{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:29:25Z","timestamp":1790710165115,"version":"4.1.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is one of the most common digestive system cancers (DSCs) with a poor prognosis. Zinc\u2010regulated transporter (ZRT)\/iron\u2010regulated transporter (IRT) like protein transporters (<jats:italic>ZIPs<\/jats:italic>) encode membrane transport proteins, which are responsible for the absorption of zinc and play important roles in the pathogenesis of various human cancers. Tumor-associated macrophages (TAMs) are important participants in the regulation of tumor microenvironment and the development of HCC. Individual role of each <jats:italic>ZIP<\/jats:italic> involved in hepatocarcinogenesis remains elusive. In this study, the transcription patterns of <jats:italic>ZIPs<\/jats:italic> in the DSCs were screened firstly through GEPIA2 database. Interestingly, the analysis of the DSCs data showed the distinct mRNA levels of <jats:italic>ZIPs<\/jats:italic> between DSCs tissues and healthy controls. Notably, the transcription levels of <jats:italic>ZIP2<\/jats:italic>, <jats:italic>ZIP5<\/jats:italic>, <jats:italic>ZIP8<\/jats:italic>, <jats:italic>ZIP9<\/jats:italic> and <jats:italic>ZIP14<\/jats:italic> were decreased significantly in the tissues of human liver cancer compared to paracarcinoma liver tissues. To further confirm the mRNA transcriptional changes of <jats:italic>Zips<\/jats:italic> in HCC, N-Nitrosodiethylamine (DEN) combined with carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) inducing mouse model of HCC were established. Consistently, the mRNA levels of <jats:italic>Zip2<\/jats:italic>, <jats:italic>Zip9<\/jats:italic>, and <jats:italic>Zip14<\/jats:italic> in liver tissues of HCC induced mice were also decreased compared with the healthy controls. In addition, mouse peritoneal elucidated macrophages (PEMs)-derived M1\/M2 macrophages <jats:italic>in vitro<\/jats:italic>, as well as human patients of HCC-derived TAMs, were used to examine the transcription levels of <jats:italic>ZIPs<\/jats:italic>. Our results showed that both <jats:italic>Zip2<\/jats:italic> and <jats:italic>Zip9<\/jats:italic> were up-regulated in M2-polarized macrophages. <jats:italic>Zip2<\/jats:italic> transcript was also up-regulated M1-polarized macrophages, but <jats:italic>Zip9<\/jats:italic> was slightly down-regulated. TAMs generated from human liver cancer tissues also displayed a decrease in <jats:italic>ZIP9<\/jats:italic> transcription compared to paracarcinoma tissues. To further explore the role of Zip9 in M1\/M2 polarization, the siRNA knockdown results revealed that <jats:italic>Zip9<\/jats:italic>, but not <jats:italic>Zip2<\/jats:italic>, could promote M2 macrophage polarization and impair M1 macrophage polarization. Mechanistically, <jats:italic>Zip9<\/jats:italic> enhances phosphorylated STAT6 to promote M2 macrophage polarization but suppresses the phosphorylation of I\u03baB\u03b1\/\u03b2 to inhibit M1 macrophage polarization. Together, our results indicate that <jats:italic>ZIP9<\/jats:italic> may involve in macrophages polarity in HCC development and may be a potent new biomarker for the diagnosis of HCC.<\/jats:p>","DOI":"10.3389\/fimmu.2022.725595","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T09:33:19Z","timestamp":1647336799000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["The Transcription of ZIP9 Is Associated With the Macrophage Polarization and the Pathogenesis of Hepatocellular 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