miR‑382 inhibits breast cancer progression and metastasis by affecting the M2 polarization of tumor‑associated macrophages by targeting PGC‑1α Corrigendum in /10.3892/ijo.2022.5449

Zhou,Hua; Gan,Mingyu; Jin,Xin; Dai,Meng; Wang,Yuanyuan; Lei,Youyang; Lin,Zijing; Ming,Jia

doi:10.3892/ijo.2022.5416

miR‑382 inhibits breast cancer progression and metastasis by affecting the M2 polarization of tumor‑associated macrophages by targeting PGC‑1α

Corrigendum in: /10.3892/ijo.2022.5449

Authors:
- Hua Zhou
- Mingyu Gan
- Xin Jin
- Meng Dai
- Yuanyuan Wang
- Youyang Lei
- Zijing Lin
- Jia Ming
View Affiliations

Affiliations: Department of Breast and Thyroid Surgery, The Affiliated Shapingba Hospital of Chongqing University, Chongqing 400030, P.R. China, Shanxi Medical University, Taiyuan, Shanxi 030607, P.R. China, Department of Critical Care Medicine, The Affiliated Fuling Hospital of Chongqing University, Chongqing 408099, P.R. China, Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
Published online on: September 6, 2022 https://doi.org/10.3892/ijo.2022.5416
Article Number: 126
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Macrophages are principal immune cells with a high plasticity in the human body that can differentiate under different conditions in the tumor microenvironment to adopt two polarized phenotypes with opposite functions. Therefore, converting macrophages from the immunosuppressive phenotype (M2) to the inflammatory phenotype (M1) is considered a promising therapeutic strategy for cancer. However, the molecular mechanisms underlying this conversion process have not yet been completely elucidated. In recent years, microRNAs (miRNAs or miRs) have been shown to play key roles in regulating macrophage polarization through their ability to modulate gene expression. In the present study, it was found that miR‑382 expression was significantly downregulated in tumor‑associated macrophages (TAMs) and M2‑polarized macrophages in breast cancer. In vitro, macrophage polarization toward the M2 phenotype and M2‑type cytokine release were inhibited by transfection with miR‑382‑overexpressing lentivirus. Similarly, the overexpression of miR‑382 inhibited the ability of TAMs to promote the malignant behaviors of breast cancer cells. In addition, peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) was identified as the downstream target of miR‑382 and it was found that PGC‑1α affected macrophage polarization by altering the metabolic status. The ectopic expression of PGC‑1α restored the phenotype and cytokine secretion of miR‑382‑overexpressing macrophages. Furthermore, PGC‑1α expression reversed the miR‑382‑induced changes in the metabolic state of TAMs and the effects of TAMs on breast cancer cells. Of note, the in vivo growth and metastasis of 4T1 cells were inhibited by miR‑382‑overexpressing TAMs. Taken together, the results of the present study suggest that miR‑382 may alter the metabolic status of macrophages by targeting PGC‑1α, thereby decreasing the proportion of TAMs with the M2 phenotype, and inhibiting the progression and metastasis of breast cancer.

