上海交通大学学报(医学版) ›› 2024, Vol. 44 ›› Issue (12): 1514-1525.doi: 10.3969/j.issn.1674-8115.2024.12.004
• 论著 · 基础研究 • 上一篇
刘晨茜1,2(), 韩林3(), 杨轶1,2, 周韩1,2, 刘亚云1,2(), 盛德乔1,2()
收稿日期:
2024-02-26
接受日期:
2024-08-05
出版日期:
2024-12-28
发布日期:
2024-12-28
通讯作者:
刘亚云,盛德乔
E-mail:381212026@qq.com;527982635@qq.com;liuyyctgu@ctgu.edu.cn;834309103@qq.com
作者简介:
刘晨茜(1995—),女,硕士生;电子信箱:381212026@qq.com基金资助:
LIU Chenxi1,2(), HAN Lin3(), YANG Yi1,2, ZHOU Han1,2, LIU Yayun1,2(), SHENG Deqiao1,2()
Received:
2024-02-26
Accepted:
2024-08-05
Online:
2024-12-28
Published:
2024-12-28
Contact:
LIU Yayun,SHENG Deqiao
E-mail:381212026@qq.com;527982635@qq.com;liuyyctgu@ctgu.edu.cn;834309103@qq.com
Supported by:
摘要:
目的·探究GPR87在调节非小细胞肺癌(non-small cell lung cancer,NSCLC)侵袭和迁移中的作用及分子机制。方法·利用生物信息学方法,包括GEO、UALCAN、KM Plotter等多个公共数据库分析平台,筛选与NSCLC侵袭相关的候选基因,并预测基因与NSCLC的临床相关性。收集宜昌市中心人民医院2018年1月—2020年8月收治的80例NSCLC临床样本及对应的临床病理资料,利用免疫组化分析肿瘤组织中GPR87的表达,并对GPR87的临床相关性进行分析。用siRNA-GPR87和pCMV-GPR87-his分别转染人肺腺癌细胞系A549和人肺鳞状细胞癌细胞系SK-MES-1,构建低表达和高表达GPR87的细胞系,运用Transwell实验探究GPR87的表达对NSCLC细胞的迁移、侵袭能力的影响,通过酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)检测细胞培养上清液中MMP7的分泌量,用RT-qPCR检测GPR87、MMP2、MMP7、MMP9、E-cadherin、N-cadherin、vimentin、snail、twist、RHOA、RHOC、ROCK1的mRNA表达水平,用ELISA检测MMP7的蛋白分泌量,用Western blotting检测GPR87、MMP9、E-cadherin、vimentin、RHOA、ROCK1的蛋白表达水平。结果·生信分析和临床样本的数据显示,GPR87 mRNA和蛋白在NSCLC中高表达,且会导致患者临床分期更差、更易发生淋巴结转移,提示GPR87可能是NSCLC高侵袭性的关键基因。GPR87表达下调可显著降低A549和SK-MES-1细胞的侵袭和迁移能力,而过表达GPR87可增强A549和SK-MES-1细胞的侵袭和迁移能力。进一步检测发现,GPR87的下调导致A549和SK-MES-1细胞中MMP2、MMP7、MMP9、RHOA、RHOC和ROCK1的mRNA表达水平,MMP7的蛋白分泌量,MMP9、RHOA、ROCK1的蛋白表达水平降低;过表达GPR87增加了细胞MMP2、MMP7、MMP9、RHOA、RHOC和ROCK1的mRNA表达水平、MMP7的蛋白分泌量、MMP9、RHOA、ROCK1的蛋白表达水平。无论GPR87敲低或者过表达,上皮间质转化相关基因和蛋白的表达均无明显变化。结论·GPR87的高表达与NSCLC的高侵袭性密切相关。在SK-MES-1和A549细胞中,GPR87可通过激活RHOA/ROCK1信号通路,促进MMPs的表达,最终促进NSCLC的侵袭与迁移。
中图分类号:
刘晨茜, 韩林, 杨轶, 周韩, 刘亚云, 盛德乔. GPR87通过激活RHO/ROCK通路促进非小细胞肺癌的侵袭和迁移[J]. 上海交通大学学报(医学版), 2024, 44(12): 1514-1525.
