人多效蛋白抑制恶性周围神经鞘瘤转移的机制研究

doi:10.3969/j.issn.1674-8115.2022.09.009

上海交通大学学报（医学版） ›› 2022, Vol. 42 ›› Issue (9): 1225-1238.doi: 10.3969/j.issn.1674-8115.2022.09.009

• 创新团队成果专栏 • 上一篇

人多效蛋白抑制恶性周围神经鞘瘤转移的机制研究

崔锡炜(), 钟民衎, 热汗姑丽·艾买尔, 王智超, 李青峰()

上海交通大学医学院附属第九人民医院整复外科，上海 200011

收稿日期:2022-03-11 接受日期:2022-07-27 出版日期:2022-08-05 发布日期:2022-08-05
通讯作者: 李青峰 E-mail:dr.cuixiwei@foxmail.com;dr.liqingfeng@shsmu.edu.cn
作者简介:崔锡炜（1996—），男，硕士生；电子信箱：dr.cuixiwei@foxmail.com。
基金资助:
国家自然科学基金面上项目(82172228);上海高水平地方高校创新团队项目(SHSMU-ZDCX20210400);上海交通大学医学院第九人民医院生物样本库项目(YBKA201901)

Role of human pleiotrophin in the metastasis of malignant peripheral nerve sheath tumor

CUI Xiwei(), CHUNG Manhon, AIMAIER Rehanguli, WANG Zhichao, LI Qingfeng()

Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

Received:2022-03-11 Accepted:2022-07-27 Online:2022-08-05 Published:2022-08-05
Contact: LI Qingfeng E-mail:dr.cuixiwei@foxmail.com;dr.liqingfeng@shsmu.edu.cn
Supported by:
National Natural Science Foundation of China(82172228);Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20210400);Biobank Project of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine(YBKA201901)

摘要/Abstract

摘要：

目的·探究人多效蛋白（pleiotrophin，PTN）对恶性周围神经鞘瘤（malignant peripheral nerve sheath tumor，MPNST）增殖、迁移与侵袭能力的影响。方法·通过免疫组织化学与生物信息学技术检测和分析PTN在MPNST组织中的表达。通过慢病毒转染分别构建过表达PTN与敲低PTN的MPNST细胞株，分别对过表达与敲低PTN的MPNST细胞进行细胞划痕实验与Transwell细胞迁移/侵袭实验，以检测PTN对细胞迁移、侵袭能力的影响；借助CCK8细胞增殖实验、EdU细胞增殖实验与细胞克隆形成实验，检测PTN对细胞增殖与集落形成能力的影响。通过Western blotting与转录组高通量测序技术，探究PTN对信号转导通路的影响。借助鼠尾静脉肿瘤细胞注射技术，分别注射敲减PTN的MPNST细胞株（实验组）和未敲减细胞株（对照组）构建MPNST裸鼠肺转移模型，探究PTN在体内环境下的生物学功能。结果·对49例MPNST患者的肿瘤组织与3例非MPNST患者的正常神经组织样本的免疫组织化学实验表明，PTN蛋白在MPNST组织中表达显著降低。细胞划痕实验与Transwell细胞迁移/侵袭实验显示，敲减PTN可促进MPNST细胞迁移与侵袭，过表达PTN可抑制MPNST细胞迁移与侵袭。CCK8细胞增殖实验、EdU细胞增殖实验与克隆形成实验显示：过表达PTN可抑制细胞增殖，但对集落形成能力无显著影响；敲减PTN对增殖与集落形成均无显著影响。Western blotting结果表明，过表达PTN可激活促分裂原活化的蛋白激酶（MAPK）通路，而敲减PTN对MAPK通路无显著影响。高通量转录组测序结果表明，过表达PTN可调节MPNST细胞中细胞程序性死亡的相关基因。体内实验表明，相较于对照组小鼠，实验组小鼠的成瘤率无显著改变，但生成肺转移灶的数量与体积显著上升，且出现严重的肺间质病变，实验组小鼠的体质量增长速度也显著低于对照组。结论·PTN在MPNST组织中低表达；过表达PTN可在体外抑制MPNST细胞的增殖、迁移与侵袭；敲减PTN的MPNST细胞对小鼠肺部的转移能力增强。

关键词: 恶性周围神经鞘瘤, 多效蛋白, 肿瘤转移, Ⅰ型神经纤维瘤病, 丛状神经纤维瘤

Abstract:

