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微小RNA-21-5p通过调控转化生长因子-β2/信号转导和转录激活因子信号通路调节CD44+胃癌干细胞的顺铂耐药性。

MiR-21-5p Modulates Cisplatin-Resistance of CD44+ Gastric Cancer Stem Cells Through Regulating the TGF-β2/SMAD Signaling Pathway.

作者信息

Nie Xinyang, Liu Jian, Wang Daohan, Li Chuan, Teng Yuxin, Li Zhufeng, Jia Yangpu, Wang Peiyao, Deng Jingyu, Li Weidong, Lu Li

机构信息

Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.

Tianjin Medical University, Tianjin, People's Republic of China.

出版信息

Int J Gen Med. 2024 Oct 11;17:4579-4593. doi: 10.2147/IJGM.S476647. eCollection 2024.

DOI:10.2147/IJGM.S476647
PMID:39411053
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11476341/
Abstract

BACKGROUND

Cisplatin (DDP) resistance in gastric cancer (GC) is likely to come from gastric cancer stem cells (GCSC). It is a new idea to study the mechanism of the DDP-resistance in GCSC from miRNA.

MATERIALS AND METHODS

CD44+ GCSCs and CD44- control cells were constructed based on the HGC27 gastric cancer cell line. DDP sensitivities in CD44+ and CD44- cells were detected via CCK-8 assay. The differential expression of miR-21-5p in these cell lines was detected by RT‒qPCR. The expression levels of downstream TGF-β2, SMAD2 and SMAD3 were determined through RT‒PCR and Western blotting. A luciferase assay was used to detect the relationship between miR-21-5p and TGFB2, and the TCGA database, clinical data from our centre, and vivo experiment were used for validation. Finally, we knocked down miR-21-5p to detect changes in cisplatin resistance in GCSCs and to verify changes in the levels of downstream pathways in GCSCs.

RESULTS

CD44+ GCSCs induced cisplatin resistance compared with CD44- cells. miR-21-5p was highly expressed in GCSCs, and the TGF-β2/SMAD pathway was also highly expressed. TGFB2 was proven to be a downstream target gene of miR-21-5p and had a positive relationship with it in phenotype. After knockdown of miR-21-5p, the TGF-β2/SMAD pathway was also inhibited, and the resistance of GCSCs to cisplatin was specifically decreased.

CONCLUSION

MiR-21-5p promotes cisplatin resistance in gastric cancer stem cells by regulating the TGF-β2/SMAD signalling pathway.

摘要

背景

胃癌（GC）中的顺铂（DDP）耐药可能源于胃癌干细胞（GCSC）。从微小RNA（miRNA）研究GCSC中DDP耐药机制是一个新思路。

材料与方法

基于HGC27胃癌细胞系构建CD44 + GCSC和CD44 - 对照细胞。通过CCK - 8法检测CD44 + 和CD44 - 细胞对DDP的敏感性。通过RT - qPCR检测这些细胞系中miR - 21 - 5p的差异表达。通过RT - PCR和蛋白质免疫印迹法测定下游TGF - β2、SMAD2和SMAD3的表达水平。采用荧光素酶报告基因检测法检测miR - 21 - 5p与TGFB2之间的关系，并利用TCGA数据库、本中心的临床数据和体内实验进行验证。最后，敲低miR - 21 - 5p以检测GCSC中顺铂耐药性的变化，并验证GCSC中下游通路水平的变化。

结果

与CD44 - 细胞相比，CD44 + GCSC诱导了顺铂耐药。miR - 21 - 5p在GCSC中高表达，TGF - β2/SMAD通路也高表达。TGFB2被证明是miR - 21 - 5p的下游靶基因，且在表型上与其呈正相关。敲低miR - 21 - 5p后，TGF - β2/SMAD通路也受到抑制，GCSC对顺铂的耐药性特异性降低。

结论

MiR - 21 - 5p通过调节TGF - β2/SMAD信号通路促进胃癌干细胞的顺铂耐药。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/6d6766661aea/IJGM-17-4579-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/959e4fcde809/IJGM-17-4579-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/bab63d05797c/IJGM-17-4579-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/ce4ec05beb85/IJGM-17-4579-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/ddd2845c6e78/IJGM-17-4579-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/0955507e524c/IJGM-17-4579-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/6d6766661aea/IJGM-17-4579-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/959e4fcde809/IJGM-17-4579-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/bab63d05797c/IJGM-17-4579-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/ce4ec05beb85/IJGM-17-4579-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/ddd2845c6e78/IJGM-17-4579-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/0955507e524c/IJGM-17-4579-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aae2/11476341/6d6766661aea/IJGM-17-4579-g0006.jpg

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