GPR87通过激活RHO/ROCK通路促进非小细胞肺癌的侵袭和迁移

doi:10.3969/j.issn.1674-8115.2024.12.004

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

GPR87通过激活RHO/ROCK通路促进非小细胞肺癌的侵袭和迁移

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()

^1.三峡大学肿瘤微环境与免疫治疗湖北省重点实验室，宜昌 443002
^2.三峡大学基础医学院，宜昌 443002
^3.三峡大学第一临床医学院，湖北省宜昌市中心人民医院病理科，宜昌 443002

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
韩林（1974—），男，硕士生；电子信箱：527982635@qq.com。第一联系人：（刘晨茜、韩林并列第一作者）
基金资助:
湖北省科技厅自然科学基金青年基金项目(2021CFB065);肿瘤微环境与免疫治疗湖北省重点实验室开放基金(2023KZL025)

GPR87 promotes invasion and migration through the RHO/ROCK pathway in non-small cell lung cancer

LIU Chenxi¹^,²(), HAN Lin³(), YANG Yi¹^,², ZHOU Han¹^,², LIU Yayun¹^,²(), SHENG Deqiao¹^,²()

^1.Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China
^2.College of Basic Medical Science, China Three Gorges University, Yichang 443002, China
^3.Department of Pathology, Yichang Central People's Hospital and The First College of Clinical Medical Science, China Three Gorges University, Yichang 443002, China

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:
Natural Science Foundation of Hubei Province(2021CFB065);Open Foundation of Hubei Province Key Laboratory of Tumor Microenvironment and Immunotherapy(2023KZL025)

摘要/Abstract

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。

关键词: GPR87, 非小细胞肺癌, 侵袭, 迁移, RHO/ROCK通路

Abstract:

Objective ·To explore the role and molecular mechanism of GPR87 in regulating the invasion and migration of non-small cell lung cancer (NSCLC). Methods ·Bioinformatics methods, including GEO, UALCAN, KM Plotter and other public database analysis platforms, were used to screen candidate genes related to NSCLC invasion and predict their clinical relevance to NSCLC. Eighty NSCLC clinical patient samples and corresponding clinical pathological data were collected from Yichang Central People's Hospital from January 2018 to August 2020. Immunohistochemistry was used to analyze the expression of GPR87 in tumor tissues and the clinical relevance of GPR87 was analyzed. siRNA-GPR87 and pCMV-GPR87-his were transfected into the human lung adenocarcinoma cell line A549 and the human lung squamous cell carcinoma cell line SK-MES-1, to construct cell lines with low and high expression of GPR87. Transwell assay was used to investigate the effect of GPR87 expression on the migration and invasion ability of NSCLC cells. ELISA was used to detect the secretion of MMP7 in the culture supernatant. RT-qPCR was used to detect the mRNA expression levels of GPR87, MMP2, MMP7, MMP9, E-cadherin,N-cadherin, vimentin,snail,twist, RHOA, RHOC, and ROCK1. ELISA was used to detect the secreted protein MMP7. Western blotting was used to detect the protein expression levels ofGPR87, MMP9, E-cadherin, vimentin, RHOA, and ROCK1. Results ·Bioinformatics analysis of clinical sample data showed that GPR87 was highly expressed in NSCLC. Patients with higher expression of GPR87 had worse clinical stage and were more prone to lymph node metastasis, suggesting that GPR87 might be a key gene for the high invasiveness of NSCLC. Downregulation of GPR87 expression significantly reduced the invasion and migration ability of A549 and SK-MES-1 cells, while overexpression of GPR87 enhanced the invasion and migration ability of A549 and SK-MES-1 cells. Further detection revealed that downregulation of GPR87 led to decreased mRNA expression levels of MMP2, MMP7, MMP9, RHOA, RHOC, and ROCK1, as well as a reduction in the secretion of MMP7 and the protein expression levels of MMP9, RHOA, and ROCK1 in A549 and SK-MES-1 cells. Overexpression of GPR87 increased the mRNA expression levels of MMP2, MMP7, MMP9, RHOA, RHOC, and ROCK1, as well as the secretion of MMP7 and the protein expression levels of MMP9, RHOA, and ROCK1. Regardless of GPR87 knockdown or overexpression, the expression of genes and proteins related to epithelial-mesenchymal transition (EMT) in the cells did not change significantly. Conclusion ·High expression of GPR87 is closely related to the high invasiveness of NSCLC. In SK-MES-1 and A549 cells, GPR87 can activate the RHOA/ROCK1 signaling pathway, promote the expression of MMPs, and ultimately promote the invasion and migration of NSCLC.

Key words: GPR87, non-small cell lung cancer (NSCLC), invasion, migration, RHO/ROCK signaling pathway

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.

图/表 12

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

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

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	P_adj	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

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
Group	Case/n	High	Low	χ²	P value
Tissue of NSCLC	80	51	29	74.862	<0.001
Adjacent non-tumor tissues	80	0	80

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
Factor	Case/n	High	Low	χ²	P value
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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GPR87通过激活RHO/ROCK通路促进非小细胞肺癌的侵袭和迁移

GPR87 promotes invasion and migration through the RHO/ROCK pathway in non-small cell lung cancer

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