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中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2021, Vol. 11 ›› Issue (03) : 161 -170. doi: 10.3877/cma.j.issn.2095-1221.2021.03.005

论著

LncRNA MIR4435-2HG调控miR-138-5p/HMGA1轴对胃癌细胞的增殖、侵袭和迁移的影响
谭志慧1, 郑倩1, 李爱娟2, 彭艳1,†()   
  1. 1. 423000　郴州，湖南省郴州市第一人民医院消化内科
    2. 423000　郴州，湖南省郴州市第一人民医院南院肿瘤科
  • 收稿日期:2019-07-23 出版日期:2021-06-01
  • 通信作者: 彭艳

The effect of lncRNA MIR4435-2HG on the proliferation, invasion and migration of gastric cancer cells by regulating miR-138-5p/HMGA1 axis

Zhihui Tan1, Qian Zheng1, Aijuan Li2, Yan Peng1,†()   

  1. 1. Department of Gastroenterology, First People's Hospital of Chenzhou City, Chenzhou 423000, China
    2. Department of Oncology, Southern Branch, First People's Hospital of Chenzhou City, Chenzhou 423000, China
  • Received:2019-07-23 Published:2021-06-01
  • Corresponding author: Yan Peng
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谭志慧, 郑倩, 李爱娟, 彭艳. LncRNA MIR4435-2HG调控miR-138-5p/HMGA1轴对胃癌细胞的增殖、侵袭和迁移的影响[J]. 中华细胞与干细胞杂志(电子版), 2021, 11(03): 161-170.

Zhihui Tan, Qian Zheng, Aijuan Li, Yan Peng. The effect of lncRNA MIR4435-2HG on the proliferation, invasion and migration of gastric cancer cells by regulating miR-138-5p/HMGA1 axis[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2021, 11(03): 161-170.

目的

探讨LncRNA MIR4435-2HG对胃癌细胞增殖、侵袭和迁移的影响及作用机制。

方法

培养正常人胃黏膜上皮细胞GES-1和胃癌细胞系AGS、SGC7901、BGC823和BGC803，AGS细胞分为对照组（正常培养细胞）、si-con组（转染乱序无意义阴性序列）、si-MIR4435-2HG组（转染MIR4435-2HG小干扰RNA）、miR-con组（转染模拟物对照序列）、miR-138-5p组（转染miR-138-5p模拟物）、si-HMGA1组（转染HMGA1小干扰RNA）、si-MIR4435-2HG+pcDNA组（共转染MIR4435-2HG小干扰RNA与空载体）和si-MIR4435-2HG+ pcDNA-HMGA1组（共转染MIR4435-2HG小干扰RNA与HMGA1过表达载体）。qRT-PCR检测细胞中MIR4435-2HG和高迁移率族蛋白A1（HMGA1）mRNA表达，Western blot检测细胞中HMGA1蛋白表达。双荧光素酶实验验证AGS细胞中MIR4435-2HG与miR-138-5p以及miR-138-5p与HMGA1之间关系。MTT检测细胞增殖，Transwell检测细胞迁移和侵袭，Western blot检测Ki67、CyclinD1、MMP2和MMP9蛋白表达。裸鼠分为对照组（接种正常培养的AGS细胞）、sh-MIR4435-2HG组（接种转染携带MIR4435-2HG基因短发夹RNA慢病毒的AGS细胞）和sh-con组（接种转染携带无关序列片段shRNA慢病毒的AGS细胞），接种21 d后测量肿瘤重量，观察MIR4435-2HG对裸鼠移植瘤生长的影响。两组间比较采用独立样本t检验，多组间比较采用单因素方差分析，组间两两比较采用SNK-q检验。

