Interleukin-6 Promotes Epithelial-Mesenchymal Transition and Cell Invasion through Integrin β6 Upregulation in Colorectal Cancer

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.

<p>Progress in Understanding the IL-6/STAT3 Pathway in Colorectal Cancer</p>

“… 41 CRC cells further augment IL-6 secretion from CAFs, but specific mechanisms still need to be revealed. 42 These studies indicate that CAFs produce abundant amounts of IL-6, and that CRC cells facilitate the process. IL-6/STAT3 signaling drives CAF activation in CRC, enhancing tumor progression.…”

“…IL-6-mediated activation of STAT3 can rapidly induce integrin β6 transcription, and the up-regulated integrin β6 inhibits E-cadherin and enhances vimentin expression to advance the EMT. 42 Further investigations are needed to uncover how STAT3 induces integrin β6 expression.…”

“…IL-6-mediated activation of STAT3 can rapidly induce integrin β6 transcription, and the up-regulated integrin β6 inhibits E-cadherin and enhances vimentin expression to advance the EMT. 42 Further investigations are needed to uncover how STAT3 induces integrin β6 expression. STAT3 can up-regulate hypoxia-inducing factor-1α (HIF-1α), 67,68 which binds to the positive regulatory element EP-1 (−153 to −148 bp) in the gene encoding carcinoembryonic antigen (CEA), inducing its expression.…”

The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia

“…Production of IL-6 by myofibroblasts isolated from CRC was also noted, in an amount higher compared to tumor-cell secretion, inducing angiogenesis via the up-regulation of VEGF-A [ 135 ]. CRC cells can themselves increase the secretion of IL-6 from fibroblasts, which in turn induces invasion and expression of the integrin β6 adhesion molecule (an indicator of tumor progression) in CRC cells [ 136 ]. The presence of myofibroblasts surrounding adipocytes was also noted in CRC, along with the increased pro- (e.g., TNF-α, IL-6, and IL-8) and anti-inflammatory cytokine (e.g., IL-5) content, as well as enhanced ECM protein synthesis due to cachexia.…”

Fluoropyrimdine therapy induced alterations in interleukins expression in colorectal cancer patients

“…IL-6 mediated the upregulation of integrin β 6, which was involved in the invasion and epithelial-mesenchymal transition of CRC cells. 9 The progression of CRC disease was correlated with the significant overexpression of IL-6 in serum 10 and in CRC tissues. 11 IL-6 was positively correlated with CRC tumor TNM stage, depth of invasion and lymph node metastasis.…”