View Figures

View References

1	Martin JD, Fukumura D, Duda DG, Boucher Y and Jain RK: Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity. Cold Spring Harb Perspect Med. 6:a0270942016. View Article : Google Scholar : PubMed/NCBI
2	Huang Q, Liang X, Ren T, Huang Y, Zhang H, Yu Y, Chen C, Wang W, Niu J, Lou J and Guo W: The role of tumor-associated macrophages in osteosarcoma progression-therapeutic implications. Cell Oncol (Dordr). 44:525–539. 2021. View Article : Google Scholar
3	Lao L, Fan S and Song E: Tumor associated macrophages as therapeutic targets for breast cancer. Adv Exp Med Biol. 1026:331–370. 2017. View Article : Google Scholar : PubMed/NCBI
4	Zhu Z, Zhang H, Chen B, Liu X, Zhang S, Zong Z and Gao M: PD-L1-mediated immunosuppression in glioblastoma is associated with the infiltration and M2-polarization of tumor-associated macrophages. Front Immunol. 11:5885522020. View Article : Google Scholar : PubMed/NCBI
5	Cersosimo F, Lonardi S, Bernardini G, Telfer B, Mandelli GE, Santucci A, Vermi W and Giurisato E: Tumor-associated macrophages in osteosarcoma: From mechanisms to therapy. Int J Mol Sci. 21:52072020. View Article : Google Scholar :
6	Macciò A, Gramignano G, Cherchi MC, Tanca L, Melis L and Madeddu C: Role of M1-polarized tumor-associated macrophages in the prognosis of advanced ovarian cancer patients. Sci Rep. 10:60962020PubMed/NCBI
7	Wang X, Li X and Wang X: Identification of immune microenvironment subtypes that predicted the prognosis of patients with ovarian cancer = Identification of immune microenvironment subtypes that predicted the prognosis of patients with ovarian cancer. J Cell Mol Med. 25:4053–4061. 2021. View Article : Google Scholar : PubMed/NCBI
8	Honkanen TJ, Tikkanen A, Karihtala P, Mäkinen M, Väyrynen JP and Koivunen JP: Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer. Sci Rep. 9:109612019. View Article : Google Scholar : PubMed/NCBI
9	Mills CD, Kincaid K, Alt JM, Heilman MJ and Hill AM: M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 164:6166–6173. 2000. View Article : Google Scholar : PubMed/NCBI
10	Gordon S and Martinez FO: Alternative activation of macrophages: Mechanism and functions. Immunity. 32:593–604. 2010. View Article : Google Scholar : PubMed/NCBI
11	Lewis CE and Pollard JW: Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66:605–612. 2006. View Article : Google Scholar : PubMed/NCBI
12	Komohara Y, Fujiwara Y, Ohnishi K and Takeya M: Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev. 99:180–185. 2016. View Article : Google Scholar
13	Mantovani A, Marchesi F, Malesci A, Laghi L and Allavena P: Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 14:399–416. 2017. View Article : Google Scholar : PubMed/NCBI
14	Shu Y and Cheng P: Targeting tumor-associated macrophages for cancer immunotherapy. Biochim Biophys Acta Rev Cancer. 1874:1884342020. View Article : Google Scholar : PubMed/NCBI
15	Davis BN and Hata A: Regulation of MicroRNA biogenesis: A miRiad of mechanisms. Cell Commun Signal. 7:182009. View Article : Google Scholar : PubMed/NCBI
16	Fathullahzadeh S, Mirzaei H, Honardoost MA, Sahebkar A and Salehi M: Circulating microRNA-192 as a diagnostic biomarker in human chronic lymphocytic leukemia. Cancer Gene Ther. 23:327–332. 2016. View Article : Google Scholar : PubMed/NCBI
17	Keshavarzi M, Sorayayi S, Jafar Rezaei M, Mohammadi M, Ghaderi A, Rostamzadeh A, Masoudifar A and Mirzaei H: MicroRNAs-based imaging techniques in cancer diagnosis and therapy. J Cell Biochem. 118:4121–4128. 2017. View Article : Google Scholar : PubMed/NCBI
18	Khalife H, Skafi N, Fayyad-Kazan M and Badran B: MicroRNAs in breast cancer: New maestros defining the melody. Cancer Genet. 246-247:18–40. 2020. View Article : Google Scholar : PubMed/NCBI
19	Liu G and Abraham E: MicroRNAs in immune response and macrophage polarization. Arterioscler Thromb Vasc Biol. 33:170–177. 2013. View Article : Google Scholar : PubMed/NCBI
20	Essandoh K, Li Y, Huo J and Fan GC: MiRNA-mediated macrophage polarization and its potential role in the regulation of inflammatory response. Shock. 46:122–131. 2016. View Article : Google Scholar : PubMed/NCBI
