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Cited by 65MicroRNA in disease regulationCancer Cells and MetastasisMetabolism, Diabetes, and Cancer

Metformin mediates induction of miR-708 to inhibit self-renewal and chemoresistance of breast cancer stem cells through targeting CD47

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Tan, Weige, Tang, Hailin, Jiang, Xinhua, Ye, Feng, Huang, Lili, Shi, Dingbo, Li, Laisheng, Huang, Xiaojia +3 more·2019·Journal of Cellular and Molecular Medicine
DOI 10.1111/jcmm.14462PMC PMC6714171
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Abstract

Breast cancer stem cells (BCSCs) have been considered responsible for cancer progression, recurrence, metastasis and drug resistance. However, the mechanisms by which cells acquire self‐renewal and chemoresistance properties are remaining largely unclear. Herein, we evaluated the role of miR‐708 and metformin in BCSCs, and found that the expression of miR‐708 is significantly down‐regulated in BCSCs and tumour tissues, and correlates with chemotherapy response and prognosis. Moreover, miR‐708 markedly inhibits sphere formation, CD44+/CD24− ratio, and tumour initiation and increases chemosensitivity of BCSCs. Mechanistically, miR‐708 directly binds to cluster of differentiation 47 (CD47), and regulates tumour‐associated macrophage‐mediated phagocytosis. On the other hand, CD47 is essential for self‐renewal, tumour initiation and chemoresistance of BCSCs, and correlates with the prognosis of breast cancer patients. In addition, the anti‐type II diabetes drug metformin are found to be involved in the miR‐708/CD47 signalling pathway. Therefore, our study demonstrated that miR‐708 plays an important tumour suppressor role in BCSCs self‐renewal and chemoresistance, and the miR‐708/CD47 regulatory axis may represent a novel therapeutic mechanism of metformin in BCSCs.

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  • CD47/miR-708 regulates tumor-associated macrophage-mediated phagocytosis.

    “A study performed by Tan et al. indicated that CD47/miR-708 regulates tumor-associated macrophage-mediated phagocytosis [180].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [180]

    The Results section reports that miR-708 overexpression or CD47 knockdown increased macrophage phagocytosis of breast cancer cells in vitro. The assays used bone marrow-derived macrophages, however, not macrophages identified as tumor-associated; that qualifier is not established by the reported experiment (page unavailable). (LLM, conf=0.88)

