The Parkinson's disease‐associated protein α‐synuclein inhibits hepatoma by exosome delivery

Numerous epidemiological studies suggest a link between Parkinson's disease (PD) and cancer. However, their relevant pathogenesis is not clear. In the present study, we investigated the potential role of exosome-delivered α-synuclein (α-syn) in the regulation between PD and liver cancer. We cultured hepatocellular carcinoma (HCC) cells with exosomes derived from conditioned medium of the PD cellular model, and injected exosomes enriched with α-syn into the striatum of a liver cancer rat model. We found that α-syn-contained exosomes from the rotenone-induced cellular model of PD suppressed the growth, migration, and invasion of HCC cells. Integrin αVβ5 in exosomes from the rotenone-induced PD model was higher than that in the control, resulting in more α-syn-contained exosomes being taken up by HCC cells. Consistently, in vivo experiments with rat models also confirmed exosome-delivered α-syn inhibited liver cancer. These findings illustrate the important role of PD-associated protein α-syn inhibiting hepatoma by exosome delivery, suggesting a new mechanism underlying the link between these two diseases and therapeutics of liver cancer.

[1]  Zhengcun Wu,et al.  SNCA correlates with immune infiltration and serves as a prognostic biomarker in lung adenocarcinoma , 2022, BMC cancer.

[2]  Delin Yang,et al.  Prognostic significance of SNCA and its methylation in bladder cancer , 2022, BMC Cancer.

[3]  B. Mollenhauer,et al.  α‐Synuclein in Plasma‐Derived Extracellular Vesicles Is a Potential Biomarker of Parkinson's Disease , 2021, Movement disorders : official journal of the Movement Disorder Society.

[4]  Y. Tao,et al.  Exosomes: key players in cancer and potential therapeutic strategy , 2020, Signal Transduction and Targeted Therapy.

[5]  H. Yin,et al.  Alarmin-painted exosomes elicit persistent antitumor immunity in large established tumors in mice , 2020, Nature Communications.

[6]  Guowei Wang,et al.  A Comparative Study of the Diagnostic Potential of Plasma and Erythrocytic α-Synuclein in Parkinson’s Disease , 2020, Neurodegenerative Diseases.

[7]  Yih-Ru Wu,et al.  Plasma and Serum Alpha-Synuclein as a Biomarker of Diagnosis in Patients With Parkinson's Disease , 2020, Frontiers in Neurology.

[8]  A. Schapira,et al.  Parkinson disease , 2019, European journal of neurology.

[9]  Kyungdo Han,et al.  Cancer risk in patients with Parkinson's disease in South Korea: A nationwide, population-based cohort study. , 2019, European journal of cancer.

[10]  Hong Tang,et al.  Exosome-mediated communication in the tumor microenvironment contributes to hepatocellular carcinoma development and progression , 2019, Journal of Hematology & Oncology.

[11]  W. Rausch,et al.  Rotenone: from modelling to implication in Parkinson's disease. , 2019, Folia neuropathologica.

[12]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[13]  N. Xia,et al.  Downregulation of metabotropic glutamate receptor 5 inhibits hepatoma development in a neurotoxin rotenone-induced Parkinson's disease model. , 2018, Toxicology letters.

[14]  M. Mattson,et al.  Intercellular transfer of pathogenic α-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal , 2018, Neurobiology of Aging.

[15]  Zhi Li,et al.  SNCA Is a Functionally Low-Expressed Gene in Lung Adenocarcinoma , 2018, Genes.

[16]  Hongyang Wang,et al.  Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer , 2018, Nature Communications.

[17]  W. An,et al.  Metabotropic glutamate receptor 5 mediates the suppressive effect of 6‐OHDA‐induced model of Parkinson's disease on liver cancer , 2017, Pharmacological research.

[18]  T. Patel,et al.  Investigation of Endocytic Pathways for the Internalization of Exosome-Associated Oligomeric Alpha-Synuclein , 2017, Front. Neurosci..

[19]  R. von Känel,et al.  Cancer co-occurrence patterns in Parkinson's disease and multiple sclerosis-Do they mirror immune system imbalances? , 2016, Cancer epidemiology.

[20]  E. Bugianesi,et al.  Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis. , 2016, Annual review of medicine.

[21]  Gary K. Schwartz,et al.  Tumour exosome integrins determine organotropic metastasis , 2015, Nature.

[22]  Gang Wang,et al.  Expression of HIP/PAP in hepatocellular carcinoma and effect of siRNA on migration and invasion in HCC cells. , 2015, Asian Pacific journal of tropical medicine.

[23]  Michael A. Hollingsworth,et al.  Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver , 2015, Nature Cell Biology.

[24]  Qi Guo,et al.  Detection of SNCA and FBN1 Methylation in the Stool as a Biomarker for Colorectal Cancer , 2015, Disease markers.

[25]  F. Wu,et al.  Rotenone impairs autophagic flux and lysosomal functions in Parkinson’s disease , 2015, Neuroscience.

[26]  M. Goldacre,et al.  Differential risks of cancer types in people with Parkinson's disease: a national record-linkage study. , 2014, European journal of cancer.

[27]  T. J. Cook,et al.  Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease , 2014, Acta Neuropathologica.

[28]  Baolin Li,et al.  CCL5 secreted from bone marrow stromal cells stimulates the migration and invasion of Huh7 hepatocellular carcinoma cells via the PI3K-Akt pathway. , 2014, International journal of oncology.

[29]  E. Masliah,et al.  Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5 – implications for dementia with Lewy bodies , 2014, Molecular Neurodegeneration.

[30]  W. Ding,et al.  Intercellular Communication by Exosome-Derived microRNAs in Cancer , 2013, International journal of molecular sciences.

[31]  A. Cashikar,et al.  Role of Ser129 phosphorylation of &agr;-synuclein in melanoma cells , 2013, Journal of Cell Science.

[32]  J. Olsen,et al.  Malignant melanoma, breast cancer and other cancers in patients with Parkinson's disease , 2012, International journal of cancer.

[33]  A. Winslow,et al.  Exosomal cell-to-cell transmission of alpha synuclein oligomers , 2012, Molecular Neurodegeneration.

[34]  Michael J. Devine,et al.  Parkinson's disease and cancer: two wars, one front , 2011, Nature Reviews Cancer.

[35]  Chris Gardiner,et al.  Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission , 2011, Neurobiology of Disease.

[36]  Hyungwon Choi,et al.  Metabolites of Purine Nucleoside Phosphorylase (NP) in Serum Have the Potential to Delineate Pancreatic Adenocarcinoma , 2011, PloS one.

[37]  J. Norman,et al.  Integrin Trafficking and the Control of Cell Migration , 2006, Traffic.

[38]  M. Feany,et al.  α-Synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease , 2005, Nature Neuroscience.

[39]  W. Ensminger,et al.  Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine. , 2004, Biopharmaceutics & drug disposition.