LIU Chenxi, HAN Lin, YANG Yi, ZHOU Han, LIU Yayun, SHENG Deqiao. GPR87 promotes invasion and migration through the RHO/ROCK pathway in non-small cell lung cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(12): 1514-1525.
Name | Forward (5'→3') | Reverse (5'→3') |
---|---|---|
siRNA-GPR87-1 | GACCUUAGUUUCAAAGCUUdTdT | AAGCUUUGAAACUAAGGUCdTdT |
siRNA-GPR87-2 | GCAUCUUGCUGAAUGGUUUdTdT | AAACCAUUCAGCAAGAUGCdTdT |
NC-siRNA | UUCUCCGAACGUGUCACGUTT | ACGUGACACGUUCGGAGAATT |
表1 siRNA序列
Tab 1 Sequences of siRNA
Name | Forward (5'→3') | Reverse (5'→3') |
---|---|---|
siRNA-GPR87-1 | GACCUUAGUUUCAAAGCUUdTdT | AAGCUUUGAAACUAAGGUCdTdT |
siRNA-GPR87-2 | GCAUCUUGCUGAAUGGUUUdTdT | AAACCAUUCAGCAAGAUGCdTdT |
NC-siRNA | UUCUCCGAACGUGUCACGUTT | ACGUGACACGUUCGGAGAATT |
Gene | Forward (5'→3') | Reverse (5'→3') |
---|---|---|
GPR87 | GGAGGCGACATCAATGCAG | AAATGAAAGTAAAGAACGATTTTGTGT |
MMP2 | GCTGGAGACAAATTCTGGAGATACA | GTATCGAAGGCAGTGGAGAGGA |
MMP7 | GAGTGAGCTACAGTGGGAACA | CTATGACGCGGGAGTTTAACAT |
MMP9 | GCCACTACTGTGCCTTTGAGTC | CCCTCAGAGAATCGCCAGTACT |
E-cadherin | GCCTCCTGAAAAGAGAGTGGAAG | TGGCAGTGTCTCTCCAAATCCG |
N-cadherin | CCTCCAGAGTTTACTGCCATGAC | GTAGGATCTCCGCCACTGATTC |
vimentin | AGGCAAAGCAGGAGTCCACTGA | ATCTGGCGTTCCAGGGACTCAT |
snail | TGCCCTCAAGATGCACATCCGA | GGGACAGGAGAAGGGCTTCTC |
twist | GCCAGGTACATCGACTTCCTCT | TCCATCCTCCAGACCGAGAAGG |
RHOA | GCAGGTAGAGTTGGCTTTATGG | CTTGTGTGCTCATCATTCCGA |
RHOC | AAGACGAGCACACCAGGAGAGA | TTGGCTGAGCACTCAAGGTAGC |
ROCK1 | GAAACAGTGTTCCATGCTAGACG | GCCGCTTATTTGATTCCTGCTCC |
β-actin | CTGGAACGGTGAAGGTGACA | AAGGGACTTCCTGTAACAACGCA |
表2 RT-qPCR引物序列
Tab 2 Sequences of primers for RT-qPCR
Gene | Forward (5'→3') | Reverse (5'→3') |
---|---|---|
GPR87 | GGAGGCGACATCAATGCAG | AAATGAAAGTAAAGAACGATTTTGTGT |
MMP2 | GCTGGAGACAAATTCTGGAGATACA | GTATCGAAGGCAGTGGAGAGGA |
MMP7 | GAGTGAGCTACAGTGGGAACA | CTATGACGCGGGAGTTTAACAT |
MMP9 | GCCACTACTGTGCCTTTGAGTC | CCCTCAGAGAATCGCCAGTACT |
E-cadherin | GCCTCCTGAAAAGAGAGTGGAAG | TGGCAGTGTCTCTCCAAATCCG |
N-cadherin | CCTCCAGAGTTTACTGCCATGAC | GTAGGATCTCCGCCACTGATTC |
vimentin | AGGCAAAGCAGGAGTCCACTGA | ATCTGGCGTTCCAGGGACTCAT |
snail | TGCCCTCAAGATGCACATCCGA | GGGACAGGAGAAGGGCTTCTC |
twist | GCCAGGTACATCGACTTCCTCT | TCCATCCTCCAGACCGAGAAGG |
RHOA | GCAGGTAGAGTTGGCTTTATGG | CTTGTGTGCTCATCATTCCGA |
RHOC | AAGACGAGCACACCAGGAGAGA | TTGGCTGAGCACTCAAGGTAGC |
ROCK1 | GAAACAGTGTTCCATGCTAGACG | GCCGCTTATTTGATTCCTGCTCC |
