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河北医学  2023, Vol. 29 Issue (12): 1985-1992    DOI: 10.3969/j.issn.1006-6233.2023.12.010
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miR-21靶向PTEN调控AKT/FoxO1信号通路对胃癌细胞凋亡的机制研究
王艳花1, 聂亚楠2, 齐俊娟1, 季艳霞1
1.河北省邯郸市中心医院, 河北 邯郸 056000
2.河北省邯郸市邯钢医院, 河北 邯郸 056000
Mechanism of miR-21 Targeting PTEN to Regulate AKT/FoxO1 Signaling Pathway on Apoptosis in Gastric Cancer Cells
WANG Yanhua, et al
Handan Central Hospital, Hebei Handan 056000, China
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摘要 目的: 探究miR-21靶向PTEN调控AKT/FoxO1信号通路对胃癌细胞凋亡的影响。方法: 将胃癌SGC-7901细胞分为miR-NC inhibitors组(SGC-7901细胞中转染miR-NC inhibitors质粒)、miR-21 inhibitors组(SGC-7901细胞中转染miR-21 inhibitors质粒)、miR-21 inhibitors+sh-PTEN组(SGC-7901细胞中转染miR-21 inhibitors和sh-PTEN质粒);Control组(不转染任何质粒的SGC-7901细胞)。qRT-PCR检测细胞中miR-21 mRNA表达;采用CCK-8、Transwell小室法和流式细胞仪检测细胞增殖、侵袭能力和凋亡率;蛋白质印迹检测细胞中PTEN、AKT、p-AKT、PI3K、p-PI3K、FoxO1蛋白表达;双荧光素酶报告检测miR-21和PTEN的靶向关系。结果: 人正常胃黏膜上皮细胞GES-1(1.00±0.10)相比,胃癌细胞SGC-7901中miR-21(1.89±0.17)表达明显升高(P<0.05)。Control组相比,miR-21 inhibitors组细胞中miR-21表达(0.83±0.10)、增殖率(45.31±4.92)%、侵袭数目(62.34±5.83)个和p-PI3K/PI3K(0.42±0.05)、p-AKT/AKT(0.51±0.05)比值均明显降低,细胞凋亡率(23.48±3.51)%、PTEN(0.98±0.10)和FoxO1(0.76±0.08)蛋白表达明显升高(P<0.0001)。pcDNA-NC组相比,pcDNA-PTEN组细胞增殖率(48.26±5.01)、侵袭细胞数(65.37±6.02)个和细胞中p-PI3K/PI3K(0.46±0.05)、p-AKT/AKT(0.55±0.06)比值均明显降低,细胞凋亡率(25.61±3.27)%及细胞中PTEN(0.91±0.09)和FoxO1(0.70±0.08)蛋白表达升高(P<0.05)。预测发现PTEN的3'UTR端与miR-21有碱基互补结合点位。miR-NC组相比,转染野生型PTEN(PTEN-WT)时miR-21组(0.32±0.03)荧光素酶活性明显降低(P<0.05)。miR-21 inhibitors组相比,miR-21 inhibitors+sh-PTEN组细胞增殖率(90.25±9.14)%和侵袭细胞数(125.69±10.31)个和细胞中p-PI3K/PI3K(0.80±0.08)、p-AKT/AKT(0.76±0.08)比值明显增加,细胞凋亡率(6.24±1.32)和细胞中PTEN(0.30±0.04)、FoxO1(0.38±0.05)蛋白表达降低(P<0.0001)。结论: 敲减miR-21可靶向负调控PTEN表达,调控AKT/FoxO1信号通路,抑制胃癌细胞的增殖和侵袭,促进凋亡。
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关键词 胃癌miR-21PTENAKT/FoxO1信号通路凋亡    
AbstractObjective: To investigate the effect of miR-21 targeting PTEN to regulate AKT/FoxO1 signaling pathway on apoptosis in gastric cancer cells. Methods: Gastric cancer SGC-7901 cells were divided into miR-NC inhibitors group (SGC-7901 cells transfected with miR-NC inhibitors plasmid), miR-21 inhibitors group (SGC-7901 cells transfected with miR-21 inhibitors plasmid), miR-21 inhibitors+sh-PTEN group (SGC-7901 cells transfected with miR-21 inhibitors and sh-PTEN plasmids); and control group (SGC-7901 cells not transfected with any plasmids). qRT-PCR was performed to detect miR-21 mRNA expression in cells; CCK-8 was used to detect cell proliferation ability; Transwell