AUTHOR=Gou Yingying , Yang Dan , Tian Taikun , Zhu Xingguo , Zhang Raorao , Ren Jiaqi , Tu Dezhen , Luo Yi , Miao Yuqing , Zhao Huan , Wang Yu , Wei Bin 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.725595

DOI=10.3389/fimmu.2022.725595

ISSN=1664-3224

ABSTRACT=<p>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 (<italic>ZIPs</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 <italic>ZIP</italic> involved in hepatocarcinogenesis remains elusive. In this study, the transcription patterns of <italic>ZIPs</italic> in the DSCs were screened firstly through GEPIA2 database. Interestingly, the analysis of the DSCs data showed the distinct mRNA levels of <italic>ZIPs</italic> between DSCs tissues and healthy controls. Notably, the transcription levels of <italic>ZIP2</italic>, <italic>ZIP5</italic>, <italic>ZIP8</italic>, <italic>ZIP9</italic> and <italic>ZIP14</italic> were decreased significantly in the tissues of human liver cancer compared to paracarcinoma liver tissues. To further confirm the mRNA transcriptional changes of <italic>Zips</italic> in HCC, N-Nitrosodiethylamine (DEN) combined with carbon tetrachloride (CCl<sub>4</sub>) inducing mouse model of HCC were established. Consistently, the mRNA levels of <italic>Zip2</italic>, <italic>Zip9</italic>, and <italic>Zip14</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 <italic>in vitro</italic>, as well as human patients of HCC-derived TAMs, were used to examine the transcription levels of <italic>ZIPs</italic>. Our results showed that both <italic>Zip2</italic> and <italic>Zip9</italic> were up-regulated in M2-polarized macrophages. <italic>Zip2</italic> transcript was also up-regulated M1-polarized macrophages, but <italic>Zip9</italic> was slightly down-regulated. TAMs generated from human liver cancer tissues also displayed a decrease in <italic>ZIP9</italic> transcription compared to paracarcinoma tissues. To further explore the role of Zip9 in M1/M2 polarization, the siRNA knockdown results revealed that <italic>Zip9</italic>, but not <italic>Zip2</italic>, could promote M2 macrophage polarization and impair M1 macrophage polarization. Mechanistically, <italic>Zip9</italic> 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 <italic>ZIP9</italic> may involve in macrophages polarity in HCC development and may be a potent new biomarker for the diagnosis of HCC.</p>