结果

与GES-1细胞比较，胃癌细胞AGS、SGC7901、BGC823、BGC803中MIR4435-2HG表达水平升高，HMGA1 mRNA和蛋白表达水平升高（P均< 0.05），选择AGS细胞进行后续实验。MIR4435-2HG靶向负调控miR-138-5p表达，miR-138-5p靶向负调控HMGA1表达。与si-con组比较，si-MIR4435-2HG组AGS细胞48 h OD值（1.13±0.12比0.86± 0.09）、迁移数量[（179.23±18.01）个比（60.15±6.05）个]、侵袭数量[（81.26±8.16 ）个比（25.64±2.59）个]、Ki67、CyclinD1、MMP2和MMP9蛋白表达水平均降低（P均< 0.05）。与miR-con组比较，miR-138-5p组AGS细胞48 h OD值（1.28±0.13比0.85±0.09）、迁移数量[（178.26±17.59）个比（69.35±6.34）个]、侵袭数量[（81.02±8.06）个比（36.76±2.49）个]、Ki67、CyclinD1、MMP2和MMP9蛋白表达水平均降低（P均< 0.05）。与si-con组比较，si-HMGA1组AGS细胞48 h OD值（1.28±0.13比0.83±0.09）、迁移数量[（175.62±17.59）个比（63.26±6.34）个]、侵袭数量[（80.16±8.06）个比（24.56±2.49）个]、Ki67蛋白表达水平（0.84±0.09比0.30±0.03），CyclinD1、MMP2和MMP9蛋白表达水平均降低（P均< 0.05）。与si-MIR4435-2HG+pcDNA组比较，si-MIR4435-2HG+pcDNA-HMGA1组AGS细胞48 h OD值（0.80±0.09比1.01±0.11）、迁移数量[（60.45±5.79）个比（119.25±12.46）个]、侵袭数量[（23.46± 2.34）个比（59.46±6.29）个]、Ki67、CyclinD1、MMP2和MMP9蛋白表达水平均升高（P均< 0.05）。与sh-con组比较，sh-MIR4435-2HG组裸鼠体内移植瘤重量[（0.40±0.03）g比（0.13±0.03）g]降低（P < 0.05）。

结论

MIR4435-2HG在胃癌细胞系中高表达，沉默MIR4435-2HG表达可能通过调控miR-138-5p/HMGA1轴抑制胃癌细胞体外增殖、迁移和侵袭，并抑制体内肿瘤生长。

关键词: 胃癌, MIR4435-2HG, miR-138-5p, HMGA1, 细胞增殖, 侵袭, 迁移
Objective

To investigate the effects of LncRNA MIR4435-2HG on proliferation, invasion and migration of gastric cancer cells and its mechanism.

Methods

Normal human gastric mucosa epithelial cells (GES-1) and gastric cancer cell lines (including AGS, SGC7901, BGC823 and BGC803) were cultured in vitro. The levels of MIR4435-2HG and HMGA1 mRNA were detected by qRT-PCR and HMGA1 protein was detected by Western Blot. Dual luciferase experiment was used to verify the relationships between MIR4435-2HG and miR-138-5p, miR-138-5p and HMGA1 in AGS cells. AGS cells were divided into NC group (control), si-con group (transfected with random nonsense negative sequence), si-MIR4435-2HG group (transfected with MIR4435-2HG small interfering RNA), miR-con group (transfected with mimic control sequence), miR-138-5p group (transfected with miR-138-5p mimics), si-HMGA1 group (transfected with HMGA1 small interfering RNA), si-MIR4435-2HG+pcDNA group (co-transfected with MIR4435-2HG small interfering RNA and empty vector) and si-MIR4435-2HG+pcDNA-HMGA1 group (co-transfected with MIR4435-2HG small interfering RNA and HMGA1 overexpression vector). Then, in all the cell lines, cell proliferation was detected by MTT, and cell migration and invasion were detected by Transwell, at the same time, the protein levels of Ki67, CyclinD1, MMP2 and MMP9 were detected by Western blot. Another in vivo animal model was established, nude mice were divided into NC group (inoculated with normal cultured AGS cells), sh-MIR4435-2HG group (inoculated and transfected with AGS cells carrying the short hairpin RNA lentivirus of MIR4435-2HG gene) and sh-con group (inoculated with AGS cells transfected with shRNA lentiviruses carrying irrelevant sequence fragments). Then, the tumor weight was measured after 21 days, and the effect of MIR4435-2HG on the growth of transplanted tumors in nude mice was observed.

