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Evaluation of anti-tumorigenic effects of anti-Lipocalin2 (anti-LCN2) monoclonal antibody against human cervical cancer xenografts in athymic nude mice

ABSTRACT: This study investigated the impact of an anti-LCN2 monoclonal antibody on STR-authenticated HeLa cells using a xenograft model in athymic nude mice. Treatment of tumors with anti-LCN2 antibody resulted in 39 – 60% reduction in tumor volume. RNA extracted from the tumors post-treatment was sequenced and aligned to human and mouse genome separately. Differential expression analysis of human mapped overexpressed genes in treated tumor revealed suppression of pro-tumorigenic TNF- and IL17 signalling pathways, whereas the corresponding mouse-mapped genes indicated pathways including activation of T-cells and T-cell mediated killing in treated tumors. M2 mouse macrophage markers showed a decline under treatment signifying tumor regression. This observed T-cell activation and debilitation of M2 mouse macrophages by anti-LCN2 underlies its potential as an immune sensitizer that can potentially devour tumor cells through T-cell mediated cytotoxicity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242667 | GEO | 2023/12/31

REPOSITORIES: GEO

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Project description:Elevated lipocalin-2 (Lcn2) has been observed in multiple human cancers, but its biological roles remain unclear. Our purpose in this study was to investigate whether Lcn2 is involved in hepatocellular carcinoma (HCC) development via its involvement in invasion and metastasis. Using unsupervised hierarchical clustering analysis of tissue samples, we identified preferential expression of Lcn2 (>2-fold change) in the tumor group (differentiated group) versus the non-tumor group (liver cirrhosis group). LCN2 immunoreactivity was positively correlated with TNM stage (r = 0.194, P = 0.020), but not with differentiation or recurrence of HCC. Over-expression of Lcn2 was observed in HLK-2, HKK-2, and HLK-5 HCC cells. Knock-down of Lcn2 by shRNA in HKK-2 cells was correlated with the down-regulation of E-cadherin, CK-8, CK-18, and desmoplakin I/II (DesI/II) and the up-regulation of N-cadherin, vimentin (VIM), and fibronectin (FN), which are markers of the epithelial-mesenchymal transition (EMT) associated with tumor progression. The characteristics of EMT were reversed by adenoviral transduction of Lcn2 into SH-J1 cells. EGF or TGF-β treatment resulted in downregulation of Lcn2 with a concomitant change in EMT. Stable Lcn2 expression in HCC cells reduced the expression of the transcription factor Twist1, resulting in the inhibition of cell proliferation, migration, and invasion in vitro, and suppressed tumor growth and metastatic ability in a mouse model. These findings suggest that Lcn2 can reverse the EMT in HCC through transcriptional suppression of Twist 1. Thus, Lcn2 is a candidate metastasis suppressor and a potential therapeutic target for HCC. Unsupervised hierarchical clustering separated the samples into two main groups: a non-tumor group (NT, n = 40) and a HCC group (HCC, n = 40), and into two subgroups: a liver cirrhosis group (LC, n = 20) and a differentiated HCC group (difHCC, n = 20). Lcn2 was one of the unique genes with a two-fold or greater difference in expression from the mean with P < 0.01 based on the t-test for hierarchical clustering analysis.

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Evaluation of anti-tumorigenic effects of anti-Lipocalin2 (anti-LCN2) monoclonal antibody against human cervical cancer xenografts in athymic nude mice

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