Hypoxia is a hallmark of progressive cancer. Hypoxic cancer cells trigger glycolysis in response to a decreased O2 supply to meet metabolic and bioenergetic demands. Meanwhile, these responses to hypoxia and alterations of the microenvironment promote cancer cell metastasis by increasing transcription of hypoxia-inducible factor (HIF)-regulated genes. However, the detailed mechanism by which hypoxia regulates cancer cell metastasis and glycolysis remains to be investigated. In the present study, we identified that metadherin (MTDH), a multifaceted oncogene, is involved in the regulation of head and neck squamous cell carcinoma (HNSCC) metastasis and invasion under hypoxic conditions. Furthermore, the study indicated that there is a positive feedback loop between HIF-1α and MTDH in HNSCC cells, and that hypoxia promotes HNSCC cell metastasis and epithelial-mesenchymal transition by mediating the HIF-1α-MTDH loop. These findings implicate HIF-1α-MTDH as a promising target for anticancer drugs in solid tumors, and help to explain the pro-tumorigenic and unfavorable effect of MTDH on HNSCC observed in our previous studies.

Derlin-1 is over-expressed to function as an oncoprotein in breast, lung and colon cancers. However, the implications of Derlin-1 involved in squamous cell carcinoma of the head and neck (SCCHN) remain unknown. This study aims to investigate the effects of Derlin-1 expression on SCCHN tissues and cells. The potential mechanism of Derlin-1 regulating SCCHN cell proliferation, apoptosis and metastasis was also indicated in this work. Western blot and immunohistochemistry (IHC) assays showed that Derlin-1 was over-expressed in 114 SCCHN samples and five SCCHN cell lines. We found that the expression of Derlin-1 was positively associated with lymph node metastasis, clinical stage and recurrence in our SCCHN patients' samples. Survival analysis indicated that high expression of Derlin-1 was significantly associated with shorter overall survival (OS) and disease-free survival (DFS). Knock down expression of Derlin-1 in SCCHN cell lines was found to inhibit cell proliferation, metastasis and promote cell apoptosis. Further experiments showed that signals of PI3K/Akt, p53 and Smad2/3 may involve in these processes. In all, Derlin-1 might be a novel prognostic marker of SCCHN patients and plays an oncogenic role in SCCHN cell progression.