三氧化二砷通过协同抑制 LIF/JAK1/STAT3 和 NF-κB 信号通路诱导肝癌肿瘤干细胞分化。

Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF-kB signaling pathways synergistically.

机构信息

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.

Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.

出版信息

Clin Transl Med. 2021 Feb;11(2):e335. doi: 10.1002/ctm2.335.

DOI:10.1002/ctm2.335

PMID:33634982

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7901720/

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.

摘要

目的

肿瘤诱导分化治疗是一种旨在诱导癌症干细胞（CSC）分化和成熟的策略。三氧化二砷（ATO）在肝细胞癌（HCC）中的诱导分化能力及其潜在机制尚不清楚。

方法

在本研究中，我们通过检测CSC 相关标志物的表达和体内外肿瘤发生能力的变化，探讨了 ATO 诱导 HCC 中 CSCs 分化的情况。我们通过体外和患者来源的异种移植模型研究了 5-氟尿嘧啶（5-FU）/顺铂与 ATO 联合治疗的效果，开发了一种联合化疗治疗 HCC 的方法。通过基因微阵列分析研究了基因表达模式的变化。

结果

ATO 通过下调 CSC 相关基因和抑制肿瘤发生能力，有效地诱导 CSCs 分化。与单独使用 5-FU/顺铂相比，ATO 与 5-FU/顺铂联合治疗显著增强了 HCC 细胞的治疗效果。ATO 和 5-FU/顺铂协同抑制 LIF/JAK1/STAT3 和 NF-kB 信号通路是其分化作用的潜在分子机制。