β-actin | CTGGAACGGTGAAGGTGACA | AAGGGACTTCCTGTAACAACGCA |
ID | Padj | P value | logFC | Gene symbol |
---|---|---|---|---|
219936_s_at | 3.47×10-5 | 2.32×10-7 | 2.43 | GPR87 |
212094_at | 1.24×10-5 | 4.70×10-8 | 2.36 | PEG10 |
209278_s_at | 1.63×10-2 | 1.53×10-3 | 2.22 | TFPI2 |
227506_at | 1.25×10-5 | 5.17×10-8 | 2.14 | SLC16A9 |
206023_at | 3.69×10-4 | 6.62×10-6 | 2.12 | NMU |
205048_s_at | 3.22×10-3 | 1.44×10-4 | 2.02 | PSPH |
220393_at | 7.91×10-3 | 5.37×10-4 | -2.05 | LGSN |
213432_at | 1.33×10-3 | 3.96×10-5 | -2.17 | MUC5B |
225728_at | 2.93×10-4 | 4.65×10-6 | -2.23 | SORBS2 |
203824_at | 1.38×10-3 | 4.19×10-5 | -2.25 | TSPAN8 |
表3 与NSCLC转移及预后相关的差异表达基因
Tab 3 DEGs associated with metastasis and prognosis in NSCLC
ID | Padj | P value | logFC | Gene symbol |
---|---|---|---|---|
219936_s_at | 3.47×10-5 | 2.32×10-7 | 2.43 | GPR87 |
212094_at | 1.24×10-5 | 4.70×10-8 | 2.36 | PEG10 |
209278_s_at | 1.63×10-2 | 1.53×10-3 | 2.22 | TFPI2 |
227506_at | 1.25×10-5 | 5.17×10-8 | 2.14 | SLC16A9 |
206023_at | 3.69×10-4 | 6.62×10-6 | 2.12 | NMU |
205048_s_at | 3.22×10-3 | 1.44×10-4 | 2.02 | PSPH |
220393_at | 7.91×10-3 | 5.37×10-4 | -2.05 | LGSN |
213432_at | 1.33×10-3 | 3.96×10-5 | -2.17 | MUC5B |
225728_at | 2.93×10-4 | 4.65×10-6 | -2.23 | SORBS2 |
203824_at | 1.38×10-3 | 4.19×10-5 | -2.25 | TSPAN8 |
图1 GPR87 与 NSCLC的生物信息学分析Note: GPR87 (A) and PSPH (B) were found to correlate with poor survival in NSCLC population with KM plotter. GPR87 mRNA levels in LUAD and LUSC (C) were both overexpressed, according to the GEPIA database. High expression of GPR87 was associated with poor clinical stage (D), age (E), race (F) and TP53 mutation status (G) in patients with LUAD, and with lymph node metastasis in patients with LUSC (H) in UALCAN database. Error bars represent the x±s. ①P=0.032, ②P=0.026, compared with the adjacent normal tissues. ③P=0.006, compared with stage1 LUAD patients. ④P<0.001, compared with the 21?40 year-old patients. ⑤P=0.005, ⑥P<0.001, compared with Caucasian patients. ⑦P<0.001, compared with the TP53-mutant group. ⑧P=0.007, ⑨P=0.005, ⑩P=0.004, compared with the N3-lymph node metastasis patients.
Fig 1 Bioinformatics analysis of GPR87 and NSCLC
图2 GPR87蛋白在NSCLC临床样本中的表达Note: Protein expression of GPR87 in 80 NSCLC samples was upregulated compared to adjacent non-tumor tissues, as shown by IHC staining. LUAD—lung adenocarcinoma; LUSC—lung squamous cell carcinoma. Line 1, ×200; line 2, ×400.
