Bone marrow mesenchymal stem cell-derived exosomes promote proliferation, invasion and migration of renal cancer cells by regulating cholestanol metabolism

Hexi WANG; Xueyang LIU; Ming LIU; Dongzi NIE; Yao ZHANG

doi:10.16016/j.1000-5404.202104189

您当前的位置：

首页 >

文章列表页 >

Bone marrow mesenchymal stem cell-derived exosomes promote proliferation, invasion and migration of renal cancer cells by regulating cholestanol metabolism

Basic Medicine | 更新时间：2026-01-09

- Bone marrow mesenchymal stem cell-derived exosomes promote proliferation, invasion and migration of renal cancer cells by regulating cholestanol metabolism
- Journal of Third Military Medical University Vol. 43, Issue 20, Pages: 2189-2198(2021)
- 作者机构：
  
  400016 重庆，重庆医科大学附属第一医院泌尿外科
- 作者简介：
- 基金信息：
- DOI：10.16016/j.1000-5404.202104189
  CLC： Q591.5;R329.2;R737.11
- Received：28 April 2021，
  
  Revised：2021-05-14，
  
  Published：30 October 2021
- 稿件说明：
移动端阅览
Hexi WANG, Xueyang LIU, Ming LIU, et al. Bone marrow mesenchymal stem cell-derived exosomes promote proliferation, invasion and migration of renal cancer cells by regulating cholestanol metabolism[J]. Journal of Third Military Medical University, 2021, 43(20): 2189-2198.
DOI：

Hexi WANG, Xueyang LIU, Ming LIU, et al. Bone marrow mesenchymal stem cell-derived exosomes promote proliferation, invasion and migration of renal cancer cells by regulating cholestanol metabolism[J]. Journal of Third Military Medical University, 2021, 43(20): 2189-2198. DOI： 10.16016/j.1000-5404.202104189.

摘要

目的

探讨骨髓间充质干细胞外泌体(bone marrow mesenchymal stem cells

BMSCs-Exos)对肾癌细胞增殖、侵袭和迁移能力的影响，明确骨髓间充质干细胞外泌体对肾癌细胞脂质代谢的影响及分子机制。

方法

通过透射电镜和免疫印迹对提取的骨髓间充质干细胞外泌体进行鉴定，摄取实验验证肾癌细胞对骨髓间充质干细胞外泌体的摄取情况。将肾癌细胞Renca分为对照组(常规培养+PBS)和实验组(小鼠BMSCs-Exos 20 μg/mL处理Renca细胞)，采用CCK-8实验观察两组细胞的增殖能力；Transwell实验观察两组细胞的侵袭和迁移能力。液相色谱质谱联用的脂质组学分析肾癌细胞脂质代谢物差异，采用Western blot和qRT-PCR检测胆固醇代谢途径关键酶的表达。

结果

在骨髓间充质干细胞上清液中成功提取分离骨髓间充质干细胞外泌体，透射电镜下呈典型的“杯口状”囊泡，Western blot检测结果发现外泌体标志性蛋白CD63、CD9高表达，且摄取实验表明骨髓间充质干细胞外泌体可被肾癌细胞摄取。细胞功能实验发现，与对照组比较，骨髓间充质干细胞外泌体处理后肾癌细胞的增殖(

0.05)、侵袭和迁移能力(

0.01)均增加。液相色谱质谱联用脂质组学分析显示，外泌体处理后肾癌细胞中牛磺熊去氧胆酸明显降低(

0.05)，胆固醇升高(

0.05)。骨髓间充质干细胞外泌体可调控HMGCR、CYP7A1、CYP7B1表达以影响肾癌细胞胆固醇代谢，促进肾癌细胞增殖和迁移。

结论

骨髓间充质干细胞外泌体可通过调控肾癌细胞内胆固醇代谢关键酶的表达，影响细胞胆固醇代谢，以调控肾癌的增殖、侵袭和迁移能力。

Abstract

Objective

To explore the effects of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on the proliferation

invasion and migration and lipid metabolism of renal cell carcinoma (RCC) cells

and investigate the possible mechanism.

Methods

Firstly

the exosomes derived from mouse BMSCs were identified by transmission electron microscopy and Western blotting. The exosomes uptake experiment of BMSCs was subsequently used to verify whether the derived exosomes could be absorbed by renal cancer cells. RCC Renca cells were divided into control (PBS) and experiment group (20 μg/mL derived exosomes). The proliferation

invasion and migration were measured by CCK-8 assay and Transwell assay

respectively. Metabolite levels were measured with liquid chromatography-mass spectrometry for the differences between the 2 groups of cells. Finally

Western blotting and real-time PCR (qRT-PCR) were utilized to detect the expression of key enzymes of cholesterol metabolism.

