Lithocholic Acid Stimulates IL-8 Expression in Human Colorectal Cancer Cells Via Activation of Erk1/2 MAPK and Suppression of STAT3 Activity

Abstract

The secondary bile acid lithocholic acid (LCA), an established tumor promoter, has been implicated in colorectal cancer (CRC) metastasis. Overexpression of interleukin-8 (IL-8) has been detected in CRC, and it contributes to poor prognosis. However, the effect of LCA on IL-8 expression is still undefined. In this study, we observed that LCA treatment induced IL-8 expression in CRC HCT116 cells. Pharmacological inhibition and mutagenesis studies indicated that Erk1/2 is critical for LCA-induced IL-8 expression. Furthermore, LCA reduced the phosphorylation of STAT3, and the STAT3 inhibitor Stattic, accelerated LCA-induced IL-8 expression, suggesting that STAT3 is involved in LCA-induced IL-8 expression. Activation of Erk1/2 functioned as an upstream signal of the STAT3 suppression induced by LCA. In conclusion, LCA activated Erk1/2 and in turn, suppressed STAT3 phosphorylation to induce IL-8 expression in HCT116 cells, thus stimulating endothelial cell proliferation and tube like formation. J. Cell. Biochem. 118: 2958-2967, 2017. © 2017 Wiley Periodicals, Inc.

Role of bile acids in colon carcinogenesis

“…Our study proved that IL-8 secreted by LCA-stimulated CRC cells, HCT116, could stimulate tube-like formation of endothelial cells. Our findings proved that BAs promote colon tumor progression via enhancing angiogenesis activity[ 49 ].…”

“…Our study indicated that LCA stimulates all of three MAPK pathways including p38, JNK, and Erk1/2[ 45 , 49 ]. MAPK activation was demonstrated to be involved in the regulation of expression of many oncogenic genes such as mucinex 2 (MUC2)[ 57 ], uPAR[ 45 ], and IL-8[ 49 ], and is implicated in CRC progression via enhancing cancer cell invasion and angiogenesis activity. Interestingly, we revealed that Erk1/2 signaling stimulated by LCA results in the inhibition of STAT3 signaling for final IL-8 expression up-regulation in CRC cell lines[ 49 ] (Figure 3 ).…”

“…IL-8 is an inflammatory cytokine that exerts potent angiogenic stimuli on endothelial cells through interaction with its cognate receptors, CXCR1 and CXCR2. It was proven to be up-regulated by secondary BAs and in turn stimulate CRC cell angiogenesis[ 49 ]. Otherwise, this cytokine induction is also mediated by MMP-2 expression and increased invasion of CRC cells[ 48 , 72 ].…”

Microbiota-Derived Metabolites in Tumor Progression and Metastasis

“…Moreover, LCA has been shown to have pro-apoptotic functions in MCF-7 and MDA-MB-231 BC cell lines, suggesting a potential therapeutic role in BC [ 44 ]. Conversely, LCA stimulates angiogenesis and metastasis in HCT116 CRC cell lines through the activation of extracellular signal-regulated kinases (Erk)1/2 and simultaneous reduction of Signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus enhancing as a consequence the expression of IL-8 which is known to be upregulated in the serum of CRC patients [ 34 ] ( Figure 2 ). In SW620 CRC cell lines, LCA upregulated via Erk1/2 the expression of the urokinase-type plasminogen activator receptor (uPAR), which is associated with invasive and metastatic behavior in several cancer types [ 45 ].…”

Colorectal cancer stem cells properties and features: evidence of interleukin-8 involvement

“…Acting as signaling molecules, BA are also potent CRC promoters: indeed, BA signal through different signaling cascades, such as MAPK, PI3K and NF-κB, in order to affect transcription of several stemness genes, including IL-8 [75] . Indeed, Nguyen et al [76] demonstrated that secondary BA lithocholic acid (LCA) induces IL-8 expression, by enhancing ERK1/2 activity and blocking STAT3 phosphorylation: LCA-induced IL-8 expression stimulates endothelial cells proliferation and tube-like formation, in in vitro models.…”