The interaction of interleukin-8 and PTEN inactivation promotes the malignant progression of head and neck squamous cell carcinoma via the STAT3 pathway

Abstract

Interleukin-8 (IL-8) expression correlates with poor prognosis in many cancers, including head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism is poorly understood. In this study, we found that overexpression of IL-8 correlated with poor outcome in HNSCC patients. IL-8 significantly increased cellular proliferation, migration, and invasion ability both in vitro and in vivo, which could be blocked by a CXCR1/2 inhibitor. IL-8 promoted the expression of MMP2, MMP9, snail, and vimentin in HNSCC cells. Furthermore, IL-8 could inactivate PTEN via phosphorylation, and then inactivated PTEN affected the phosphorylation of STAT3. Recombinant PTEN that internalized in cytoplasm decreased the expression of phosphorylated STAT3, while knockdown of PTEN led to the increased expression of phosphorylated STAT3. A STAT3 inhibitor could reverse the upregulation of invasionassociated proteins mediated by IL-8 stimulation. Furthermore, overexpression of snail and inactivated PTEN jointly promoted the autocrine effect of IL-8 on tumor cells. Last, there were positive correlations between IL-8 and snail, vimentin expression in HNSCC tissues. In summary, our study demonstrates that PTEN acts as a novel "molecular switch" to regulate IL-8/STAT3 signaling, promoting the progression of HNSCC, and indicating that this pathway may be a potential therapeutic target for HNSCC.

Interleukin-6 and Interleukin-8 Regulate STAT3 Activation Migration/Invasion and EMT in Chrysophanol-Treated Oral Cancer Cell Lines

“…Similar effects have been found in other cancers—namely, IL-6 has been shown to induce the activation of the EMT program via STAT3 activation in breast cancer [ 54 ] and to play a role in cancer stemness of osteosarcoma cells via STAT3 activation [ 55 ]. Xu et al reported that IL-8 promoted the malignant progression of HNSCC cells via STAT3 phosphorylation [ 56 ]. Therefore, the induction of EMT through the STAT3 signaling pathway, mediated by IL-6 and IL-8, is important to the metastasis of HNSCC, and is associated with poor clinical outcomes [ 32 ].…”

Chemokine-Cytokine Networks in the Head and Neck Tumor Microenvironment

“…Similarly, CCL21/CCR7 axis has been shown to promote MMP-9 release, stimulate tumor cell survival, adhesion, invasion, and metastasis in HNSCC [ 134 , 135 , 136 , 137 ]. IL-8 and its receptors CXCR1 and CXCR2 are overexpressed in HNSCC and involved in progression, metastasis, and aggressive tumor phenotype [ 161 , 219 ]. The underlying mechanisms revealed inactivation of PTEN and activation of the STAT3 signaling pathway by IL-8/CXCR1/2 axis in promoting aggressive HNSCC phenotype [ 219 ].…”

“…IL-8 and its receptors CXCR1 and CXCR2 are overexpressed in HNSCC and involved in progression, metastasis, and aggressive tumor phenotype [ 161 , 219 ]. The underlying mechanisms revealed inactivation of PTEN and activation of the STAT3 signaling pathway by IL-8/CXCR1/2 axis in promoting aggressive HNSCC phenotype [ 219 ]. In addition to IL-8, migration inhibitory factor (MIF) from tumor cells induces CXCR2-dependent chemotaxis, improved neutrophil survival, and release of CCL4 and MMP-9, helping develop aggressive HNSCC phenotype [ 220 ].…”

Small in Size, but Large in Action: microRNAs as Potential Modulators of PTEN in Breast and Lung Cancers

“…STAT3 and PTEN demonstrate interactions in cancer cells. IL-8 can reduce PTEN expression via phosphorylation to stimulate STAT3 signaling, resulting in enhanced cancer progression [ 161 ]. Furthermore, STAT3 can function as an upstream mediator of PTEN by activating lncRNA cancer susceptibility candidate 9 (CASC9) to diminish PTEN expression, resulting in bladder cancer progression [ 162 ].…”