转录因子B-MYB激活长链非编码RNA CCAT1并上调SOCS3，以促进结直肠癌的化疗耐药性。
Transcription factor B-MYB activates lncRNA CCAT1 and upregulates SOCS3 to promote chemoresistance in colorectal cancer.
发表日期：2023 Feb 20
作者：
Feng Liu, Yutingzi Wang, Yang Cao, Zhiwei Wu, De Ma, Jun Cai, Jie Sha, Qing Chen
来源：
CHEMICO-BIOLOGICAL INTERACTIONS
摘要：
目前，奥沙利铂（OXA）耐药已成为改善结直肠癌（CRC）患者临床结果的重要障碍。此外，长链非编码RNA（lncRNAs）已在癌症化疗耐药中有所记录，并我们的生物信息学分析表明CCAT1 lncRNA参与了CRC的发展。在这种情况下，本研究旨在阐明CCAT1在CRC耐受OXA方面效应的上游和下游机制。通过生物信息学分析，预测了CRC样本中CCAT1和上游B-MYB的表达，然后在CRC细胞系中使用RT-qPCR验证了预测结果。因此，观察到CRC细胞中B-MYB和CCAT1的过表达。使用SW480细胞系构建了OXA耐药细胞系（SW480R）。在SW480R细胞中进行B-MYB和CCAT1的异位表达和敲除实验，以阐明它们在CRC恶性表型和OXA的半数最大抑制浓度（IC50）中的作用。发现CCAT1促进了CRC细胞对OXA的耐药性。机制上，B-MYB在转录水平上激活CCAT1，CCAT1通过升高SOCS3启动子甲基化而招募DNMT1抑制SOCS3表达。通过这种机制，增强了CRC细胞对OXA的耐药性。同时，在裸鼠的SW480R细胞异种移植模型中复制了这些体外发现。总之，B-MYB可能通过调节CCAT1/DNMT1/SOCS3轴促进CRC细胞对OXA的化疗耐药性。 Copyright © 2023 Elsevier B.V. All rights reserved.
Currently, resistance to oxaliplatin (OXA) has become an important obstacle to improving the clinical outcome of patients with colorectal cancer (CRC). Moreover, long non-coding RNAs (lncRNAs) have been documented in cancer chemoresistance, and our bioinformatic analysis suggested an involvement of lncRNA CCAT1 in CRC development. In this context, this study aimed to clarify the upstream and downstream mechanisms underpinning the effect of CCAT1 in the resistance of CRC to OXA. The expression of CCAT1 and the upstream B-MYB in the CRC samples was predicted by bioinformatics analysis and then verified using RT-qPCR in CRC cell lines. Accordingly, overexpression of B-MYB and CCAT1 was observed in CRC cells. SW480 cell line was used for the construction of OXA-resistant cell line (SW480R). Ectopic expression and knockdown experiments of B-MYB and CCAT1 were conducted in SW480R cells to delineate their roles in the malignant phenotypes and half-maximal (50%) inhibitory concentration (IC50) of OXA. It was found that CCAT1 promoted the resistance of CRC cells to OXA. Mechanistically, B-MYB transcriptionally activated CCAT1, which recruited DNMT1 to inhibit SOCS3 expression through elevating the SOCS3 promoter methylation. By this mechanism, the resistance of CRC cells to OXA was enhanced. Meanwhile, these in vitro findings were reproduced in vivo on xenografts of SW480R cells in nude mice. To sum up, B-MYB might promote the chemoresistance of CRC cells to OXA via regulating the CCAT1/DNMT1/SOCS3 axis.Copyright © 2023 Elsevier B.V. All rights reserved.