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  1. [1]Bray F, Ferlay J, Soerjomataram I, et al. GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(2018): 394‐ 424. 30207593
  2. [2]Lin X, Chen W, Wei F, Zhou BP, Hung MC, Xie X. Nanoparticle delivery of miR‐34a eradicates long‐term‐cultured breast cancer stem cells via targeting C22ORF28 directly. Theranostics. 2017; 7: 4805‐ 4824. 29187905 PMC5706101
  3. [3]Lv C, Li F, Li X, et al. MiR‐31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists. Nat Commun. 2017; 8: 1036. 29051494 PMC5648844
  4. [4]Takahashi RU, Miyazaki H, Takeshita F, et al. Loss of microRNA‐27b contributes to breast cancer stem cell generation by activating ENPP1. Nat Commun. 2015; 6: 7318. 26065921 PMC4490376
  5. [5]Lang JY, Hsu JL, Meric‐Bernstam F, et al. BikDD eliminates breast cancer initiating cells and synergizes with lapatinib for breast cancer treatment. Cancer Cell. 2011; 20: 341‐ 356. 21907925 PMC3172580
  6. [6]Ryu S, McDonnell K, Choi H, et al. Suppression of miRNA‐708 by polycomb group promotes metastases by calcium‐induced cell migration. Cancer Cell. 2013; 23: 63‐ 76. 23328481
  7. [7]Lin KT, Yeh YM, Chuang CM, et al. Glucocorticoids mediate induction of microRNA‐708 to suppress ovarian cancer metastasis through targeting Rap1B. Nat Commun. 2015; 6: 5917. 25569036 PMC4354140
  8. [8]Liu T, Wu X, Chen T, Luo Z, Hu X. Downregulation of DNMT3A by miR‐708‐5p inhibits lung cancer stem cell‐like phenotypes through repressing Wnt/beta‐catenin signaling. Clin Cancer Res. 2018; 24: 1748‐ 1760. 28972040
  9. [9]Huang W, Wang WT, Fang K, et al. MIR‐708 promotes phagocytosis to eradicate T‐ALL cells by targeting CD47. Mol Cancer. 2018; 17: 12. 29368647 PMC5782377
  10. [10]Baer C, Oakes CC, Ruppert AS, et al. Epigenetic silencing of miR‐708 enhances NF‐kappaB signaling in chronic lymphocytic leukemia. Int J Cancer. 2015; 137: 1352‐ 1361. 25704289
  11. [11]Saini S, Majid S, Shahryari V, et al. miRNA‐708 control of CD44(+) prostate cancer‐initiating cells. Cancer Res. 2012; 72: 3618‐ 3630. 22552290
  12. [12]Koh E, Lee EJ, Nam GH, et al. Exosome‐SIRPalpha, a CD47 blockade increases cancer cell phagocytosis. Biomaterials. 2017; 121: 121‐ 129. 28086180
  13. [13]Casey SC, Baylot V, Felsher DW. The MYC oncogene is a global regulator of the immune response. Blood. 2018; 131: 2007‐ 2015. 29514782 PMC5934797
  14. [14]Cioffi M, Trabulo S, Hidalgo M, et al. Inhibition of CD47 effectively targets pancreatic cancer stem cells via dual mechanisms. Clin Cancer Res. 2015; 21: 2325‐ 2337. 25717063
  15. [15]Barrera L, Montes‐Servin E, Hernandez‐Martinez JM, et al. CD47 overexpression is associated with decreased neutrophil apoptosis/phagocytosis and poor prognosis in non‐small‐cell lung cancer patients. Br J Cancer. 2017; 117: 385‐ 397. 28632731 PMC5537491
  16. [16]Nagahara M, Mimori K, Kataoka A, et al. Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients. Clin Cancer Res. 2010; 16: 4625‐ 4635. 20705613
  17. [17]Advani R, Flinn I, Popplewell L, et al.: CD47 Blockade by Hu5F9‐G4 and Rituximab in Non‐Hodgkin's Lymphoma. N Engl J Med 379: 1711‐ 1721, 2018. 30380386 PMC8058634
  18. [18]Betancur PA, Abraham BJ, Yiu YY, et al. A CD47‐associated super‐enhancer links pro‐inflammatory signalling to CD47 upregulation in breast cancer. Nat Commun. 2017; 8: 14802. 28378740 PMC5382276
  19. [21]Shi P, Liu W, Tala H, et al. Metformin suppresses triple‐negative breast cancer stem cells by targeting KLF5 for degradation. Cell Discov. 2017; 3: 17010. 28480051 PMC5396048
  20. [22]Xie X, Tang H, Pengliu Y, et al. Development of PEA‐15 using a potent non‐viral vector for therapeutic application in breast cancer. Cancer Lett. 2015; 356: 374‐ 381. 25304382 PMC4571276
  21. [23]Gong C, Tan W, Chen K, et al. Prognostic value of a BCSC‐associated MicroRNA signature in hormone receptor‐positive HER2‐negative breast cancer. EBioMedicine. 2016; 11: 199‐ 209. 27566954 PMC5049991
  22. [24]Wang L, Bu P, Ai Y, et al. A long non‐coding RNA targets microRNA miR‐34a to regulate colon cancer stem cell asymmetric division. eLife. 2016; 5. PMC4859802 27077950
  23. [25]Bradley CA. Diabetes: metformin in breast cancer. Nat Rev Endocrinol. 2017; 13: 251. 28361930
  24. [26]Pulito C, Mori F, Sacconi A, et al. Metformin‐induced ablation of microRNA 21–5p releases Sestrin‐1 and CAB39L antitumoral activities. Cell Discov. 2017; 3: 17022. 28698800 PMC5501975
  25. [27]Abdul‐Rahman O, Sasvari‐Szekely M, Ver A, et al. Altered gene expression profiles in the hippocampus and prefrontal cortex of type 2 diabetic rats. BMC Genom. 2012; 13: 81. PMC3299604 22369239
  26. [28]Wang T, Fahrmann JF, Lee H, et al. JAK/STAT3‐regulated fatty acid beta‐oxidation is critical for breast cancer stem cell self‐renewal and chemoresistance. Cell Metab. 2018; 27: 1357. PMC6116734 29874570
  27. [29]Tabassum I, Mahmood H, Faheem M. Type 2 diabetes mellitus as a risk factor for female breast cancer in the population of northern Pakistan. Asian Pac J Cancer Prev. 2016; 17: 3255‐ 3258. 27509959
  28. [30]Chong RW, Vasudevan V, Zuber J, Solomon SS. Metformin has a positive therapeutic effect on prostate cancer in patients with type 2 diabetes mellitus. Am J Med Sci. 2016; 351: 416‐ 419. 27079349 PMC4834891
  29. [31]Ma FJ, Liu ZB, Qu L, et al. Impact of type 2 diabetes mellitus on the prognosis of early stage triple‐negative breast cancer in People's Republic of China. Onco Targets Ther. 2014; 7: 2147‐ 2154. 25473296 PMC4251575
  30. [32]Tseng CH. Metformin may reduce breast cancer risk in Taiwanese women with type 2 diabetes. Breast Cancer Res Treat. 2014; 145: 785‐ 790. 24816805
  31. [34]Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA. 2013; 110: 972‐ 977. 23277563 PMC3549132

