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Delivery of SIRT1 by cancer-associated adipocyte-derived extracellular vesicles regulates immune response and tumorigenesis of ovarian cancer cells

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Abstract

Purpose

This study intends to investigate the possible molecular mechanism of immune response and tumorigenesis in ovarian cancer cells, mediated by sirtuin 1 (SIRT1)-containing extracellular vesicles (EVs) derived from cancer-associated adipocytes (CAAs) (CAA-EVs).

Methods

Differentially expressed genes in EVs from CAAs were screened by RNA transcriptome sequencing, and the downstream pathway was predicted in silico. The binding between SIRT1 and CD24 was investigated by luciferase activity and ChIP-PCR assays. EVs were extracted from human ovarian cancer tissue-isolated CAAs, and the internalization of CCA-EVs by ovarian cancer cells was characterized. The ovarian cancer cell line was injected into mice to establish an animal model. Flow cytometry was performed to analyze the proportions of M1 and M2 macrophages, CD8+ T, T-reg, and CD4+ T cells. TUNEL staining was used to detect cell apoptosis in the mouse tumor tissues. ELISA detection was performed on immune-related factors in the serum of mice.

Results

CAA-EVs could deliver SIRT1 to ovarian cancer cells, thereby affecting the immune response of ovarian cancer cells in vitro and promoting tumorigenesis in vivo. SIRT1 could transcriptionally activate the expression of CD24, and CD24 could up-regulate Siglec-10 expression. CAA-EVs-SIRT1 activated the CD24/Siglec-10 axis and promoted CD8+ T cell apoptosis, thereby promoting tumorigenesis in mice.

Conclusion

CAA-EVs-mediated transfer of SIRT1 regulates the CD24/Siglec-10 axis to curb immune response and promote tumorigenesis of ovarian cancer cells.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Maoz A, Matsuo K, Ciccone MA, Matsuzaki S, Klar M, Roman LD, et al. Molecular pathways and targeted therapies for malignant ovarian germ cell tumors and sex cord-stromal tumors: a contemporary review. Cancers (Basel). 2020;12:1398.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Zilovic D, Ciurliene R, Sabaliauskaite R, Jarmalaite S. Future screening prospects for ovarian cancer. Cancers (Basel). 2021;13:3840.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Eisenhauer EA. Real-world evidence in the treatment of ovarian cancer. Ann Oncol. 2017;28:61–5.

    Google Scholar 

  4. Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393:1240–53.

    PubMed  Google Scholar 

  5. Osborne LC, Dhanji S, Snow JW, Priatel JJ, Ma MC, Miners MJ, et al. Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R alpha mutant mice. J Exp Med. 2007;204:619–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pekalski ML, Garcia AR, Ferreira RC, Rainbow DB, Smyth DJ, Mashar M, et al. Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2. JCI Insight. 2017. https://doi.org/10.1172/jci.insight.9373910.1172/jci.insight.93739.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Starzer AM, Preusser M, Berghoff AS. Immune escape mechanisms and therapeutic approaches in cancer: the cancer-immunity cycle. Ther Adv Med Oncol. 2022;14:17588359221096220.

    PubMed  PubMed Central  Google Scholar 

  8. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.

    PubMed  Google Scholar 

  9. Munteanu R, Onaciu A, Moldovan C, Zimta AA, Gulei D, Paradiso AV, et al. Adipocyte-based cell therapy in oncology the role of cancer-associated adipocytes and their reinterpretation as delivery platforms. Pharmaceutics. 2020;12:402.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Tian W, Lei N, Zhou J, Chen M, Guo R, Qin B, et al. Extracellular vesicles in ovarian cancer chemoresistance, metastasis, and immune evasion. Cell Death Dis. 2022;13:64.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Shen P, Deng X, Chen Z, Ba X, Qin K, Huang Y, et al. SIRT1: a potential therapeutic target in autoimmune diseases. Front Immunol. 2021;12:779177.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lin Z, Fang D. The roles of SIRT1 in Cancer. Genes Cancer. 2013;4:97–104.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang X, Chen J, Sun L, Xu Y. SIRT1 deacetylates KLF4 to activate Claudin-5 transcription in ovarian cancer cells. J Cell Biochem. 2018;119:2418–26.

