The mechanism of high mobility group box-1 protein and its bidirectional regulation in tumors.

High mobility group protein box-1 (HMGB1) is a nonhistone chromatin-related protein widely found in eukaryotic cells. It is involved in the transcription, replication and repair of DNA to maintain nuclear homeostasis. It participates in cell growth, differentiation and signal transduction. Recent studies showed that HMGB1 has a bidirectional regulatory effect on tumors by regulating TLR4/MYD88/NF-κB and RAGE/AMPK/mTOR signaling pathways. On one hand, it is highly expressed in a variety of tumors, promoting tumor proliferation and invasion, whilst on the other hand, it induces autophagy and apoptosis of tumor cells and stimulates tumor-infiltrating lymphocytes to produce anti-tumor immune response. At present, HMGB1 could be used as a target to regulate the drug-resistance and prognostication in cancer. Clinical applications of HMGB1 in cancer need further in-depth studies.

FUT6 inhibits the proliferation, migration, invasion, and EGF-induced EMT of head and neck squamous cell carcinoma (HNSCC) by regulating EGFR/ERK/STAT signaling pathway.

Glycosylation change is one of the landmark events of tumor occurrence and development, and tumor cells may be inhibited by regulating the aberrant expression of glycosyltransferases. Currently, fucosyltransferase VI (FUT6), which is involved in the synthesis of α-1, 3 fucosyl bond, has been detected to be closely associated with multiple tumors, but its function and mechanism in head and neck squamous cell carcinoma (HNSCC) still need further research. In this study, FUT6 knockdown and overexpression strategies were used to investigate the effects of FUT6 on cell proliferation, migration, and invasion, as well as the growth and metastasis of HNSCC in a xenografts mouse model. The protein expression levels of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), Signal Transducer and Activator of Transcription (STAT), protein kinase B (AKT), c-Myc, and epithelial-mesenchymal transition (EMT) markers were determined by western blot analysis. Our research found that the mRNA expression of FUT6 was lower in HNSCC tissues than in normal mucosal epithelial tissues. In Cal-27 and FaDu cells, FUT6 overexpression inhibited cell proliferation, migration and invasion, causing upregulation of ZO-1 and E-cadherin, downregulation of N-cadherin and Vimentin, and finally decreased the phosphorylation levels of EGFR, ERK, STAT, and c-Myc. In HSC-3 cells, knockdown of FUT6 promoted cell proliferation, migration and invasion, downregulating ZO-1 and E-cadherin, upregulating N-cadherin and Vimentin, and increased the phosphorylation levels of EGFR, ERK, STAT, and c-Myc. In the HNSCC xenografts mouse, FUT6 overexpression inhibited tumor growth and metastasis. In summary, FUT6 controls the proliferation, migration, invasion, and EGF-induced EMT of HNSCC by regulating EGFR/ERK/STAT signaling pathway, indicating its potential future therapeutic application for HNSCC.