21	Graff JW, Dickson AM, Clay G, McCaffrey AP and Wilson ME: Identifying functional microRNAs in macrophages with polarized phenotypes. J Biol Chem. 287:21816–21825. 2012. View Article : Google Scholar : PubMed/NCBI
22	Zhang S, Ge W, Zou G, Yu L, Zhu Y, Li Q, Zhang Y, Wang Z and Xu T: MiR-382 targets GOLM1 to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival. Am J Cancer Res. 8:120–131. 2018.PubMed/NCBI
23	Xu M, Jin H, Xu CX, Sun B, Song ZG, Bi WZ and Wang Y: miR-382 inhibits osteosarcoma metastasis and relapse by targeting Y box-binding protein 1. Mol Ther. 23:89–98. 2015. View Article : Google Scholar :
24	Yao H, Xia D, Li ZL, Ren L, Wang MM, Chen WS, Hu ZC, Yi GP and Xu L: MiR-382 functions as tumor suppressor and chemosensitizer in colorectal cancer. Biosci Rep. 39:BSR201804412019. View Article : Google Scholar :
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
26	Taki M, Abiko K, Ukita M, Murakami R, Yamanoi K, Yamaguchi K, Hamanishi J, Baba T, Matsumura N and Mandai M: Tumor immune microenvironment during epithelial-mesenchymal transition. Clin Cancer Res. 27:4669–4679. 2021. View Article : Google Scholar : PubMed/NCBI
27	Ye XZ, Xu SL, Xin YH, Yu SC, Ping YF, Chen L, Xiao HL, Wang B, Yi L, Wang QL, et al: Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J Immunol. 189:444–453. 2012. View Article : Google Scholar : PubMed/NCBI
28	Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL and Howe PH: TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol. 12:286–293. 2010. View Article : Google Scholar : PubMed/NCBI
29	Cai J, Xia L, Li J, Ni S, Song H and Wu X: Tumor-associated macrophages derived TGF-β-induced epithelial to mesenchymal transition in colorectal cancer cells through Smad2,3-4/Snail signaling pathway. Cancer Res Treat. 51:252–266. 2019. View Article : Google Scholar
30	Liu CY, Xu JY, Shi XY, Huang W, Ruan TY, Xie P and Ding JL: M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab Invest. 93:844–854. 2013. View Article : Google Scholar : PubMed/NCBI
31	Lei Y, Zhou H, Dai M, Jin X and Ming J: Effects of Mir-382 on biological characteristics of triple negative breast cancer cell line 4T1 through PGC-1α. J Third Mil Med Univ. 41:1415–1422. 2019.
32	Jin X, Ni TG, Wang N, Luo H, Lei Y and Ming J: Mechanism of mitochondria-mediated PGC-1α in macrophage polarization. J Third Mil Med Univ. 41:56–62. 2019.
33	Dai M, Jin X, Lei YY and Ming: Effect of miR-382 overexpressing tumor-associated macrophages on biological properties of triple-negative breast cancer 4T1 cells. J Third Mil Med Univ. 40:1375–1382. 2018.
34	Hobson-Gutierrez SA and Carmona-Fontaine C: The metabolic axis of macrophage and immune cell polarization. Dis Model Mech. 11:dmm0344622018. View Article : Google Scholar : PubMed/NCBI
35	Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG and Pearce EJ: Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood. 115:4742–4749. 2010. View Article : Google Scholar : PubMed/NCBI
36	Zhao M, Wang Y, Li L, Liu S, Wang C, Yuan Y, Yang G, Chen Y, Cheng J, Lu Y and Liu J: Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics. 11:1845–1863. 2021. View Article : Google Scholar : PubMed/NCBI
37	Campbell CT, Kolesar JE and Kaufman BA: Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number. Biochim Biophys Acta. 1819:921–929. 2012. View Article : Google Scholar : PubMed/NCBI
38	Klinge CM: Estrogenic control of mitochondrial function. Redox Biol. 31:1014352020. View Article : Google Scholar : PubMed/NCBI
39	Cruz-Bermúdez A, Laza-Briviesca R, Vicente-Blanco RJ, García-Grande A, Coronado MJ, Laine-Menéndez S, Palacios-Zambrano S, Moreno-Villa MR, Ruiz-Valdepeñas AM, Lendinez C, et al: Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition. Free Radic Biol Med. 135:167–181. 2019. View Article : Google Scholar
40	Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A and Bray F: Cancer statistics for the year 2020: An overview. Int J Cancer. Apr 5–2021.Epub ahead of print. View Article : Google Scholar
41	Butowski N, Colman H and De Groot JF: Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: An Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro Oncol. 18:557–564. 2016. View Article : Google Scholar :