    CAS  PubMed  Google Scholar 

  14. Duan J, Yin M, Shao Y, Zheng J, Nie S. Puerarin induces platinum-resistant epithelial ovarian cancer cell apoptosis by targeting SIRT1. J Int Med Res. 2021;49:3000605211040762.

    CAS  PubMed  Google Scholar 

  15. Wang TW, Chern E, Hsu CW, Tseng KC, Chao HM. SIRT1-mediated expression of CD24 and epigenetic suppression of novel tumor suppressor miR-1185-1 increases colorectal cancer stemness. Cancer Res. 2020;80:5257–69.

    CAS  PubMed  Google Scholar 

  16. Barkal AA, Brewer RE, Markovic M, Kowarsky M, Barkal SA, Zaro BW, et al. CD24 signalling through macrophage siglec-10 is a target for cancer immunotherapy. Nature. 2019;572:392–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat Rev Immunol. 2007;7:255–66.

    CAS  PubMed  Google Scholar 

  18. Abram CL, Lowell CA. Shp1 function in myeloid cells. J Leukoc Biol. 2017;102:657–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Li Y, Zhou J, Zhuo Q, Zhang J, Xie J, Han S, et al. Malignant ascite-derived extracellular vesicles inhibit T cell activity by upregulating Siglec-10 expression. Cancer Manag Res. 2019;11:7123–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee J, Hong BS, Ryu HS, Lee HB, Lee M, Park IA, et al. Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism. PLoS ONE. 2017;12:e0174126.

    PubMed  PubMed Central  Google Scholar 

  21. Dai X, Xie Y, Dong M. Cancer-associated fibroblasts derived extracellular vesicles promote angiogenesis of colorectal adenocarcinoma cells through miR-135b-5p/FOXO1 axis. Cancer Biol Ther. 2022;23:76–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Pan D, Chen J, Feng C, Wu W, Wang Y, Tong J, et al. Preferential localization of MUC1 glycoprotein in exosomes secreted by non-small cell lung carcinoma cells. Int J Mol Sci. 2019;20:3213.

    Google Scholar 

  23. Gu YY, Yu J, Zhang JF, Wang C. Suppressing the secretion of exosomal miR-19b by gw4869 could regulate oxaliplatin sensitivity in colorectal cancer. Neoplasma. 2019;66:39–45.

    CAS  PubMed  Google Scholar 

  24. Fang X, Xu X, Lin X, Liu R. Downregulated spinal IRF8 and BDNF in NAC are involved in neuropathic pain-induced depression relief via pulsed radiofrequency on dorsal root ganglion in rat SNI model. Brain Res Bull. 2019;146:192–200.

    CAS  PubMed  Google Scholar 

  25. Qi G, Zhang C, Ma H, Li Y, Peng J, Chen J, et al. CDCA8, targeted by MYBL2, promotes malignant progression and olaparib insensitivity in ovarian cancer. Am J Cancer Res. 2021;11:389–415.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhou J, Li X, Wu X, Zhang T, Zhu Q, Wang X, et al. Exosomes Released from Tumor-Associated Macrophages Transfer miRNAs That Induce a Treg/Th17 Cell Imbalance in Epithelial Ovarian Cancer. Cancer Immunol Res. 2018;6:1578–92.

    CAS  PubMed  Google Scholar 

  27. Zheng J, Mao Y, Dong P, Huang Z, Yu F. Long noncoding RNA HOTTIP mediates SRF expression through sponging miR-150 in hepatic stellate cells. J Cell Mol Med. 2019;23:1572–80.

    CAS  PubMed  Google Scholar 

  28. Li CW, Lim SO, Xia W, Lee HH, Chan LC, Kuo CW, et al. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun. 2016;7:12632.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen WX, Wang DD, Zhu B, Zhu YZ, Zheng L, Feng ZQ, et al. Exosomal miR-222 from adriamycin-resistant MCF-7 breast cancer cells promote macrophages M2 polarization via PTEN/Akt to induce tumor progression. Aging (Albany NY). 2021;13:10415–30.

    CAS  PubMed  Google Scholar 

  30. He L, Zhu W, Chen Q, Yuan Y, Wang Y, Wang J, et al. Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis. Theranostics. 2019;9:8206–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Guo JC, Yang YJ, Zheng JF, Zhang JQ, Guo M, Yang X, et al. Silencing of long noncoding RNA HOXA11-AS inhibits the Wnt signaling pathway via the upregulation of HOXA11 and thereby inhibits the proliferation, invasion, and self-renewal of hepatocellular carcinoma stem cells. Exp Mol Med. 2019;51:1–20.

