ZHX2 inhibited HCC development through regulating polarization of Tumor-Associated Macrophages
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摘要
Background and objective: Hepatocellular carcinoma(HCC) is the second most common cause of cancer-related death. Tumor microenvironment plays an important role in the development of cancer. Tumor associated macrophages(TAMs)are essential components of tumor microenvironment. Recent studies have confirmed the upregulation of M2-associated genes in TAMs in HCC but the mechanism remains unknown. ZHX2, a member of ZHX family, is a novel tumor suppressor. Our previous data has proved the diminished expression of ZHX2 in hepatoma cells and that ZHX2 can inhibit HCC progression. Here we aimed to explore the role of ZHX2 in the regulation of TAMs and the progress of HCC. Methods: For in vitro experiment, RAW264.7 and THP1 cells were used. ZHX2-shRNA was used to knock down ZHX2. Transwell assay was used to estimate the migration capacity of macrophages. Growth curve was used to evaluate proliferation ability of HCC cells. Elisa assay was used to measure the level of cytokines. For orthotopic HCC animal model, myeloid cell-derived ZHX2 deficiency mouse(LysoCre+ZHX2loxp/loxp) was used. Results: First we found that ZHX2 expression level was down-regulated in TAMs from both HCC patients and the orthotopic HCC animal model. Furthermore, in vitro experiments demonstrated that ZHX2 expression on THP1 and RAW264.7 cells can be repressed by hepatoma conditional medium stimulation. Interference of ZHX2 in the macrophages greatly promoted the expression of M2-associated genes, weakened the secretion of pro-inflammation cytokines, thus accelerated the development of HCC.Conclusion: ZHX2 suppressed the HCC development through educating TAMs to anti-tumor phenotype.
Background and objective: Hepatocellular carcinoma(HCC) is the second most common cause of cancer-related death. Tumor microenvironment plays an important role in the development of cancer. Tumor associated macrophages(TAMs)are essential components of tumor microenvironment. Recent studies have confirmed the upregulation of M2-associated genes in TAMs in HCC but the mechanism remains unknown. ZHX2, a member of ZHX family, is a novel tumor suppressor. Our previous data has proved the diminished expression of ZHX2 in hepatoma cells and that ZHX2 can inhibit HCC progression. Here we aimed to explore the role of ZHX2 in the regulation of TAMs and the progress of HCC. Methods: For in vitro experiment, RAW264.7 and THP1 cells were used. ZHX2-sh RNA was used to knock down ZHX2. Transwell assay was used to estimate the migration capacity of macrophages. Growth curve was used to evaluate proliferation ability of HCC cells. Elisa assay was used to measure the level of cytokines. For orthotopic HCC animal model, myeloid cell-derived ZHX2 deficiency mouse(LysoCre+ZHX2loxp/loxp) was used. Results: First we found that ZHX2 expression level was down-regulated in TAMs from both HCC patients and the orthotopic HCC animal model. Furthermore, in vitro experiments demonstrated that ZHX2 expression on THP1 and RAW264.7 cells can be repressed by hepatoma conditional medium stimulation. Interference of ZHX2 in the macrophages greatly promoted the expression of M2-associated genes, weakened the secretion of pro-inflammation cytokines, thus accelerated the development of HCC.Conclusion: ZHX2 suppressed the HCC development through educating TAMs to anti-tumor phenotype.
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