Objective ·To investigate the role of pleiotrophin (PTN) in the proliferation, migration and invasion of malignant peripheral nerve sheath tumor (MPNST). Methods ·The expression of PTN was verified by immunochemistry and bioinformatics analysis. By lentivirus transfection, the PTN-overexpressing and the PTN-knocked-down MPNST cell lines were established. To validate the role of PTN in MPNST migration and invasion, cell wound healing assay and Transwell migration/invasion assays were performed in boththe PTN-overexpressing MPNST cells and the PTN-knocked-down cells. By CCK8 assay, EdU assay and colony formation assay, the effects of PTN on the proliferation and the colony formation capabilities were evaluated. The pathway expression pattern regulated by PTN was validated by Western blotting and high-throughput transcriptome sequencing. To identify the biological function of PTN in vivo, an MPNST lung metastatic model in Balb/c nude mice was established. By mouse tail intravenous injection technique, PTN-knocked-down MPNST cells (experimental group) and negative control cells (control group) were injected into Balb/c nude mice, respectively. Results ·According to the immunochemistry staining results of the MPNST tissue samples from 49 patients and the normal nerve tissue samples from 3 non-MPNST people, PTN was significantly down-regulated in the MPNST tissues. In cell wound healing assay and Transwell migration/invasion assay, knocking down PTN significantly enhanced the migration and invasion capabilities of MPNST cells, while PTN overexpression inhibited them. The results of CCK8 assay, EdU assay and colony formation assay indicated that PTN overexpression hindered the proliferation of MPNST cells while colony formation was barely impacted; no significant differences in these assays were detected in the PTN-knocked-down cells. According to Western blotting assay, PTN overexpression activated mitogen activated protein kinase (MAPK) pathway while knocking down PTN showed mild influence. Transcriptome high-throughput sequencing showed that the expression levels of the genes related with programmed cell death pathway changed in the PTN-overexpressing cells. In the in vivo experiments, there was no significant difference in the tumor formation rate; however, the quantity and the volume of lung metastasis lesions were both larger in the experimental group. The most mice in the experimental group were diagnosed with severe pulmonary interstitial disease, and their growth rate of body mass also decreased. Conclusion ·PTN is down-regulated in the MPNST tissue and overexpressing PTN inhibites proliferation, migration and invasion of the MPNST cells in vitro. The ability of PTN-knocked-down MPNST cells to metastasize to the lungs in mice is enhanced.

Key words: malignant peripheral nerve sheath tumor (MPNST), pleiotrophin (PTN), tumor metastasis, neurofibromatosis type 1, plexiform neurofibroma

中图分类号:

R739.43

崔锡炜, 钟民衎, 热汗姑丽·艾买尔, 王智超, 李青峰. 人多效蛋白抑制恶性周围神经鞘瘤转移的机制研究[J]. 上海交通大学学报（医学版）, 2022, 42(9): 1225-1238.

CUI Xiwei, CHUNG Manhon, AIMAIER Rehanguli, WANG Zhichao, LI Qingfeng. Role of human pleiotrophin in the metastasis of malignant peripheral nerve sheath tumor[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(9): 1225-1238.

图/表 9

表1 使用的抗体信息

Tab 1 The antibodies used in this study

Antibody	Lot.	Manufacturer
Anti-PTN primary antibody （IHC）	Sc-74443	Santa Cruz
Anti-PTN primary antibody	Ab79411	Abcam
Anti-ACTB primary antibody	D190826	Sangon
p44/42 MAPK primary antibody	4695	CST
Phospho-p44/42 MAPK primary antibody	4370	CST
MEK1/2 primary antibody	4694	CST
Phospho-MEK1/2 primary antibody	2338	CST
AKT （pan） primary antibody	4691	CST
Phospho-AKT primary antibody	4060	CST
Anti N-cadherin primary antibody	Ab76011	Abcam
Anti E-cadherin primary antibody	Ab40722	Abcam
Anti-Slug primary antibody	Ab51772	Abcam
Anti-Snail primary antibody	Ab53519	Abcam
Anti-vimentin primary antibody	Ab92547	Abcam
Anti-α-SMA primary antibody	Ab7817	Abcam
Anti-FAK primary antibody	Ab40794	Abcam
Anti-pFAK （Y397） primary antibody	Ab81298	Abcam
Anti-SRC primary antibody	Ab109381	Abcam
Anti-pSRC （Y419） primary antibody	Ab185617	Abcam
DYKDDDDK （flag） primary antibody	14793	CST
Donkey to goat secondary antibody	Ab97110	Abcam
Goat to rabbit secondary antibody	Ab97080	Abcam
Rabbit to mouse secondary antibody	Ab6728	Abcam

表2 实时荧光定量PCR引物序列

Tab 2 Primers sequences for RT-qPCR

Primer	Sequence
PPIA forward	5'-CCCACCGTGTTCTTCGACATT-3'
PPIA reverse	5'-GGACCCGTATGCTTTAGGATGA-3'
PTN forward	5'-GAAGTCTGAAGCGAGCCCTG-3'
PTN reverse	5'-GCTTGAGGTTTGGGCTTGGT-3'