Results

Compared with GES-1, the levels of MIR4435-2HG in AGS, SGC7901, BGC823 and BGC803 were significantly increased (P < 0.05), and the levels of HMGA1 mRNA and protein were significantly increased (P < 0.05). Thus, AGS cells were used to conduct follow-up experiments and the results were showed that MIR4435- 2HG negatively regulated by miR-138-5p, and miR-138-5p negatively regulated by HMGA1. Compared with the si-con group, 48 h later, the OD value in the si-MIR4435-2HG group significantly reduced (1.13±0.12 vs 0.86±0.09, P < 0.05), migration and invasion rate also significantly reduced (179.23±18.01 vs 60.15±6.05, 81.26±8.16 vs 25.64±2.59, respectively, P < 0.05), and the protein expression of Ki67, CyclinD1, MMP2 and MMP9 also significantly reduced (P < 0.05). Compared with the miR-con group, after 48 h, the OD value in the miR-138-5p group reduced (1.28±0.13 vs 0.85±0.09, P < 0.05), and migration and invasion rate also significantly reduced (178.26±17.59 vs 69.35±6.34, 81.02±8.06 vs 36.76±2.49, respectively, P < 0.05), and the protein expression of Ki67, CyclinD1, MMP2 and MMP9 significantly reduced (P < 0.05). Compared with the si-con group, the OD value in the si-HMGA1 group reduced at 48 h (1.28±0.13 vs 0.83±0.09, P < 0.05), migration and invasion rate reduced significantly (175.62±17.59 vs 63.26±6.34, 80.16±8.06 vs 24.56±2.49, respectively, P < 0.05), and the protein expression of Ki67, CyclinD1, MMP2 and MMP9 significantly reduced (P < 0.05). Compared with si-MIR4435-2HG+pcDNA group, the OD value in the si-MIR4435-2HG+pcDNA-HMGA1 group significantly increased at 48 h (0.80±0.09 vs 1.01±0.11, P < 0.05), and migration, invasion rate also significantly increased (60.45±5.79 vs 119.25±12.46, 23.46±2.34 vs 59.46±6.29, respectively, P < 0.05), and the protein expression of Ki67, CyclinD1, MMP2 and MMP9 increased (P < 0.05). Compared with the sh-con group, only the weight of transplanted tumors in nude mice of sh-MIR4435-2HG group was significantly reduced [(0.40±0.03)g vs (0.13±0.03)g, P < 0.05].

Conclusion

MIR4435-2HG was highly expressed in gastric cancer cells. Silencing MIR4435-2HG expression may inhibit the proliferation, migration and invasion of gastric cancer cells in vitro and inhibit tumor growth in vivo by regulating miR-138-5p/HMGA1 axis.