Fig 2 Expression of GPR87 protein in NSCLC samples
Group | Case/n | Expression of GPR87/n | χ2 | P value | |
---|---|---|---|---|---|
High | Low | ||||
Tissue of NSCLC | 80 | 51 | 29 | 74.862 | <0.001 |
Adjacent non-tumor tissues | 80 | 0 | 80 |
表4 GPR87在NSCLC肿瘤组织及癌旁正常组织中的蛋白表达量
Tab 4 Protein expression levels of GPR87 in NSCLC tumors and adjacent non-tumor tissues
Group | Case/n | Expression of GPR87/n | χ2 | P value | |
---|---|---|---|---|---|
High | Low | ||||
Tissue of NSCLC | 80 | 51 | 29 | 74.862 | <0.001 |
Adjacent non-tumor tissues | 80 | 0 | 80 |
Factor | Case/n | Expression of GPR87/n | χ2 | P value | |
---|---|---|---|---|---|
High | Low | ||||
Subgroup | 1.524 | 0.217 | |||
LUAD | 48 | 28 | 20 | ||
LUSC | 32 | 23 | 9 | ||
Age/year | 0.197 | 0.657 | |||
≥65 | 36 | 22 | 14 | ||
<65 | 44 | 29 | 15 | ||
Gender | 0.442 | 0.506 | |||
Male | 48 | 32 | 16 | ||
Female | 32 | 19 | 13 | ||
Smoking | 0.548 | 0.459 | |||
Yes/ever | 43 | 29 | 14 | ||
No | 37 | 22 | 15 | ||
Differentiation | 1.847 | 0.174 | |||
Good | 11 | 5 | 6 | ||
Middle/poor | 69 | 46 | 23 | ||
Stage | 10.498 | 0.001 | |||
Ⅰ/Ⅱ | 65 | 36 | 29 | ||
Ⅲ/Ⅳ | 15 | 15 | 0 | ||
Lymphatic metastasis | 5.485 | 0.019 | |||
No | 50 | 27 | 23 | ||
Yes | 30 | 24 | 6 |
表5 GPR87与NSCLC患者的临床相关性分析
Tab 5 The relevance of GPR87 expression to clinicopathological characteristics in NSCLC patients
Factor | Case/n | Expression of GPR87/n | χ2 | P value | |
---|---|---|---|---|---|
High | Low | ||||
Subgroup | 1.524 | 0.217 | |||
LUAD | 48 | 28 | 20 | ||
LUSC | 32 | 23 | 9 | ||
Age/year | 0.197 | 0.657 | |||
≥65 | 36 | 22 | 14 | ||
<65 | 44 | 29 | 15 | ||
Gender | 0.442 | 0.506 | |||
Male | 48 | 32 | 16 | ||
Female | 32 | 19 | 13 | ||
Smoking | 0.548 | 0.459 | |||
Yes/ever | 43 | 29 | 14 | ||
No | 37 | 22 | 15 | ||
Differentiation | 1.847 | 0.174 | |||
Good | 11 | 5 | 6 | ||
Middle/poor | 69 | 46 | 23 | ||
Stage | 10.498 | 0.001 | |||
Ⅰ/Ⅱ | 65 | 36 | 29 | ||
Ⅲ/Ⅳ | 15 | 15 | 0 | ||
Lymphatic metastasis | 5.485 | 0.019 | |||
No | 50 | 27 | 23 | ||
Yes | 30 | 24 | 6 |
图3 GPR87 mRNA和蛋白在不同NSCLC细胞模型中的表达分析Note: Relative mRNA expression of GPR87 in SK-MES-1 and A549 cells, as predicted by CCLE (A), analyzed by RT-qPCR analysis (B), and relative protein expression of GPR87 by Western blotting analysis (C). Relative mRNA expression of GPR87 by RT-qPCR analysis (D) and relative protein expression of GPR87 by Western blotting analysis (E) in SK-MES-1 cells treated with siRNA-GPR87. GPR87 protein expression in A549 cells treated with pCMV-GPR87-his by Western blotting analysis (F). Error bars represent the x±s. ①P=0.037, ②P=0.008, compared with SK-MES-1. ③P<0.001, compared with SK-MES-1. ④P=0.008, ⑤P=0.005, ⑥P=0.006, compared with control group. ⑦P<0.001, compared with control group.
