Sauerland; P Fenaux; M Sanz Journal: Leukemia Date: 2015-01-28 Impact factor: 11.528
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