    PubMed  Google Scholar 

  32. Mufazalov IA, Regen T, Schelmbauer C, Kuschmann J, Muratova AM, Nikolaev A, et al. Generation of a Novel T Cell Specific Interleukin-1 Receptor Type 1 Conditional Knock Out Mouse Reveals Intrinsic Defects in Survival, Expansion and Cytokine Production of CD4 T Cells. PLoS ONE. 2016;11:e0161505.

    PubMed  PubMed Central  Google Scholar 

  33. Qu QX, Xie F, Huang Q, Zhang XG. Membranous and cytoplasmic expression of PD-L1 in ovarian cancer cells. Cell Physiol Biochem. 2017;43:1893–906.

    CAS  PubMed  Google Scholar 

  34. Xue J, Sharma V, Hsieh MH, Chawla A, Murali R, Pandol SJ, et al. Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis. Nat Commun. 2015;6:7158.

    CAS  PubMed  Google Scholar 

  35. Yu PN, Yan MD, Lai HC, Huang RL, Chou YC, Lin WC, et al. Downregulation of miR-29 contributes to cisplatin resistance of ovarian cancer cells. Int J Cancer. 2014;134:542–51.

    CAS  PubMed  Google Scholar 

  36. Salem M, Shan Y, Bernaudo S, Peng C. miR-590–3p Targets Cyclin G2 and FOXO3 to Promote Ovarian Cancer Cell Proliferation, Invasion, and Spheroid Formation. Int J Mol Sci. 1810;2019:20.

    Google Scholar 

  37. Zhu D, Yuan D, Guo R, Zhang L, Guo T, Zhao Y, et al. Overexpression of miR-148a inhibits viability and invasion of ovarian cancer OVCAR3 cells by targeting FOXO3. Oncol Lett. 2019;18:402–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Prantner AM, Yin C, Kamat K, Sharma K, Lowenthal AC, Madrid PB, et al. Molecular Imaging of Mesothelin-Expressing Ovarian Cancer with a Human and Mouse Cross-Reactive Nanobody. Mol Pharm. 2018;15:1403–11.

    CAS  PubMed  Google Scholar 

  39. Chen F, Xu Y, Chen Y, Shan S. TIGIT enhances CD4(+) regulatory T-cell response and mediates immune suppression in a murine ovarian cancer model. Cancer Med. 2020;9:3584–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Fang Y, Tian Y, Huang Q, Wan Y, Xu L, Wang W, et al. Deficiency of TREK-1 potassium channel exacerbates blood-brain barrier damage and neuroinflammation after intracerebral hemorrhage in mice. J Neuroinflammation. 2019;16:96.

    PubMed  PubMed Central  Google Scholar 

  41. Frazzi R. SIRT1 in secretory organ cancer. Front Endocrinol (Lausanne). 2018;9:569.

    PubMed  Google Scholar 

  42. Bose S, Saha P, Chatterjee B, Srivastava AK. Chemokines driven ovarian cancer progression, metastasis and chemoresistance: Potential pharmacological targets for cancer therapy. Semin Cancer Biol. 2022;86:568–79.

    CAS  PubMed  Google Scholar 

  43. Arneth B. Tumor Microenvironment. Medicina (Kaunas). 2019;56:15.

    PubMed  Google Scholar 

  44. Mukherjee A, Bilecz AJ, Lengyel E. The adipocyte microenvironment and cancer. Cancer Metastasis Rev. 2022;41:575–87.

    CAS  PubMed  Google Scholar 

  45. Wu Q, Li B, Li Z, Li J, Sun S, Sun S. Cancer-associated adipocytes: key players in breast cancer progression. J Hematol Oncol. 2019;12:95.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Maacha S, Bhat AA, Jimenez L, Raza A, Haris M, Uddin S, et al. Extracellular vesicles-mediated intercellular communication: roles in the tumor microenvironment and anti-cancer drug resistance. Mol Cancer. 2019;18:55.

    PubMed  PubMed Central  Google Scholar 

  47. Czystowska-Kuzmicz M, Sosnowska A, Nowis D, Ramji K, Szajnik M, Chlebowska-Tuz J, et al. Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma. Nat Commun. 2019;10:3000.