Key words: Gastric cancer, LncRNA MIR4435-2HG, miR-138-5p, HMGA1, Cell proliferation, Invasion, Migration
表1 引物序列信息
基因 序列（5’→3’） 预期扩增产物长度（bp）
MIR4435-2HG 上游CGGAGCATGGAACTCGACA 242
下游CAAGTCTCACACATCCGGG
HMGA1 上游GAAAAGGACGGCACTGAGAA 236
下游CTTCCTGGAGTTGTGGTGGT
GAPDH 上游AAGGTGAAGGTCGGAGTCA 198
下游AATGAAGGGGTCATTGATG
miR-138-5p 上游GGGAGCTGGTGTGTGAAT 106
下游CAGTGCGTGTCGTGGAGT
U6 上游TGCATCTCCATCTTCTACCCAAT 134
下游CCGACTGTGAGTGCCACTGT
表2 胃癌细胞中MIR4435-2HG和HMGA1表达（±s）
分组 实验次数 MIR4435-2HG HMGA1mRNA HMGA1蛋白
GES-1 3 0.56±0.06 0.84±0.05 0.34±0.05
AGS 3 2.56±0.26a 2.35±0.12a 1.15±0.12a
SGC7901 3 1.98±0.21a 2.15±0.10a 1.05±0.10a
BGC823 3 2.05±0.20a 2.01±0.10a 1.01±0.10a
BGC803 3 2.21±0.23a 1.95±0.09a 1.03±0.09a
F值   127.104 348.800 106.580
P值   < 0.001 < 0.001 < 0.001
图1 Western blot检测HMGA1蛋白表达
表3 miR-138-5p对WT-MIR4435-2HG和MUT-MIR4435-2HG荧光素酶活性影响（±s）
分组 实验次数 WT-MIR4435-2HG MUT-MIR4435-2HG
miR-con 3 1.00±0.10 1.01±0.11
miR-138-5p 3 0.42±0.05 0.98±0.11
t值   15.563 0.579
P值   <0.001 0.571
图2 MIR4435-2HG与miR-138-5p核苷酸序列结合位点
表4 miR-138-5p对WT-HMGA1和MUT-HMGA1荧光素酶活性影响（±s）
分组 实验次数 WT MUT
miR-con 3 1.02±0.10 1.00±0.12
miR-138-5p 3 0.39±0.05 1.01±0.10
t值   16.905 0.192
P值   < 0.001 0.850
表5 MIR4435-2HG靶向miR-138-5p调控HMGA1表达（±s）
分组 实验次数 miR-138-5p HMGA1蛋白
si-con 3 1.00±0.10 1.13±0.07
si-MIR4435-2HG 3 2.13±0.14 0.35±0.02
t值   18.548 32.142
P值   < 0.001 < 0.001
si-MIR4435-2HG+anti-miR-con 3 2.10±0.12 0.37±0.01
si-MIR4435-2HG+anti-miR-138-5p 3 1.30±0.05 0.81±0.04
t值   26.740 32.015
P值   < 0.001 < 0.001
图3 MIR4435-2HG靶向miR-138-5p调控HMGA1表达
表6 沉默MIR4435-2HG抑制AGS细胞增殖、侵袭和迁移及裸鼠移植瘤生长（±s，n = 3）
分组 OD490 nm 迁移数（个） 侵袭数（个） Ki67 CyclinD1 MMP2 MMP9
0 h 24 h 48 h 72 h
对照组 0.35±0.04 0.63±0.06 1.19±0.12 1.89±0.19 180.01±18.10 80.23±8.05 0.86±0.08 1.23±0.12 1.05±0.11 0.95±0.10
si-con 0.34±0.04 0.60±0.07 1.13±0.12 1.82±0.19 179.23±18.01 81.26±8.16 0.88±0.09 1.20±0.15 1.03±0.11 0.99±0.10
si-MIR4435-2HG 0.34±0.03 0.52±0.06ab 0.86±0.09ab 1.36±0.14ab 60.15±6.05ab 25.64±2.59ab 0.32±0.03ab 0.48±0.05ab 0.37±0.06ab 0.40±0.05ab
F值 0.220 7.215 22.610 24.382 186.563 197.950 176.961 123.556 145.424 130.440
P值 0.805 0.004 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
图4 Western blot检测Ki67、CyclinD1、MMP2和MMP9蛋白表达水平
图5 倒置显微镜观察细胞迁移和侵袭（结晶紫染色，×200）
图6 小鼠移植瘤重量比较
表7 miR-138-5p过表达抑制胃癌细胞AGS增殖、迁移和侵袭（±s，n = 3）
分组 OD490 nm 迁移数（个） 侵袭数（个） Ki67 CyclinD1 MMP2 MMP9
0 h 24 h 48 h 72 h
