SOX2 promotes chemoresistance, cancer stem cells properties, and epithelial-mesenchymal transition by β-catenin and Beclin1/autophagy signaling in colorectal cancer.
SOX2 promotes chemoresistance, cancer stem cells properties, and epithelial-mesenchymal transition by β-catenin and Beclin1/autophagy signaling in colorectal cancer.
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SOX2 通过 β-catenin 和 Beclin1/自噬信号在结直肠癌中促进化疗耐药、癌症干细胞特性和上皮间质转化。
DOI：
10.1038/s41419-021-03733-5
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发表时间：
2021-05-05
影响因子：
9
通讯作者：
Zheng H
中科院分区：
文献类型：
--
作者：
Zhu Y;Huang S;Chen S;Chen J;Wang Z;Wang Y;Zheng H
性别决定区Y-box 2（SOX 2）是胚胎和诱导多能干细胞的主要调节因子，驱动癌症干细胞（CSC）的特性，促进肿瘤的发生，并有助于肿瘤的侵袭性。我们以前的研究已经证明了SOX 2在结直肠癌（CRC）中的致癌作用。在这项研究中，我们试图阐明潜在的机制。体外细胞功能实验检测细胞的耐药性、增殖能力、干细胞性、迁移能力和侵袭能力。通过染色质免疫沉淀、免疫共沉淀、荧光素酶报告基因分析和免疫荧光研究SOX 2对ABCC 2、β-catenin和Beclin 1的调控。通过结直肠癌组织和异种移植模型分析SOX 2-β-catenin/Beclin 1-ABCC 2轴在体内的致癌作用。在这里，我们报道了SOX 2通过转录激活ABCC 2表达来维持化疗耐药性。抑制β-连环蛋白或自噬信号传导抑制了SOX 2驱动的化学抗性、干性和上皮-间质转化（EMT）。机制上，SOX 2与β-catenin结合并增加其核表达和转录活性。SOX 2对Beclin 1表达的转录激活，从而激活自噬并诱导恶性表型。此外，β-catenin或Beclin 1的过表达促进ABCC 2的表达。临床分析表明，ABCC 2和Beclin 1的高表达与SOX 2的表达呈正相关，且与结直肠癌患者的不良预后相关。最后，异种移植模型显示，抑制SOX 2表达和自噬抑制体内肿瘤生长和化疗耐药性。总之，我们证明了SOX 2-β-catenin/Beclin 1/自噬信号转导轴调节CRC化疗耐药性、干性和EMT的新机制。我们的研究结果为CRC致癌机制提供了新的见解，并可能有助于开发CRC的潜在治疗候选药物。
Sex-determining region Y-box2 (SOX2), a master regulator of embryonic and induced pluripotent stem cells, drives cancer stem cells (CSCs) properties, fuels tumor initiation, and contributes to tumor aggressiveness. Our previous study has demonstrated the oncogenic role of SOX2 in colorectal cancer (CRC). In this study, we sought to elucidate the underlying mechanisms. Cell function experiments were performed to detect chemoresistance, proliferation, stemness, migration, and invasion in vitro. Chromatin immunoprecipitation, co-immunoprecipitation, luciferase reporter assay, and immunofluorescence were performed to explore the regulation of ABCC2, β-catenin, and Beclin1 by SOX2. The carcinogenic role of SOX2-β-catenin/Beclin1-ABCC2 axis in vivo was analyzed by CRC tissues and xenograft models. Here, we reported that SOX2 sustained chemoresistance by transcriptional activation of ABCC2 expression. Suppressing either β-catenin or autophagy signaling curbed SOX2-driven chemoresistance, stemness, and epithelial–mesenchymal transition (EMT). Mechanistically, SOX2 combined with β-catenin and increased its nuclear expression and transcriptional activity. Transcriptional activation of Beclin1 expression by SOX2 consequently activating autophagy and inducing malignant phenotype. Furthermore, overexpression of β-catenin or Beclin1 facilitated ABCC2 expression. The clinical analyses showed that high expression of ABCC2 and Beclin1 were positively correlated with SOX2 and were associated with poor prognosis in CRC patients. Finally, xenograft models revealed that inhibition of SOX2 expression and autophagy restrained tumor growth and chemoresistance in vivo. Conclusively, we demonstrated a novel mechanism by which the SOX2-β-catenin/Beclin1/autophagy signaling axis regulates chemoresistance, stemness, and EMT in CRC. Our findings provide novel insights into CRC carcinogenesis and may help develop potential therapeutic candidates for CRC.
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