Open AccessArsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF‐kB signaling pathways synergistically
Author(s) -
Zhang Xin,
Hu Bo,
Sun YunFan,
Huang XiaoWu,
Cheng JianWen,
Huang Ao,
Zeng HaiYing,
Qiu ShuangJian,
Cao Ya,
Fan Jia,
Zhou Jian,
Yang XinRong
Publication year - 2021
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.335
Subject(s) - arsenic trioxide , cancer research , cisplatin , stat3 , cancer stem cell , chemistry , hepatocellular carcinoma , downregulation and upregulation , differentiation therapy , cellular differentiation , signal transduction , stem cell , biology , microbiology and biotechnology , medicine , apoptosis , gene , chemotherapy , biochemistry , acute promyelocytic leukemia , retinoic acid
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.