Abstract
NLRC3 (NLR family caspase recruitment domain containing 3) has been reported as a factor of inhibiting inflammatory responses. It’s role in HCC (hepatocellular carcinoma) is still unknown. In this study we firstly used the GEO (Gene Expression Omnibus) database and mIHC (multiple immunohistochemical analysis) with TMAs (tumor tissue microarrays) of HCC patients to evaluate NLRC3 levels. The tumor-bearing mouse models were also established with NLRC3 over-expressing and knock-down Hepal-6 cells to assess its effect. The data showed high NLRC3 expression was related with favorable overall survival (P=0.0386) and disease-free survival (P=0.0458). In addition, NLRC3 expression showed a positive correlation between CD8+ T cells infiltration. In vivo, NLRC3-overexpressing Hepal-6 tumors showed increased CD8+ T cell infiltration. NLRC3-knockdown Hepa1-6 tumors displayed decreased CD8+ T cell infiltration. At the same time, we also found the positive correlations between NLRC3 and CCL5 (C-C motif chemokine ligand 5, P<0.0001, R2 = 0.2372) as well as CXCL9 (C-X-C motif chemokine ligand 9, P<0.0001, R2 = 0.2338) expressions. So NLRC3 high expression represents a novel predictor for positive survival outcomes in HCC patients, and NLRC3 is involved in CD8+ T cell infiltration, which is correlated with increased CCL5 and CXCL9 in TME (tumor microenvironment). This study implies that boosting NLRC3 is a promising treatment to enhance survival in HCC patients.
Highlights
According to the latest data survey, hepatocellular carcinoma (HCC) ranks the second-highest mortality of all tumors in the world [1]
We followingly verified this relationship by IHC analysis of tissue microarrays (TMAs) with clinical 211 HCC patients, whose clinical and pathologic characteristics were summarized in According to the expression of NLR family caspase recruitment domain containing 3 (NLRC3) in tumor tissues, patients were classified into NLRC3-high group (n = 147) and NLRC3-low group (n = 64)
It was confirmed that NLRC3 was positively correlated with C-X-C motif chemokine ligand 9 (CXCL9) (P
Summary
According to the latest data survey, HCC (hepatocellular carcinoma) ranks the second-highest mortality of all tumors in the world [1]. Inflammation is associated with cancer and appears to responsible for various aspects of tumor development [8]. An inflammatory TME (tumor microenvironment) is formed by the interactions of tumor cells, stromal cells, and inflammatory cells [9], so the identification of potential biomarkers related with inflammation is assumed its priority especially in HCC study. NLRC3 (NLR family caspase recruitment domain containing 3) has been reported as a factor of inhibiting inflammatory responses. It was previously reported that NLRC3 prevents the growth of colorectal cancer by inhibiting PI3K-mTOR (mammalian target of rapamycin) pathway [10]. We suppose NLRC3 maybe links with CD8+ T cell infiltration in HCC
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