图1 PTN 在TCGA数据库33种恶性肿瘤中的表达分析Note： PTN was up-regulated in the tumors in red and down-regulated in the tumors in green. No significant differences were observed in other tumors. T—tumor tissue; N—normal tissue control; ACC—adrenocortical carcinoma; BLCA—bladder urothelial carcinoma; BRCA—breast invasive carcinoma; CESC—cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL—cholangiocarcinoma; COAD—colon adenocarcinoma; DLBC—lymphoid neoplasm diffuse large B-cell lymphoma; ESCA—esophageal carcinoma; HNSC—head and neck squamous cell carcinoma; KICH—kidney chromophobe; KIRC—kidney renal clear cell carcinoma; KIRP—kidney renal papillary cell carcinoma; LAML—acute myeloid leukemia; LIHC—liver hepatocellular carcinoma; LUAD—lung adenocarcinoma; LUSC—lung squamous cell carcinoma; MESO—mesothelioma; OV—ovarian serous cystadenocarcinoma; PAAD—pancreatic adenocarcinoma; PCPG—pheochromocytoma and paraganglioma; PRAD—prostate adenocarcinoma; READ—rectum adenocarcinoma; SARC—sarcoma; SKCM—skin cutaneous melanoma; STAD—stomach adenocarcinoma; TGCT—testicular germ cell tumors; THCA—thyroid carcinoma; THYM—thymoma; UCEC—uterine corpus endometrial carcinoma; UCS—uterine carcinosarcoma; UVM—uveal melanoma.

Fig 1 Bioinformatics analysis of PTN in 33 kinds of malignancies based on TCGA database

图2 PTN在MPSNT组织中的表达情况以及 PTN 过表达与 PTN 敲低的MPNST细胞系的构建Note： A. Immunohistochemistry of PTN in normal nerve tissues and MPNST tissues (×20). B. RT-qPCR and Western blotting of MPNST cell lines transfected by lentiviruses with PTN knocked-down (shA and shB) or overexpressing (OE). ①P=0.000, compared with the control group (NC).

Fig 2 Expression of PTN in the MPNST tissues and the establishment of PTN-overexpressing/-knocked-down MPNST celllines

图3 敲低 PTN 基因对MPNST细胞的增殖、迁移与侵袭能力的影响Note： A. Cell wound healing assay (×20). B. Transwell migration/invasion assay (hematoxylin staining, ×20). C. EdU assay (×20). D. Colony formation assay (hematoxylin staining, ×1). E. CCK8 assay. ①P=0.011, ②P=0.005, ③P=0.003, ④P=0.044, ⑤P=0.000, ⑥P=0.008, compared with NC.

Fig 3 Effect of knocking PTN down on the proliferation, migration and invasion potential of MPNST cells

图4 过表达 PTN 基因对MPNST细胞的增殖、迁移与侵袭能力的影响Note： A. Cell wound healing assay (×20). B. Transwell migration/invasion assay (hematoxylin staining, ×20). C. EdU assay (×20). D. Colony formation assay (hematoxylin staining, ×1). E. CCK8 assay. ①P=0.007, ②P=0.047, ③P=0.003, ④P=0.044, ⑤P=0.000, ⑥P=0.002, ⑦P=0.005, compared with NC.

Fig 4 Effect of PTN overexpression on the proliferation, migration and invasion potential of MPNST cells

图5 Western blotting检测 PTN 过表达或敲减细胞株信号通路蛋白表达的变化Note： A. MAPK pathway-related proteins detected by Western blotting. B. EMT-related proteins detected by Western blotting. C. FAK-SRC and PI3K-AKT pathway-related proteins detected by Western blotting.

Fig 5 Changes of the signal pathway proteins expression in the PTN-overexpressing or -knocked-down cell lines

图6 过表达 PTN 的MPNST细胞株相对于对照组表达变化的基因功能富集分析Note： A. Enrichment score dot plot of the genes up-regulated in the PTN-overexpressing cells. B. Enrichment score dot plot of the genes down-regulated in the PTN-overexpressing cells.

Fig 6 Function enrichment analysis of the genes with changed expression in the MPNST cell line overexpressing PTN relative to the control cells

图7 S462-shA组与S462-NC组裸鼠的肺转移灶成瘤实验Note： A. H-E staining of MPNST lung metastatic lesions. B. Number of metastatic nodules in S462-shA group and S462-NC group. C. Means of relative body mass of S462-shA group and S462-NC group. ①P=0.002, ②P=0.001, compared with S462-NC group.

Fig 7 Lung metastasis experiment of S462-shA group and S462-NC group in nude mice

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Role of human pleiotrophin in the metastasis of malignant peripheral nerve sheath tumor

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