对照组 0.32±0.04 0.64±0.07 1.20±0.12 1.88±0.21 175.63±15.26 80.88±8.23 0.85±0.08 1.18±0.12 1.02±0.11 0.98±0.10
miR-con 0.33±0.04 0.68±0.07 1.28±0.13 1.93±0.20 178.26±17.59 81.02±8.06 0.86±0.09 1.15±0.12 1.05±0.10 0.96±0.10
miR-138-5p 0.33±0.03 0.51±0.06ab 0.85±0.09ab 1.45±0.15ab 69.35±6.34ab 36.76±2.49ab 0.28±0.03ab 0.45±0.05ab 0.38±0.05ab 0.35±0.04ab
F值 0.220 15.918 35.840 17.637 178.956 126.533 193.266 147.192 153.309 160.292
P值 0.805 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
图7 Western blot检测Ki67、CyclinD1、MMP2、MMP9蛋白表达
表8 沉默HMGA1基因抑制AGS细胞的增殖、迁移和侵袭（±s，n = 3）
分组 HMGA1蛋白 OD490 nm 迁移数（个）
0 h 24 h 48 h 72 h
对照 1.12±0.08 0.35±0.04 0.65±0.07 1.21±0.12 1.91±0.21 178.59±15.26
si-con 1.10±0.07 0.33±0.04 0.70±0.07 1.28±0.13 1.97±0.20 175.62±17.59
si-HMGA1 0.48±0.04ab 0.33±0.03 0.50±0.06ab 0.83±0.09ab 1.35±0.15ab 63.26± 6.34ab
F值   0.878 21.828 40.180 29.617 200.363
P值 < 0.001 0.429 < 0.001 < 0.001 < 0.001 < 0.001
分组 侵袭数（个） HMGA1 Ki67 CyclinD1 MMP2 MMP9
对照 81.25±8.23 1.12±0.12 0.88±0.08 1.20±0.12 1.06±0.11 1.01±0.10
si-con 80.16±8.06 1.15±0.12 0.84±0.09 1.18±0.12 1.05±0.10 0.98±0.10
si-HMGA1 24.56±2.49ab 0.36±0.04ab 0.30±0.03ab 0.45±0.05ab 0.40±0.05ab 0.42±0.06ab
F值 204.313 178.016 183.974 157.543 156.988 126.343
P值 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
图8 Western blot检测HMGA1、Ki67、CyclinD1、MMP2和MMP9蛋白表达
表9 HMGA1过表达部分逆转MIR4435-2HG对AGS细胞增殖、迁移和侵袭的影响（±s，n = 3）
分组 HMGA1 mRNA OD490 nm 迁移数（个）
0 h 24 h 48 h 72 h
si-con 2.30±0.25 0.35±0.05 0.62±0.07 1.15±0.12 1.85±0.19 147.56±14.56
si-MIR4435-2HG 0.89±0.11a 0.34±0.04 0.50±0.05a 0.85±0.09a 1.35±0.14a 61.23±6.04a
si-MIR4435-2HG+pcDNA-con 0.91±0.10 0.34±0.04 0.52±0.06 0.80±0.09 1.30±0.14 60.45±5.79
si-MIR4435-2HG+pcDNA-HMGA1 1.82±0.20b 0.34±0.05 0.60±0.07b 1.01±0.11b 1.68±0.17b 119.25±12.46b
F值 140.706 0.110 7.849 21.379 155.390 155.518
P值 < 0.001 0.954 < 0.001 < 0.001 < 0.001 < 0.001
分组 侵袭数（个） HMGA1蛋白 Ki67 CyclinD1 MMP2 MMP9
si-con 80.16±8.01 1.05±0.12 0.88±0.09 1.10±0.10 0.95±0.10 1.05±0.11
si-MIR4435-2HG 22.16±2.59a 0.43±0.05a 0.35±0.04a 0.40±0.05a 0.38±0.04a 0.45±0.05a
si-MIR4435-2HG+pcDNA-con 23.46±2.34 0.45±0.05 0.36±0.05 0.38±0.04 0.39±0.05 0.44±0.06
si-MIR4435-2HG+pcDNA-HMGA1 59.46±6.29b 0.72±0.07b 0.72±0.07b 0.85±0.09b 0.80±0.10b 0.78±0.09b
F值 250.967 129.577 147.982 201.986 125.178 117.445
P值 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
图9 Western blot检测HMGA1、Ki67、CyclinD1、MMP2和MMP9蛋白表达
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