NLRC3 High Expression Represents a Novel Predictor for Positive Overall Survival Correlated With CCL5 and CXCL9 in HCC Patients

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.

NLRC3 is a potential prognostic biomarker that is correlated with immune cell infiltration in lung adenocarcinoma

“…Previous studies have confirmed that NLRC3 prevents colorectal cancer growth by suppressing the PI3K-mTOR signaling pathway and that it may suppress HCC progression by promoting CD8 + T-cell infiltration 7 , 8 . Our study revealed a significant correlation between the expression of NLRC3 and the tumor immune microenvironment of LUAD.…”

“…Recent studies have shown that NLRC3 is dysregulated across many cancers and implicated in their progression. For example, NLRC3 prevents colorectal cancer growth by suppressing the PI3K-mTOR signaling pathway and may suppress hepatocellular carcinoma (HCC) progression by promoting CD8 + T-cell infiltration 7 , 8 . However, information available on the expression, regulation, and clinical significance of NLRC3 in LUAD remains lacking.…”

Serum CXCL5 Detects Early Hepatocellular Carcinoma and Indicates Tumor Progression

“…However, the distinct role of CXCL9 remains less clear as experimental studies report direct angiostatic and antifibrotic effects of the CXCL9/CXCR3 under pre-cirrhotic conditions [ 29 ], while elevated CXCL9 serum levels potentially contribute to hepatic as well as extrahepatic organ dysfunction in cirrhotic patients predicting poor overall survival [ 30 ]. In HCC, CXCL9 is associated with the recruitment of tumor-infiltrating immune cells (mainly CD4+ and CD8+ lymphocytes) shaping the TME and possibly amplifying anti-tumor responses of cytotoxic T cells [ 31 ]. Former studies identified different cytokines associated with HCC development in different underlying liver diseases.…”

Construction of immunotherapy-related prognostic gene signature and small molecule drug prediction for cutaneous melanoma

“…CTLA4, an immunological checkpoint molecule, can influence the TME of CM by binding to B7 (CD80/CD86) molecules on melanoma antigen-presenting cells to down-regulate T cell activation ( 44 ). The chemokine CXCL9 (C-X-C motif chemokine ligand 9) correlates positively with CD8 + T cell infiltration in solid malignancies ( 45 , 46 ). CXCL9 is abundantly expressed in several solid tumors, including CM, and it stimulates the infiltration of CD4 + T and CD8 + T lymphocytes into tumor cell regions, hence boosting the response of cytotoxic T lymphocytes and destroying tumor cells ( 47 , 48 ).…”