{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:08:26Z","timestamp":1791144506147,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      Liver metastasis is a frequent occurrence in patients with colorectal cancer (CRC), with 15%\u201025% of CRC patients having liver metastases at the time of initial diagnosis. Specifically, some regional\u2010stage patients with mild symptoms (stage 1 or 2) will also advance to liver metastases rapidly, even if the CRC lesion\n                      <jats:italic toggle=\"yes\">in situ<\/jats:italic>\n                      is resected in time. Nevertheless, the precise\u00a0mechanism of liver metastasis is\u00a0still unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>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\u2010time quantitative PCR, western blot, immunoprecipitation, chromatin and re\u2010chromatin 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\u2010135a\u20105p from the blood circulation into the liver. Exosomal miR\u2010135a\u20105p initiated the large tumor suppressor kinase 2\u2013yes\u2010associated protein\u2013matrix metalloproteinase 7 axis to promote the occurrence of CRC liver metastasis, and cluster of differentiation 30\u2013TNF receptor\u2013associated factor 2\u2013p65\u2013mediated immunosuppression signaling also contributed to this process.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Hypoxia\u2010induced exosomal miR\u2010135a\u20105p correlates with the development, clinical severity, and prognosis of CRC liver metastases through the premetastatic niche; and our findings revealed that miR\u2010135a\u20105p might be a promising target in halting CRC liver metastases.<\/jats:p>\n                  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