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Hepatocellular carcinoma (HCC) is one of the most common digestive system cancers (DSCs) with a poor prognosis. Zinc‐regulated transporter (ZRT)/iron‐regulated transporter (IRT) like protein transporters ( ZIPs ) 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  ZIP  involved in hepatocarcinogenesis remains elusive. In this study, the transcription patterns of  ZIPs  in the DSCs were screened firstly through GEPIA2 database. Interestingly, the analysis of the DSCs data showed the distinct mRNA levels of  ZIPs  between DSCs tissues and healthy controls. Notably, the transcription levels of  ZIP2 ,  ZIP5 ,  ZIP8 ,  ZIP9  and  ZIP14  were decreased significantly in the tissues of human liver cancer compared to paracarcinoma liver tissues. To further confirm the mRNA transcriptional changes of  Zips  in HCC, N-Nitrosodiethylamine (DEN) combined with carbon tetrachloride (CCl 4 ) inducing mouse model of HCC were established. Consistently, the mRNA levels of  Zip2 ,  Zip9 , and  Zip14  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  in vitro , as well as human patients of HCC-derived TAMs, were used to examine the transcription levels of  ZIPs . Our results showed that both  Zip2  and  Zip9  were up-regulated in M2-polarized macrophages.  Zip2  transcript was also up-regulated M1-polarized macrophages, but  Zip9  was slightly down-regulated. TAMs generated from human liver cancer tissues also displayed a decrease in  ZIP9  transcription compared to paracarcinoma tissues. To further explore the role of Zip9 in M1/M2 polarization, the siRNA knockdown results revealed that  Zip9 , but not  Zip2 , could promote M2 macrophage polarization and impair M1 macrophage polarization. Mechanistically,  Zip9  enhances phosphorylated STAT6 to promote M2 macrophage polarization but suppresses the phosphorylation of IκBα/β to inhibit M1 macrophage polarization. Together, our results indicate that  ZIP9  may involve in macrophages polarity in HCC development and may be a potent new biomarker for the diagnosis of HCC.

The Transcription of ZIP9 Is Associated With the Macrophage Polarization and the Pathogenesis of Hepatocellular Carcinoma