Results

Exosomes were successfully derived from the supernatant of mouse BMSCs. Transmission electron microscopy displayed that the mBMSC-derived exosomes showed typical cup-shaped vesicles. Western blotting showed that the levels of exosome-specific proteins CD63 and CD9 were highly expressed after exosome treatment. And the obtained exosomes could be uptaken by RCC cells. The derived exosome treatment significantly promoted proliferation (

0.05) and invasion and migration (

0.01) in RCC cells. Liquid chromatography-mass spectrometry indicated that the treatment also resulted in decreased level of tauroursodeoxycholic acid (TUDCA) (

0.05) and elevated level of cholesterol (

0.05) in RCC cells. Moreover

the treatment could affect the cholesterol metabolism of RCC cells

via

regulating the expression levels of HMGCR

CYP7A1 and CYP7B1

and thus promote the cell proliferation and invasion and migration.

Conclusion

BMSCs-derived exosomes can affect the cholesterol metabolism by regulating the key enzymes

and thus promote the proliferation

invasion and migration of RCC cells.

关键词

Keywords

references

CHEN S J, LIN J H, YAO X D, et al . Nrdp1-mediated degradation of BRUCE decreases cell viability and induces apoptosis in human 786-O renal cell carcinoma cells[J ] . Exp Ther Med, 2016, 12(2): 597-602. DOI: 10.3892/etm.2016.3356.

MEEKS J J, ROBERTSON A G. Immune signatures dominate molecular subtyping to predict response to neoadjuvant immunotherapy[J]. Eur Urol, 2020, 77(6): 711-712. DOI: 10.1016/j.eururo.2020.03.021.

MOTZER R J, AGARWAL N, BEARD C, et al . NCCN clinical practice guidelines in oncology: kidney cancer[J ] . J Natl Compr Canc Netw, 2009, 7(6): 618-630. DOI: 10.6004/jnccn.2009.0043.

CHOW W H, DONG L M, DEVESA S S. Epidemiology and risk factors for kidney cancer[J]. Nat Rev Urol, 2010, 7(5): 245-257. DOI: 10.1038/nrurol.2010.46.

XU W H, XU Y, TIAN X, et al . Large-scale transcriptome profiles reveal robust 20-signatures metabolic prediction models and novel role of G6PC in clear cell renal cell carcinoma[J ] . J Cell Mol Med, 2020, 24(16): 9012-9027. DOI: 10.1111/jcmm.15536.

MOTZER R J, ESCUDIER B, GEORGE S, et al . Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial[J ] . Cancer, 2020, 126(18): 4156-4167. DOI: 10.1002/cncr.33033.

ABDALLAH B M, KASSEM M. Human mesenchymal stem cells: from basic biology to clinical applications[J]. Gene Ther, 2008, 15(2): 109-116. DOI: 10.1038/sj.gt.3303067.

GNECCHI M, DANIELI P, MALPASSO G, et al . Paracrine mechanisms of mesenchymal stem cells in tissue repair[J ] . Methods Mol Biol, 2016, 1416: 123-146. DOI: 10.1007/978-1-4939-3584-0_7.

LEEJ K, PARK S R, JUNG B K, et al . Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells[J ] . PLoS ONE, 2013, 8(12): e84256. DOI: 10.1371/journal.pone.0084256.

HUANG Y, LIU W, HE B, et al . Exosomes derived from bone marrow mesenchymal stem cells promote osteosarcoma development by activating oncogenic autophagy[J ] . J Bone Oncol, 2020, 21: 100280. DOI: 10.1016/j.jbo.2020.100280.

QI J, ZHOU Y L, JIAO Z Y, et al . Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth through hedgehog signaling pathway[J ] . Cell Physiol Biochem, 2017, 42(6): 2242-2254. DOI: 10.1159/000479998.

MATASSA D, AGLIARULO I, AVOLIO R, et al . TRAP1 regulation of cancer meta bolism: dual role as oncogene or tumor suppressor[J ] . Genes, 2018, 9(4): 195. DOI: 10.3390/genes9040195.

HASHMI S, WANG Y, SUMAN D S, et al . Human cancer: Is it linked to dysfunctional lipid metabolism?[J ] . Biochim et Biophys Acta, 2015, 1850(2): 352-364. DOI: 10.1016/j.bbagen.2014.11.004.

DRABKIN H A, GEMMILL R M. Cholesterol and the development of clear-cell renal carcinoma[J]. Curr Opin Pharmacol, 2012, 12(6): 742-750. DOI: 10.1016/j.coph.2012.08.002.

LIU Z, LIU X W, LIU S, et al . Cholesterol promotes the migration and invasion of renal carcinoma cells by regulating the KLF5/miR-27a/FBXW7 pathway[J ] . Biochem Biophys Res Commun, 2018, 502(1): 69-75. DOI: 10.1016/j.bbrc.2018.05.122.

WANG X J, LI H Z, LU X X, et al . Melittin-induced long non-coding RNA NONHSAT105177 inhibits proliferation and migration of pancreatic ductal adenocarcinoma[J ] . Cell Death Dis, 2018, 9(10): 940. DOI: 10.1038/s41419-018-0965-3.

MCATEE C O, BOOTH C, ELOWSKY C, et al . Prostate tumor cell exosomes containing hyaluronidase Hyal1 stimulate prostate stromal cell motility by e ngagement of FAK-mediated integrin signaling[J ] . Matrix Biol, 2019, 78/79: 165-179. DOI: 10.1016/j.matbio.2018.05.002.

