Abstract
Human stanniocalcin-1 (STC1) is a glycoprotein known to participate in inflammation and tumor progression. However, its role in cancer-macrophage interaction at the tumor environment is not known. In this study, the co-culture of the human metastatic hepatocellular carcinoma cell line (MHCC97L) stably transfected with a control vector (MHCC97L/P), or STC1-overexpressing vector (MHCC97L/S1) with human leukemia monocytic cell line (THP-1) was conducted. We reported that MHCC97L/S1 suppressed the migratory activity of THP-1. Real-time PCR analysis revealed the downregulation of the pro-migratory factors, monocyte-chemoattractant protein receptors, CCR2 and CCR4, and macrophage-migratory cytokine receptor, CSF-1R. Transcriptomic analysis of the THP-1 cells co-cultured with either MHCC97L/P or MHCC97L/S1, detected 1784 differentially expressed genes. The Ingenuity Canonical Pathway analysis predicted that RhoA signaling was associated with the inhibition of the cell migration. Western blot analysis revealed a significant reduction of Ser19-phosphorylation on MLC2, a Rho-A downstream target, in the THP-1 cells. Xenograft tumors derived from MHCC97/S1 in mice showed a remarkable decrease in infiltrating macrophages. Collectively, this is the first report to demonstrate the inhibitory effect of STC1-overexpressing cancer cells on macrophage migration/infiltration. Our data support further investigations on the relationship between tumor STC1 level and macrophage infiltration.
Highlights
Human stanniocalcin-1 (STC1) is a widely expressed glycoprotein in various tissues and is reported to be involved in many biological functions [1, 2]
The Boyden chamber assay showed that MHCC97L/S1 inhibited the migration of PMAtreated THP-1 cells (Fig 1A)
A similar observation was found in the assay using the monocyte chemoattractant protein MCP-1 (200 ng/ml) (Fig 1B)
Summary
Human stanniocalcin-1 (STC1) is a widely expressed glycoprotein in various tissues and is reported to be involved in many biological functions [1, 2]. Genetic analysis showed that the STC1 gene is located at the metastatic susceptibility locus of 8p, associated with tumor progression and metastases [3, 4]. Considerable numbers of clinical studies reported the dysregulation of STC1 in different types of cancers [2]. Experimental studies using different cancer cell models unraveled the roles of STC1 in cell proliferation/apoptosis, inflammation, migration, and angiogenesis. STC1 is a downstream target gene of HIF-1α, the key transcriptional factor mediating inflammatory responses and tumor transformation [5,6,7,8]. In tumor microenvironment (TME), the dynamics of cancer progression are regulated through the interactions of genetics, immunological, and various micro-environmental factors.
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