    PubMed  PubMed Central  Google Scholar 

  48. Liu ZM, Wang YB, Yuan XH. Exosomes from murine-derived GL26 cells promote glioblastoma tumor growth by reducing number and function of CD8+T cells. Asian Pac J Cancer Prev. 2013;14:309–14.

    PubMed  Google Scholar 

  49. Maybruck BT, Pfannenstiel LW, Diaz-Montero M, Gastman BR. Tumor-derived exosomes induce CD8(+) T cell suppressors. J Immunother Cancer. 2017;5:65.

    PubMed  PubMed Central  Google Scholar 

  50. Roy S, Das A, Vernekar M, Mandal S, Chatterjee N. Understanding the correlation between metabolic regulator SIRT1 and exosomes with CA-125 in ovarian cancer: A clinicopathological study. Biomed Res Int. 2022;2022:5346091.

    PubMed  PubMed Central  Google Scholar 

  51. Wang Z, Yan Y, Lou Y, Huang X, Liu L, Weng Z, et al. Diallyl trisulfide alleviates chemotherapy sensitivity of ovarian cancer via the AMPK/SIRT1/PGC1alpha pathway. Cancer Sci. 2023;114:357–69.

    CAS  PubMed  Google Scholar 

  52. Qin J, Liu Y, Lu Y, Liu M, Li M, Li J, et al. Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression. Sci Rep. 2017;7:10592.

    PubMed  PubMed Central  Google Scholar 

  53. Song S, Tang H, Quan W, Shang A, Ling C. Estradiol initiates the immune escape of non-small cell lung cancer cells via ERbeta/SIRT1/FOXO3a/PD-L1 axis. Int Immunopharmacol. 2022;107: 108629.

    CAS  PubMed  Google Scholar 

  54. Sammar M, Siwetz M, Meiri H, Fleming V, Altevogt P, Huppertz B. Expression of CD24 and Siglec-10 in first trimester placenta: implications for immune tolerance at the fetal-maternal interface. Histochem Cell Biol. 2017;147:565–74.

    CAS  PubMed  Google Scholar 

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Funding

This study was supported by Medical Key Supporting Project of Suzhou City (No. SZFCXK202142); Key Projects of Medical and Health Science and Technology Plan of Suzhou Hi-tech Zone (No. 2020Z008) and Suzhou Science and Technology Development Plan (No. SKJYD2021058).

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, School of Medicine, Huzhou University, Huzhou, 313000, Zhejiang Province, China

    Qingling Zheng

  2. Department of Pathology, Suzhou Science & Technology Town Hospital, Huqiu District, No. 1, Lijiang Road, Suzhou, 215153, Jiangsu Province, China

    Xiuluan Du, Jin Zhang, Yanxiang Liu, Xin Dai & Donghua Gu

  3. Department of Pathology, School of Medicine, Huzhou University, Huzhou, 313000, Zhejiang Province, China

    Weijia Dong

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  1. Qingling Zheng
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  2. Xiuluan Du
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  3. Jin Zhang
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  4. Yanxiang Liu
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  6. Xin Dai
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Contributions

QZ, XD, JZ and YL designed the study. WD, XD and DG collated the data, designed and developed the database, carried out data analyses and produced the initial draft of the manuscript. QZ and XD contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

Corresponding author

Correspondence to Donghua Gu.

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Our study was approved by the Clinical Ethics Committee and all tissue donors were required to sign a written informed consent.

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Supplementary Information

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12094_2023_3240_MOESM1_ESM.eps

Supplementary file1 Fig. S1 Extraction and identification of normal-EVs and CAA-EVs. A: TEM to identify the structure of normal-EVs and CAA-EVs; B: Nanoparticle size analysis to detect the diameter size of normal-EVs and CAA-EVs; C: Western blot to detect the protein expression of TSG101, CD63, CD81, and GRP94 in normal adipocytes and in CAAs and their EVs. Cell experiments were repeated three times (EPS 4133 kb)

Supplementary file2 (DOCX 26 kb)

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Zheng, Q., Du, X., Zhang, J. et al. Delivery of SIRT1 by cancer-associated adipocyte-derived extracellular vesicles regulates immune response and tumorigenesis of ovarian cancer cells. Clin Transl Oncol 26, 190–203 (2024). https://doi.org/10.1007/s12094-023-03240-3

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  • DOI: https://doi.org/10.1007/s12094-023-03240-3

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