CREWE C, JOFFIN N, RUTKOWSKI J M, et al . An endothelial-to-adipocyte extracellular vesicle axis governed by metabolic state[J ] . Cell, 2018, 175(3): 695-708. e13. DOI: 10.1016/j.cell.2018.09.005.

MATHIVANAN S, JI H, SIMPSON R J. Exosomes: extracellular organelles important in intercellular communication[J]. J Proteomics, 2010, 73(10): 1907-1920. DOI: 10.1016/j.jprot.2010.06.006.

CHEN H L, LI J J, JIANG F, et al . MicroRNA-4461 derived from bone marrow mesenchymal stem cell exosomes inhibits tumorigenesis by downregulating COPB 2 expression in colorectal cancer[J ] . Biosci Biotechnol Biochem, 2020, 84(2): 338-346. DOI: 10.1080/09168451.2019.1677452..

YUAN Y, ZHOU C, CHEN X, et al . Suppression of tumor cell proliferation and migration by human umbilical cord mesenchymal stem cells: a possible role for apoptosis and Wnt signaling[J ] . Oncol Lett, 2018, 15(6): 8536-8544. DOI: 10.3892/ol.2018.8368.

HUANG B, SONG B, XU C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities[J]. Nat Metab, 2020, 2(2): 132-141. DOI: 10.1038/s42255-020-0174-0.

CHRISTENSON E, MERLIN S, SAITO M, et al . Cholesterol effects on BAX pore activation[J ] . J Molecular Biol, 2008, 381(5): 1168-1183. DOI: 10.1016/j.jmb.2008.06.037.

LI Y C, PARK M J, YE S K, et al . Elevated levels of cholesterol-rich lipid rafts in cancer cells are correlated with apoptosis sensitivity induced by cholesterol-depleting agents[J ] . Am J Pathol, 2006, 168(4): 1107-1118. DOI: 10.2353/ajpath.2006.050959.

MARTÍNEZ-ABUNDIS E, GARCÍA N, CORREA F, et al . Changes in specific lipids regulate BAX-induced mitochondrial permeability transition[J ] . FEBS J, 2007, 274(24): 6500-6510. DOI: 10.1111/j.1742-4658.2007.06166.x.

SWINNEN J V, BRUSSELMANS K, VERHOEVEN G. Increased lipogenesis in cancer cells: new players, novel targets[J]. Curr Opin Clin Nutr Metab Care, 2006, 9(4): 358-365. DOI: 10.1097/01.mco.0000232894.28674.30.

GEBHARD R L, CLAYMAN R V, PRIGGE W F, et al . Abnormal cholesterol metabolism in renal clear cell carcinoma[J ] . J Li pid Res, 1987, 28(10): 1177-1184.

FREDERICKS W J, YIN H K, LAL P, et al . Ectopic expression of the TERE1 (UBIAD1) protein inhibits growth of renal clear cell carcinoma cells: altered metabolic phenotype associated with reactive oxygen species, nitric oxide and SXR target genes involved in cholesterol and lipid metabolism[J ] . Int J Oncol, 2013, 43(2): 638-652. DOI: 10.3892/ijo.2013.1985.

HENRICH S E, MCMAHON K M, PLEBANEK M P, et al . Prostate cancer extracellular vesicles mediate intercellular communication with bone marrow cells and promote metastasis in a cholesterol-dependent manner[J ] . J Extracell Vesicles, 2020, 10(2): e12042. DOI: 10.1002/jev2.12042.

MORI M A, LUDWIG R G, GARCIA-MARTIN R, et al . Extracellular miRNAs: from biomarkers to mediators of physiology and disease[J ] . Cell Metab, 2019, 30(4): 656-673. DOI: 10.1016/j.cmet.2019.07.011.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

UHRF2 promotes migration and proliferation of human hepatocellular carcinoma cells by PI3K/Akt signaling pathway

Effects of exosomes derived from placental mesenchymal stem cells on high glucose-induced senescence in human dermal fibroblasts

Effect of fibroblast growth factor 21 on migration and invasion of human pancreatic cancer cells in an inflammatory environment

Fluorescent small molecule IR-61 improves pulmonary fibrosis induced by intratracheal bleomycin in rats

MicroRNA-107 promotes migration and invasion of gastric cancer cells by targeting Notch2

Related Author

Fengjuan CHENG

Jingjie SUN

Xianyun FANG

Siyuan CHEN

Shangjing LIU

Kejia WU

Zhaodi LI

Shiming JIANG

Related Institution

Department of Cell Biology and Genetics, Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University

Department of Hepatobillary Surgery, the First Affiliated Hospital of Chongqing Medical University

Graduate School, Tianjin Medical University

Research Center for Tissue Repair and Regeneration, Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Division of innovative Medical Research, Chinese PLA General Hospital

Department of Pathology, Molecular Medicine Diagnostics Center, Chongqing Medical University

⁰