Abstract
The metastatic potential of colorectal cancer (CRC) is intensively promoted by the tumor microenvironment (TME) in a paracrine manner. As a pleiotropic inflammatory cytokine, Interleukin-6 (IL-6) is produced and involved in CRC, the same scenario where integrin αvβ6 also becomes upregulated. However, the relationship between IL-6 and integrin αvβ6 as well as their involvement in the crosstalk between CRC and TME remains largely unclear. In the present study, we demonstrated a positive correlation between the expression of IL-6 and integrin β6 in CRC samples. The mutually promotive interaction between CRC and TME was further determined by an indirect coculture system. CRC cells could augment the secretion of IL-6 from fibroblasts, which in return induced invasion and integrin β6 expression of CRC cells. Through the classic IL-6 receptor/STAT-3 signaling pathway, IL-6 mediated the upregulation of integrin β6, which was involved in the invasion and epithelial-mesenchymal transition of CRC cells induced by IL-6. Taken together, our results reveal a paracrine crosstalk between IL-6 signals originating from the TME and increased the integrin β6 level of CRC. IL-6 induces CRC invasion via upregulation of integrin β6 through the IL-6 receptor/STAT-3 signaling pathway. Combined inhibition of IL-6 along with integrin β6-targeted strategy may indicate new directions for antitumor strategies for CRC.
Highlights
Due to environmental causes and risk factors in modern society such as intestinal pathogens and inflammation, colorectal cancer (CRC) is among the most common malignancies [1]
To further investigate whether there was a correlation between IL-6 and β6 expression, the samples were divided into high and low expression groups based on IL-6 immunostaining, and the IHC scores of integrin β6 from two groups were compared by Mann-Whitney analysis, which indicated that the IL-6-high group demonstrated higher immunostaining of integrin β6 than the IL-6-low group (Figure 1(e))
We found that the MAPK/Ets-1 signaling pathway was involved in the dysregulation of integrin β6 [47]; through pathway inhibitors, we found that ERK/MAPK and PI3K pathways were dispensable in IL-6-induced integrin β6 expression, suggesting the preferred role of the STAT-3 pathway in IL6-mediated CRC progression
Summary
Due to environmental causes and risk factors in modern society such as intestinal pathogens and inflammation, colorectal cancer (CRC) is among the most common malignancies [1]. Even though many vital molecular mechanisms have been revealed involved in cancer progression, it seems not realistic to prevent CRC metastasis by targeting one oncogene or signaling pathway within cancer cells [2]. The tumor consists of malignant cancer cells and stromal cells that constitute the tumor microenvironment (TME). More and more studies have discovered that the metastatic potential of cancer cells depends on certain oncogenes and signaling pathways and is intensively promoted by the TME in a paracrine manner [3]. The stromal cells in the TME can be activated by cancer cells but pro-
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