CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway

Abstract

Laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) are common head and neck cancers with a high propensity for lymph node (LN) and lung metastasis. Here, we report that LHSCCs express high levels of functional CXCR4 receptors, native for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). Primary tumor immunohistochemistry from LHSCC patients has revealed significant expression of CXCR4 and CXCL12. Greater expression of CXCR4 but not that of CXCL12 is correlated with LN and distant metastasis. Reverse transcription-polymerase chain reaction and western blots have demonstrated that CXCR4 messenger RNA (mRNA) and protein were expressed in LHSCC cell lines as well, but failed to detect CXCL12 mRNA expression. CXCL12 treatment enhanced extracellular signal-regulated kinase (ERK) pathway activation and the motility/invasiveness of LHSCC cell lines, which were blocked by treatment with a CXCR4 antagonist (AMD3100) and a specific MEK inhibitor (U0126). Results show that the mRNA and protein levels of matrix metalloproteinase (MMP)-13, but not MMP-2 or MMP-9, were elevated in HEp-2 cells in response to CXCL12. Again, U0126 almost inhibited the induction of MMP-13 in HEp-2 cells by stimulating CXCL12. The transcriptional factor, c-Jun, a downstream factor of ERK pathway, was found to be readily phosphorylated and translocated to the nucleus after 10 min of exposure to CXCL12. Blockage of c-Jun activity by transfection with c-jun antisense oligodeoxynucleotide significantly decreased CXCL12-induced MMP-13 expression and cell invasion. CXCL12 seems to enhance LHSCC cell invasion through paracrine-activated CXCR4, which triggers ERK/c-Jun-dependent MMP-13 upregulation.

New miRNA expression abnormalities in laryngeal squamous cell carcinoma

“…While Luo et al found CXCR4 overexpression to be associated with metastatic LSCC [22], no differences in CXCR4 expression were observed between cancer tissue and counterpart normal tissue in the present study, and no relationship was found with cancer lymph node metastasis. The reason for this discrepancy may be that while both Tan et al [38] and Luo et al [22] found their group of laryngeal cancer samples to contain more lymph node positive samples, 63% of the samples in our group were lymph node negative. CXCR4 overexpression could potentially act as an indicator of lymph node metastasis, but additional studies are needed.…”

“…Many studies have reported that various malignancies, including those of the lung and kidney, use chemokine pathways to disseminate cancer cells to target organs [41]. Sev-eral studies have indicated that the CXCR4/CXCL12 axis also plays a crucial role in promoting metastasis in laryngeal cancer [38]. CXCR4 encodes C-X-C chemokine receptor 4, a member of GPCR receptor family which is found to be overexpressed in many cancer types such as HNSCC.…”

Deltonin induced both apoptosis and autophagy in head and neck squamous carcinoma FaDu cell

“…ERK1/2 phosphorylates caspase-9 at Thr125 then inhibits caspase-9 processing and caspase-3 activation [42]. Inhibition of ERK1/2 phosphorylation is proved to blockade CXCL12-induced FaDu migration and chemoinvasion, suggesting that activation of ERK1/2 is an important step in the signal that leads to increased migration and chemoinvasion of HNSCC [43]. A very recent research showed that ERK1/2 MAPK mediated FaDu cell death via a caspase-independent mechanism [44].…”

In Vivo Invasion of Head and Neck Squamous Cell Carcinoma Cells Does Not Require Macrophages

“…In vitro studies of HNSCC cell lines have demonstrated that CXCL12 can stimulate proliferation and invasion. 45 Further analysis of the mechanism of induction of proliferation indicates that CXCL12 induces ERK activation through transactivation of the EGFR and can occur through release of EGFR ligands. 41,46,47 ADAM17/TACE has been associated with tumor progression in oral squamous cell carcinoma 48 and other cancers, 49,50 and can cleave multiple EGFR ligands, including TGF-␣, HB-EGF, and AREG.…”