assay for cell invasion shift ability; flow cytometry for apoptosis rate; protein blotting for PTEN, AKT, p-AKT, PI3K, p-PI3K, FoxO1 protein expression in cells; dual luciferase reporter for targeting relationship between miR-21 and PTEN. Results: Compared with normal human gastric mucosal epithelial cell GES-1 (1.00±0.10), the expression of miR-21 (1.89 ± 0.17) in gastric cancer cell SGC-7901 was significantly increased (P<0.05). Compared with the control group, the expression of miR-21 (0.83 ± 0.10), proliferation rate (45.31 ± 4.92)%, number of invasions (62.34 ± 5.83), and p-PI3K/PI3K (0.42 ± 0.05), p-AKT/AKT (0.51 ± 0.05) ratios were significantly reduced in the miR-21 inhibitors group, while the apoptosis rate (23.48 ± 3.51)%, PTEN (0.98 ± 0.10), and FoxO1 (0.76 ± 0.08) protein expression were significantly increased (P<0.001). Compared with the pcDNA-NC group, the cell proliferation rate (48.26 ± 5.01), number of invasive cells (65.37 ± 6.02), and p-PI3K/PI3K (0.46 ± 0.05), p-AKT/AKT (0.55 ± 0.06) ratios in the pcDNA-PTEN group were significantly reduced, while the cell apoptosis rate (25.61 ± 3.27)% and the expression of PTEN (0.91 ± 0.09) and FoxO1 (0.70 ± 0.08) proteins in the cells were increased (P<0.05). It was predicted that the 3'UTR end of PTEN had complementary binding sites with miR-21. Compared with the miR-NC group, the luciferase activity of the miR-21 group (0.32 ± 0.03) was significantly reduced (P<0.05) when transfected with wild-type PTEN (PTEN-WT). Compared with the miR-21 inhibitors group, the miR-21 inhibitors+sh-PTEN group showed a significant increase in cell proliferation rate (90.25 ± 9.14)%, invasion cell count (125.69 ± 10.31), and p-PI3K/PI3K (0.80 ± 0.08), p-AKT/AKT (0.76 ± 0.08) ratios. The apoptosis rate (6.24 ± 1.32) and the expression of PTEN (0.30 ± 0.04) and FoxO1 (0.38 ± 0.05) proteins in the cells were also decreased (P<0.001). Conclusion: Knockdown of miR-21 can target negative regulation of PTEN expression, modulate AKT/FoxO1 signaling pathway, inhibit proliferation and invasion of gastric cancer cells, and promote apoptosis.
Key wordsGastric cancer    miR-21    PTEN    AKT/FoxO1 signaling pathway    Apoptosis
    
基金资助:2020年度河北医学科研课题计划,(编号:20200195)
引用本文:   
王艳花, 聂亚楠, 齐俊娟, 季艳霞. miR-21靶向PTEN调控AKT/FoxO1信号通路对胃癌细胞凋亡的机制研究[J]. 河北医学, 2023, 29(12): 1985-1992.
WANG Yanhua, et al. Mechanism of miR-21 Targeting PTEN to Regulate AKT/FoxO1 Signaling Pathway on Apoptosis in Gastric Cancer Cells. HeBei Med, 2023, 29(12): 1985-1992.
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