42	Edelman MJ, Wang X, Hodgson L, Cheney RT, Baggstrom MQ, Thomas SP, Gajra A, Bertino E, Reckamp KL, Molina J, et al: Phase III randomized, placebo-controlled, double-blind trial of celecoxib in addition to standard chemotherapy for advanced non-small-cell lung cancer with cyclooxygenase-2 overexpression: CALGB 30801 (Alliance). J Clin Oncol. 35:2184–2192. 2017. View Article : Google Scholar : PubMed/NCBI
43	Reid T, Oronsky B, Scicinski J, Scribner CL, Knox SJ, Ning S, Peehl DM, Korn R, Stirn M, Carter CA, et al: Safety and activity of RRx-001 in patients with advanced cancer: A first-in-human, open-label, dose-escalation phase 1 study. Lancet Oncol. 16:1133–1142. 2015. View Article : Google Scholar : PubMed/NCBI
44	Chatterjee B, Saha P, Bose S, Shukla D, Chatterjee N, Kumar S, Tripathi PP and Srivastava AK: MicroRNAs: As critical regulators of tumor-associated macrophages. Int J Mol Sci. 21:71172020. View Article : Google Scholar
45	Gholamin S, Mirzaei H, Razavi SM, Hassanian SM, Saadatpour L, Masoudifar A, ShahidSales S and Avan A: GD2-targeted immunotherapy and potential value of circulating microRNAs in neuroblastoma. J Cell Physiol. 233:866–879. 2018. View Article : Google Scholar
46	Yang J, Zhang Z, Chen C, Liu Y, Si Q, Chuang TH, Li N, Gomez-Cabrero A, Reisfeld RA, Xiang R and Luo Y: MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene. Oncogene. 33:3014–3023. 2014. View Article : Google Scholar
47	Banerjee S, Xie N, Cui H, Tan Z, Yang S, Icyuz M, Abraham E and Liu G: MicroRNA let-7c regulates macrophage polarization. J Immunol. 190:6542–6549. 2013. View Article : Google Scholar : PubMed/NCBI
48	Huang C, Liu XJ, Qun Zhou, Xie J, Ma TT, Meng XM and Li J: MiR-146a modulates macrophage polarization by inhibiting Notch1 pathway in RAW264.7 macrophages. Int Immunopharmacol. 32:46–54. 2016. View Article : Google Scholar : PubMed/NCBI
49	Lei J, Fu Y, Zhuang Y, Zhang K and Lu D: miR-382-3p suppressed IL-1β induced inflammatory response of chondrocytes via the TLR4/MyD88/NF-κB signaling pathway by directly targeting CX43. J Cell Physiol. 234:23160–23168. 2019. View Article : Google Scholar : PubMed/NCBI
50	Huang J, Wang F, Argyris E, Chen K, Liang Z, Tian H, Huang W, Squires K, Verlinghieri G and Zhang H: Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med. 13:1241–1247. 2007. View Article : Google Scholar : PubMed/NCBI
51	Wang X, Xue N, Zhao S, Shi Y, Ding X and Fang Y: Upregulation of miR-382 contributes to renal fibrosis secondary to aristolochic acid-induced kidney injury via PTEN signaling pathway. Cell Death Dis. 11:6202020. View Article : Google Scholar : PubMed/NCBI
52	Zhou H, Wang Y, Lin Z and Ming J: Mir-382-5p affects the polarization of breast cancer tumor-associated macrophages through the Akt/mTOR signaling pathway. J Third Mil Med Univ. 43:1358–1365. 2021.
53	Chawla A: Control of macrophage activation and function by PPARs. Circ Res. 106:1559–1569. 2010. View Article : Google Scholar : PubMed/NCBI
54	Niu Z, Shi Q, Zhang W, Shu Y, Yang N, Chen B, Wang Q, Zhao X, Chen J, Cheng N, et al: Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs. Nat Commun. 8:7662017. View Article : Google Scholar
55	Liu Y, Xu R, Gu H, Zhang E, Qu J, Cao W, Huang X, Yan H, He J and Cai Z: Metabolic reprogramming in macrophage responses. Biomark Res. 9:12021. View Article : Google Scholar : PubMed/NCBI
56	Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM and Puigserver P: PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell. 23:287–301. 2013. View Article : Google Scholar : PubMed/NCBI
57	Bost F and Kaminski L: The metabolic modulator PGC-1α in cancer. Am J Cancer Res. 9:198–211. 2019.
58	Abdalla HB, Napimoga MH, Lopes AH, de Macedo Maganin AG, Cunha TM, Van Dyke TE and Clemente Napimoga JT: Activation of PPAR-γ induces macrophage polarization and reduces neutrophil migration mediated by heme oxygenase 1. Int Immunopharmacol. 84:1065652020. View Article : Google Scholar
59	Zhang X, Zhang Y, Meng Q, Sun H, Wu S, Xu J, Yun J, Yang X, Li B, Zhu H, et al: MicroRNA-382-5p is involved in pulmonary inflammation induced by fine particulate matter exposure. Environ Pollut. 262:1142782020. View Article : Google Scholar : PubMed/NCBI