Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer
- PDF / 15,841,699 Bytes
- 19 Pages / 595.276 x 790.866 pts Page_size
- 119 Downloads / 211 Views
Open Access
RESEARCH
Tumor‑derived exosomal miR‑934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer 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* and Dawei Li1,2*
Abstract Background: 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 tumorderived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Methods: 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. Results: 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 cellderived 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. Conclusions: 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. Keywords: Colorectal cancer liver metastasis, Exosome, miR-934, M2 macrophage polarization, Premetastatic niche
*Correspondence: [email protected]; [email protected]; [email protected] † Senlin Zhao, Yushuai Mi, and Bingjie Guan have contributed equally to this work 1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China 2 Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, Shanghai 200032, China Full list of author information is available at the end of the article
Introduction Although the combination of surgery, chemotherapy, targeted therapy, and immunotherapy has partially improved the clinical efficacy of colorectal cancer (CRC) therapy, CRC still ranks third in terms of incidence and is the second leading cause of cance
Data Loading...