Cited by

Sorted by citations

Authors
Tan, W., Tang, H., Jiang, X., Ye, F., Huang, L., Shi, D., Li, L., Huang, X., Li, L., Xie, X., & Xie, X.
Affiliations
  • First Affiliated Hospital of Guangzhou Medical University (CN)
  • Sun Yat-sen University Cancer Center (CN)
  • Guangzhou Medical University (CN)
  • The First Affiliated Hospital, Sun Yat-sen University (CN)
Corresponding author
  • Xie, Xiaoming
  • Xie, Xinhua
ORCID
Venue
Journal of Cellular and Molecular Medicine
Publisher
Wiley
Published
2019-07-05
Volume
23
Issue
9
Pages
5994-6004
ISSN
  • 1582-1838 (ISSN-L)
  • 1582-4934
DOI
10.1111/jcmm.14462
PMC
PMC6714171
OpenAlex
W2955317546
Cited by
65
References
3
Citations by year
2026: 3 · 2025: 6 · 2024: 10 · 2023: 6 · 2022: 13 · 2021: 11 · 2020: 11 · 2019: 3 · 2015: 1
FWCI
3.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cellular and Molecular Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (81302318, 81602691, 81772961, 81672598)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
metformin, miR-708, breast cancer stem cells, CD47, self-renewal, chemoresistance, tumour-associated macrophages, phagocytosis, tumor suppressor microRNA, chemotherapy response, tumor initiation
MeSH terms
Cell Self Renewal, Breast, Breast Neoplasms, Female, Humans, Macrophages, Metformin, Middle Aged, Phagocytosis, Neoplastic Stem Cells, Signal Transduction, Gene Expression Regulation, Neoplastic, Hyaluronan Receptors, Drug Resistance, Neoplasm, RNA Interference, RNA, Small Interfering, MicroRNAs, Cell Line, Tumor, CD24 Antigen, CD47 Antigen, MCF-7 Cells

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