Abstract
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 (CCl4) 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.
Highlights
Digestive system cancers (DSCs, including esophageal cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, hepatocellular carcinoma, and pancreatic cancer) are common malignant cancers and the cause of death worldwide [1]
To explore the roles of ZIPs in DSCs, data were retrieved from patients with DSCs in the Gene Expression Profiling Interactive Analysis (GEPIA) and 72 normal samples from The Cancer Genome Atlas (TCGA) databases, we found except ZIP12, almost all ZIP genes had obviously different transcription
The mRNA Levels of ZIP2/ZIP5/ZIP8/ZIP9/ ZIP14 Are Decreased in the Liver Tissues of hepatocellular carcinoma (HCC) Patients
Summary
Digestive system cancers (DSCs, including esophageal cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, hepatocellular carcinoma, and pancreatic cancer) are common malignant cancers and the cause of death worldwide [1]. The survival rates of these cancers have been greatly improved in recent years due to the advancement of early diagnosis and treatment strategies, the incidence and mortality of these cancers have increased [2, 3]. Among these DSCs, hepatocellular carcinoma (HCC) is the sixth most common primary malignant tumor in the world, and it is the fourth leading cause of human death [4]. An association between lower systemic zinc levels and DSCs has been demonstrated in various human disorders, such as hepatitis, colorectal cancer and gastric cancer [7–9]
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