TY - JOUR
T1 - Hypoxia-Inducible Exosomes Facilitate Liver-Tropic Premetastatic Niche in Colorectal Cancer
AU - Sun, Hao
AU - Meng, Qingtao
AU - Shi, Chengyu
AU - Yang, Hongbao
AU - Li, Xiaobo
AU - Wu, Shenshen
AU - Familiari, Giuseppe
AU - Relucenti, Michela
AU - Aschner, Michael
AU - Wang, Xuehao
AU - Chen, Rui
N1 - Funding Information:
Supported by the National Science for Distinguished Young Schlolars (82025031), the National Natural Science Foundation of China (81861138017, 91943301), The State Key Program of the National Natural Science Foundation of China (81730088), the Ministry of Foreign Affairs and International Cooperation of Italy (CN18GR10); and the National Institute of Environmental Health Sciences (R01 ES10563, R01 ES07331, and R01 ES020852, to M.A.).
Publisher Copyright:
© 2021 by the American Association for the Study of Liver Diseases.
PY - 2021/11
Y1 - 2021/11
N2 - Background and Aims: Liver metastasis is a frequent occurrence in patients with colorectal cancer (CRC), with 15%-25% of CRC patients having liver metastases at the time of initial diagnosis. Specifically, some regional-stage patients with mild symptoms (stage 1 or 2) will also advance to liver metastases rapidly, even if the CRC lesion in situ is resected in time. Nevertheless, the precise mechanism of liver metastasis is still unclear. Approach and Results: Fresh tumor tissues from patients with CRC, adjacent noncancerous tissues, and colorectal adenoma tissues were subjected to microarray analysis to identify differentially expressed microRNA. Exosomes from human serum and cell culture medium were separated, quantitated, and verified by transmission electronic microscopy and Zetasizer Nano. Luciferase reporter assay, real-time quantitative PCR, western blot, immunoprecipitation, chromatin and re-chromatin immunoprecipitation, migration and invasion assay, PDX mouse model, flow cytometry, immunohistochemistry, and immunofluorescence staining were employed to explore the regulation among CRC liver metastases, immunosuppression, and cell adhesion. In this study, we demonstrated that the hypoxic microenvironment in primary CRC lesions boosted exosome release, selectively initiated favorable premetastatic niche formation in the liver but not in other organs. Mechanistically, Kupffer cells (KCs) can phagocytose exosomes containing highly expressed miR-135a-5p from the blood circulation into the liver. Exosomal miR-135a-5p initiated the large tumor suppressor kinase 2–yes-associated protein–matrix metalloproteinase 7 axis to promote the occurrence of CRC liver metastasis, and cluster of differentiation 30–TNF receptor–associated factor 2–p65–mediated immunosuppression signaling also contributed to this process. Conclusions: Hypoxia-induced exosomal miR-135a-5p correlates with the development, clinical severity, and prognosis of CRC liver metastases through the premetastatic niche; and our findings revealed that miR-135a-5p might be a promising target in halting CRC liver metastases.
AB - Background and Aims: Liver metastasis is a frequent occurrence in patients with colorectal cancer (CRC), with 15%-25% of CRC patients having liver metastases at the time of initial diagnosis. Specifically, some regional-stage patients with mild symptoms (stage 1 or 2) will also advance to liver metastases rapidly, even if the CRC lesion in situ is resected in time. Nevertheless, the precise mechanism of liver metastasis is still unclear. Approach and Results: Fresh tumor tissues from patients with CRC, adjacent noncancerous tissues, and colorectal adenoma tissues were subjected to microarray analysis to identify differentially expressed microRNA. Exosomes from human serum and cell culture medium were separated, quantitated, and verified by transmission electronic microscopy and Zetasizer Nano. Luciferase reporter assay, real-time quantitative PCR, western blot, immunoprecipitation, chromatin and re-chromatin immunoprecipitation, migration and invasion assay, PDX mouse model, flow cytometry, immunohistochemistry, and immunofluorescence staining were employed to explore the regulation among CRC liver metastases, immunosuppression, and cell adhesion. In this study, we demonstrated that the hypoxic microenvironment in primary CRC lesions boosted exosome release, selectively initiated favorable premetastatic niche formation in the liver but not in other organs. Mechanistically, Kupffer cells (KCs) can phagocytose exosomes containing highly expressed miR-135a-5p from the blood circulation into the liver. Exosomal miR-135a-5p initiated the large tumor suppressor kinase 2–yes-associated protein–matrix metalloproteinase 7 axis to promote the occurrence of CRC liver metastasis, and cluster of differentiation 30–TNF receptor–associated factor 2–p65–mediated immunosuppression signaling also contributed to this process. Conclusions: Hypoxia-induced exosomal miR-135a-5p correlates with the development, clinical severity, and prognosis of CRC liver metastases through the premetastatic niche; and our findings revealed that miR-135a-5p might be a promising target in halting CRC liver metastases.
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U2 - 10.1002/hep.32009
DO - 10.1002/hep.32009
M3 - Article
C2 - 34110633
AN - SCOPUS:85114460045
SN - 0270-9139
VL - 74
SP - 2633
EP - 2651
JO - Hepatology
JF - Hepatology
IS - 5
ER -