Fig 3 Analysis of GPR87 mRNA and protein expression in NSCLC cell models
图4 Transwell检测 GPR87 对NSCLC细胞迁移和侵袭的影响Note: Representative images (×200) and quantification of migrated (A) and invaded (B) cells, analyzed by using the Transwell matrix penetration assay in SK-MES-1 and A549 cells treated with siRNA-GPR87. Representative images (×200) and quantification of migrated (C) and invaded (D) cells, analyzed by Transwell matrix penetration assay in SK-MES-1 and A549 cells treated with pCMV-GPR87-his. Error bars represent the x±s. ①P<0.001, compared with the NC group. ②P=0.008, compared with the Vector group. ③P<0.001, compared with the Vector group.
Fig 4 Effect of GPR87 on migration and invasion in NSCLC cell lines by the Transwell assay
图5 GPR87 对NSCLC细胞MMPs表达的影响Note: A. The mRNA expression of MMP2, MMP7 and MMP9 in SK-MES-1 cells treated with siRNA-GPR87 was decreased, as detected by RT-qPCR. B. The protein expression of MMP7 in the supernatant of SK-MES-1 and A549 cells treated with siRNA-GPR87 was decreased, as detected by ELISA. The protein expression of active-MMP9 and GPR87 was decreased in SK-MES-1 (C) and A549 cells (D) treated with siRNA-GPR87, as detected by Western blotting. E. The mRNA expression of MMP2, MMP7 and MMP9 was increased in A549 cells treated with pCMV-GPR87-his, as detected by RT-qPCR. F. The protein expression of MMP7 in the supernatant of SK-MES-1 and A549 cells treated with pCMV-GPR87-his was increased, as detected by ELISA. The protein expression of active-MMP9 and GPR87 was increased in A549 (G) and SK-MES-1 cells (H) treated with pCMV-GPR87-his, as detected by Western blotting. Error bars represent the x±s. ①P<0.001, ②P=0.008, ③P=0.013,④P=0.041, ⑤P=0.009, ⑥P=0.043, compared with the NC group. ⑦P=0.007, ⑧P<0.001, ⑨P=0.003, ⑩P=0.002, 11P=0.005, 12P=0.008, 13P=0.001, 14P=0.021, compared with the Vector group.
Fig 5 Effect of GPR87 on the expression of MMPs in NSCLC cell lines
图6 GRP87 对NSCLC细胞EMT的影响Note: The mRNA expression (A) of E-cadherin, N-cadherin, vimentin, snail, and twist, and the protein expression (B) of E-cadherin and vimentin did not change in SK-MES-1 cells treated with siRNA-GPR87. The mRNA expression of E-cadherin, N-cadherin, and vimentin (C), and the protein expression of E-cadherin and vimentin (D) did not change in A549 cells treated with pCMV-GPR87-his. Error bars represent the x±s. ①P<0.001, compared with the NC group. ②P=0.008, compared with the Vector group.
Fig 6 Effect of GPR87 on EMT in NSCLC cell lines
图7 GPR87 对NSCLC细胞RHO/ROCK通路的影响Note: A. The mRNA expression of RHOA, RHOC and ROCK1 was decreased in SK-MES-1 cells treated with siRNA-GPR87. B. The protein expression of RHOA and ROCK1 in SK-MES-1 and A549 cells treated with siRNA-GPR87 was decreased, as detected by Western blotting. C. The mRNA expression of RHOA, RHOC and ROCK1 in A549 cells treated with pCMV-GPR87-his was increased. D. The protein expression of RHOA and ROCK1 was increased in SK-MES-1 and A549 cells treated with pCMV-GPR87-his, as detected by Western blotting. Error bars represent the x±s. ①P=0.008, ②P=0.035, ③P=0.041, ④P=0.005, ⑤P<0.001, ⑥P=0.019, ⑦P=0.026, compared with the NC group.⑧P=0.003, ⑨P=0.002, ⑩P=0.007, 11P<0.001, 12P=0.008, compared with the Vector group.
Fig 7 Effect of GPR87 on the RHO/ROCK signaling pathway in NSCLC cell lines
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