Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer

Springer Science and Business Media LLC - Tập 13 - Trang 1-19 - 2020
Senlin Zhao1,2, Yushuai Mi3, Bingjie Guan4, Binbin Zheng4, Ping Wei2,5,6, Yanzi Gu7, Zhengxiang Zhang8, Sanjun Cai1,2, Ye Xu1,2, Xinxiang Li1,2, Xuefeng He1,2, Xinyang Zhong1,2, Guichao Li2,9, Zhiyu Chen2,10, Dawei Li1,2
1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
3Department of Gastrointestinal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
4Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
5Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
6Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
7Department of Biobank, Fudan University Shanghai Cancer Center, Shanghai, China
8Department of Oncology, Yijishan Hospital of Wannan Medical College, Wuhu, China
9Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
10Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

Tóm tắt

Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.

Tài liệu tham khảo

Wolf AMD, Fontham ETH, Church TR, Flowers CR, Guerra CE, LaMonte SJ, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68:250–81. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. Beckers RCJ, Lambregts DMJ, Lahaye MJ, Rao SX, Kleinen K, Grootscholten C, et al. Advanced imaging to predict response to chemotherapy in colorectal liver metastases—a systematic review. HPB (Oxford). 2018;20:120–7. Christofori G. New signals from the invasive front. Nature. 2006;441:444–50. Liu Y, Cao X. Characteristics and significance of the pre-metastatic niche. Cancer Cell. 2016;30:668–81. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. Simons M, Raposo G. Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21:575–81. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 2013;32:623–42. Zhang J, Li S, Li L, Li M, Guo C, Yao J, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genom Proteom Bioinf. 2015;13:17–24. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97. Yang F, Ning Z, Ma L, Liu W, Shao C, Shu Y, et al. Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts. Mol Cancer. 2017;16:148. Cheng H, Wang Z, Fu L, Xu T. Macrophage polarization in the development and progression of ovarian cancers: an overview. Front Oncol. 2019;9:421. Teng F, Tian WY, Wang YM, Zhang YF, Guo F, Zhao J, et al. Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. J Hematol Oncol. 2016;9:8. Bach DH, Hong JY, Park HJ, Lee SK. The role of exosomes and miRNAs in drug-resistance of cancer cells. Int J Cancer. 2017;141:220–30. Conde-Vancells J, Rodriguez-Suarez E, Embade N, Gil D, Matthiesen R, Valle M, et al. Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. J Proteome Res. 2008;7:5157–66. Nelson MP, Christmann BS, Dunaway CW, Morris A, Steele C. Experimental Pneumocystis lung infection promotes M2a alveolar macrophage-derived MMP12 production. Am J Physiol Lung Cell Mol Physiol. 2012;303:L469–75. Cook KB, Kazan H, Zuberi K, Morris Q, Hughes TR. RBPDB: a database of RNA-binding specificities. Nucleic Acids Res. 2011;39:D301–8. Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, Perez-Hernandez D, Vazquez J, Martin-Cofreces N, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:2980. Wang X, Luo G, Zhang K, Cao J, Huang C, Jiang T, et al. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis. Cancer Res. 2018;78:4586–98. Kuroda E, Ho V, Ruschmann J, Antignano F, Hamilton M, Rauh MJ, et al. SHIP represses the generation of IL-3-induced M2 macrophages by inhibiting IL-4 production from basophils. J Immunol. 2009;183:3652–60. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell. 2000;100:387–90. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA. 1999;96:4240–5. Wang D, Wang X, Si M, Yang J, Sun S, Wu H, et al. Exosome-encapsulated miRNAs contribute to CXCL12/CXCR4-induced liver metastasis of colorectal cancer by enhancing M2 polarization of macrophages. Cancer Lett. 2020;474:36–52. Liang ZX, Liu HS, Wang FW, Xiong L, Zhou C, Hu T, et al. LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization. Cell Death Dis. 2019;10:829. Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, et al. The cellular and molecular origin of tumor-associated macrophages. Science. 2014;344:921–5. Ohandjo AQ, Liu Z, Dammer EB. Transcriptome network analysis identifies CXCL13-CXCR5 signaling modules in the prostate tumor immune microenvironment. Sci Rep. 2019;9:14963. Allen IC, Wilson JE, Schneider M, Lich JD, Roberts RA, Arthur JC, et al. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling. Immunity. 2012;36:742–54. Kazanietz MG, Durando M, Cooke M. CXCL13 and its receptor CXCR5 in cancer: inflammation, immune response, and beyond. Front Endocrinol (Lausanne). 2019;10:471. Yan H, Ren S, Lin Q, Yu Y, Chen C, Hua X, et al. Inhibition of UBE2N-dependent CDK6 protein degradation by miR-934 promotes human bladder cancer cell growth. FASEB J. 2019;33:12112–23. Hu Y, Zhang Q, Cui J, Liao ZJ, Jiao M, Zhang YB, et al. Oncogene miR-934 promotes ovarian cancer cell proliferation and inhibits cell apoptosis through targeting BRMS1L. Eur Rev Med Pharmacol Sci. 2019;23:5595–602. Saad MA, Kuo SZ, Rahimy E, Zou AE, Korrapati A, Rahimy M, et al. Alcohol-dysregulated miR-30a and miR-934 in head and neck squamous cell carcinoma. Mol Cancer. 2015;14:181. Affo S, Yu LX, Schwabe RF. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu Rev Pathol. 2017;12:153–86. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35. Chen X, Ying X, Wang X, Wu X, Zhu Q, Wang X. Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep. 2017;38:522–8. Fang T, Lv H, Lv G, Li T, Wang C, Han Q, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018;9:191. Hussain M, Adah D, Tariq M, Lu Y, Zhang J, Liu J. CXCL13/CXCR5 signaling axis in cancer. Life Sci. 2019;227:175–86. Zheng Z, Cai Y, Chen H, Chen Z, Zhu D, Zhong Q, et al. CXCL13/CXCR5 axis predicts poor prognosis and promotes progression through PI3K/AKT/mTOR pathway in clear cell renal cell carcinoma. Front Oncol. 2018;8:682. Zhu Z, Zhang X, Guo H, Fu L, Pan G, Sun Y. CXCL13-CXCR5 axis promotes the growth and invasion of colon cancer cells via PI3K/AKT pathway. Mol Cell Biochem. 2015;400:287–95.
Thông tin
Thông tin xuất bản

Springer Science and Business Media LLC

Tập 13

1-19

Thông tin tác giả