SIRT1 通过 p53/miR-101/KPNA3 轴促进结直肠癌的进展和化疗耐药性。
SIRT1 promotes the progression and chemoresistance of colorectal cancer through the p53/miR-101/KPNA3 axis.
机构信息
Department of Anorectal Surgery, The First People's Hospital of Wenling, Wenling, China.
出版信息
Cancer Biol Ther. 2023 Dec 31;24(1):2235770. doi: 10.1080/15384047.2023.2235770.
INTRODUCTION
Sirtuin 1 (SIRT1) is a key modulator in several types of cancer, including colorectal cancer (CRC). Here, we probed into the molecular mechanism of SIRT1 regulating the development and chemoresistance of CRC.
METHODS
Differentially expressed genes related to the growth, metastasis and chemoresistance of CRC were identified by bioinformatics analysis. The expression of SIRT1 in clinical tissues from CRC patients and CRC cell lines was detected by RT-qPCR. Interactions among SIRT1, p53, miR-101 and KPNA3 were analyzed. The effect of SIRT1 on the cell viability, migration, invasion, epithelial-mesenchymal transformation and chemoresistance to 5-FU was evaluated using loss-function investigations in CRC cells. Finally, a xenograft model of CRC and a metastasis model were constructed for further exploration of the roles of SIRT1 in vivo.
RESULTS
SIRT1 was elevated in CRC tissues and cell lines. SIRT1 decreased p53 via deacetylation, and consequently downregulated the expression of miR-101 while increasing that of the miR-101 target gene KPNA3. By this mechanism, SIRT1 enhanced the proliferation, migration, invasion, epithelial-mesenchymal transformation, and resistance to 5-FU of CRC cells. In addition, in vivo data also showed that SIRT1 promoted the growth, metastasis and chemoresistance to 5-FU of CRC cells via regulation of the p53/miR-101/KPNA3 axis.
CONCLUSIONS
In conclusion, SIRT1 can function as an oncogene in CRC by accelerating the growth, metastasis and chemoresistance to 5-FU of CRC cells through the p53/miR-101/KPNA3 axis.
简介
Sirtuin 1（SIRT1）是多种癌症（包括结直肠癌（CRC））的关键调节剂。在这里，我们探讨了 SIRT1 调节 CRC 发生和化疗耐药的分子机制。
方法
通过生物信息学分析鉴定与 CRC 生长、转移和化疗耐药相关的差异表达基因。通过 RT-qPCR 检测 CRC 患者临床组织和 CRC 细胞系中 SIRT1 的表达。分析 SIRT1、p53、miR-101 和 KPNA3 之间的相互作用。在 CRC 细胞中通过功能丧失研究评估 SIRT1 对细胞活力、迁移、侵袭、上皮-间充质转化和对 5-FU 的化疗耐药性的影响。最后，构建 CRC 异种移植模型和转移模型，进一步探讨 SIRT1 在体内的作用。
结果
SIRT1 在 CRC 组织和细胞系中上调。SIRT1 通过去乙酰化降低 p53，从而下调 miR-101 的表达，同时增加 miR-101 靶基因 KPNA3 的表达。通过这种机制，SIRT1 增强了 CRC 细胞的增殖、迁移、侵袭、上皮-间充质转化和对 5-FU 的耐药性。此外，体内数据还表明，SIRT1 通过调节 p53/miR-101/KPNA3 轴促进 CRC 细胞的生长、转移和对 5-FU 的化疗耐药性。
结论
总之，SIRT1 通过 p53/miR-101/KPNA3 轴加速 CRC 细胞的生长、转移和对 5-FU 的化疗耐药性，在 CRC 中可作为一种癌基因发挥作用。
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