Hypoxia-inducible gene 2 promotes the immune escape of hepatocellular carcinoma from nature killer cells through the interleukin-10-STAT3 signaling pathway

Abstract

Background The study examines the expression and function of hypoxia-inducible gene 2 (HIG2) in hepatocellular carcinoma (HCC) tissues and cells. Methods Forty patients with HCC were included in the study. Bioinformatic analysis was used to analyze the clinical relevance of HIG2 expression in HCC tissue samples. Immunohistochemistry was employed to determine the expression of target proteins in tumor tissues. Hepatic HepG2 and SMMC-7721 cells were transfected with HIG2 -targeting siRNA with Lipofectamine 2000. qRT-PCR was carried out to determine gene expression levels, while Western blotting was used to determine protein expression. A CCK-8 assay was performed to detect proliferation of cells, while migration and invasion of cells were studied by Transwell assay. Flow cytometry was carried out to detect surface markers and effector molecules in Nature killercells, as well as the killing effect of NK cells. Results HIG2 expression was upregulated in HCC. Silencing of HIG2 suppressed HCC cell migration and invasion. The killing effect of NK cells on HCC cells was enhanced after HIG2 was silenced in HCC cells. Conditioned media from HIG2 -silenced SMMC-7721 cells inhibited the phenotype and function of NK cells. HCC cells with silenced expression of HIG2 modulated the activity of NK cells via STAT3. HIG2 promoted the evasion of HCC cells from killing by NK cells through upregulation of IL-10 expression. Conclusion The study demonstrates that HIG2 activates the STAT3 signaling pathway in NK cells by promoting IL-10 release by HCC cells, thereby inhibiting the killing activity of NK cells, and subsequently promoting the recurrence and metastasis of HCC.

Mining TCGA Database for Tumor Microenvironment-Related Genes of Prognostic Value in Hepatocellular Carcinoma

“…Then, we constructed the PPI network to better understand the interactions of DEGs, and the top three modules show that they were all significantly related to the pathway of immunologic and inflammatory response. CCR7 , PTPRC ( CD45 ), and IL10 were the most connected nodes in these modules, in which CCR7 was a crucial molecule in the mechanism of HCC's progression and metastasis [27–29], PTPRC involved in the regulation of cytokine-induced signaling in malignancies [30–32], and IL10 has been reported to increase the susceptible risk of HCC [33], decrease immunologic activity [34], and promote immune tolerance in the tumor milieu [35, 36]. Finally, survival analysis was performed to explore the potential prognostic value of 289 DEGs, and we identified 12 TME-related genes that showed significant correlation between gene expression and poor outcomes in HCC cases.…”

ERCC6L promotes the progression of hepatocellular carcinoma through activating PI3K/AKT and NF-κB signaling pathway

“…Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the third most common cause of cancer-related deaths worldwide, often accompanied with invasive fast growing and metastasis [1,2].…”

“…Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the third most common cause of cancer-related deaths worldwide, often accompanied with invasive fast growing and metastasis [ 1 , 2 ]. Although therapeutic strategies including surgery resection, liver transplantation and radiotherapy have greatly improved [ 3 ], there are limited effective therapies for patients with advanced HCC.…”

<p>Development and Verification of the Hypoxia-Related and Immune-Associated Prognosis Signature for Hepatocellular Carcinoma</p>

“…50 Hypoxia has a profound effect on the NK cell infiltrate property, together with its influence on responses mediated by immune statuses in cancer tissues. 51,52 Berchem et al illustrated that microvesicles derived from tumors under hypoxia had negative regulation on the functions of NK cells through the mechanism related to transferring miR23a and TGF-β, 53 which suggested that the impaired cytotoxicity of NK cells might be induced by oxygen deficit. In brief, the prognostic gene signature developed in this study was able to accurately indicate the immunocyte infiltration degrees in high-and low-risk patients.…”