State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China.
Beijing Research Institute of Orthopaedics and Traumatology, Beijing JiShuiTan Hospital, Beijing 100035, PR China.
Life Sci. 2021 Jul 1;276:119405. doi: 10.1016/j.lfs.2021.119405. Epub 2021 Mar 31.
Gastric cancer stem cells (GCSCs) have been used as a therapeutic target. This study aims to estimate the role of miR-98-5p (termed miR-98) in the development of GCSCs.
The expression of miR-98 in CD44 GCSCs was verified by RT-PCR. The miR-98 was overexpressed in CD44 GCSCs by Lentivirus. The ability of self-renewal, invasion, chemoresistance and tumorigenicity was detected in vitro or in vivo after overexpression of miR-98. The target genes of miR-98 were predicted and verified by luciferase reporter assays. The effects miR-98/BCAT1 signaling on the chemoresistance and tumorigenicity of CD44 GCSCs were investigated in a xenograft model by rescue experiments.
We have shown that miR-98 was decreased in CD44 GCSCs. The overexpression of miR-98 could inhibit the expression of stem-related genes and the ability of self-renewal, invasion, and tumorigenicity of GCSCs. Also, we found that miR-98 overexpression enhances the sensitivity to cisplatin treatment in vitro. Using a xenograft model, we showed that miR-98 overexpression reversed paclitaxel resistance to CD44 GCSCs. Finally, we found that branched-chain aminotransferases 1 (BCAT1) is a target gene of miR-98. Overexpressed BCAT1 reversed xenograft tumor formation ability and attenuated the paclitaxel chemosensitivity induced by miR-98 downregulation. Furthermore, BCAT1 restoration affected the expression of invasion and drug resistance-related genes.
This study revealed miR-98 inhibits gastric cancer cell stemness and chemoresistance by targeting BCAT1, suggesting that this miR-98/BCAT1 axis represents a potential therapeutic target in gastric cancer.
胃癌干细胞（GCSC）已被用作治疗靶点。本研究旨在评估 miR-98-5p（称为 miR-98）在 GCSC 发展中的作用。
通过 RT-PCR 验证 miR-98 在 CD44 GCSC 中的表达。通过慢病毒过表达 CD44 GCSC 中的 miR-98。过表达 miR-98 后，在体外或体内检测自我更新、侵袭、化疗耐药和致瘤能力。通过荧光素酶报告基因检测预测和验证 miR-98 的靶基因。通过挽救实验在异种移植模型中研究 miR-98/BCAT1 信号对 CD44 GCSC 化疗耐药性和致瘤性的影响。
我们已经表明 miR-98 在 CD44 GCSC 中减少。miR-98 的过表达可以抑制干细胞相关基因的表达以及 GCSC 的自我更新、侵袭和致瘤能力。此外，我们发现 miR-98 过表达增强了体外顺铂治疗的敏感性。通过异种移植模型，我们表明 miR-98 过表达逆转了紫杉醇对 CD44 GCSC 的耐药性。最后，我们发现支链氨基酸转氨酶 1（BCAT1）是 miR-98 的靶基因。过表达的 BCAT1 逆转了异种移植肿瘤形成能力，并减弱了 miR-98 下调诱导的紫杉醇化疗敏感性。此外，BCAT1 的恢复影响了侵袭和耐药相关基因的表达。
本研究表明，miR-98 通过靶向 BCAT1 抑制胃癌细胞干性和化疗耐药性，提示该 miR-98/BCAT1 轴可能成为胃癌的潜在治疗靶点。
