Abstract
To assess the role of transcription factor μE3 (TFE3) in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC), human HNSCC tissue arrays were investigated for TFE3 expression. Human HNSCC tissues with neoadjuvant inductive chemotherapey (docetaxel, cisplatin and fluorouracil, TPF) and mice HNSCC tissues from transgenic mice model were evaluated for TFE3 expression and the hypoxia pathway. The roles of EGF/EGFR mediated hypoxia in TFE3 nuclear expression were analyzed in vitro and in vivo. TFE3 expression was higher in human HNSCC tissues compared with that in normal oral mucosa. Moreover, high TFE3 expression was related to HIF-1α, PAI-1, and EGFR, which demonstrated the activation of the hypoxia pathway in HNSCC tissues. Furthermore, elevated TFE3 expression was observed in HNSCC after cisplatin-based chemotherapy, and high TFE3 expression may indicate poor response to TPF inductive chemotherapy. Furthermore, similar changes with increased TFE3 were observed in HNSCC of the transgenic mouse HNSCC model. Hypoxic culture in the human HNSCC cell line increased TFE3 expression, which promoted cell survival under hypoxia. EGFR inhibiton by cetuximab could attenuate hypoxia-induced TFE3 in the HNSCC cell line and transgenic mouse HNSCC model. These findings indicated that TFE3 was an important hypoxia-induced transcriptional factor in HNSCC. TFE3 could be regarded as a durgable therapeutic oncotarget by EGFR inhibition.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in humans, with about 450,000 newly diagnosed cases worldwide every year [1]
The results indicated that increased transcription factor μE3 (TFE3) expression was significantly associated with head and neck cancer compared with the normal counterpart (P = 0.032)
Western blot analysis of TFE3 and plasminogen activator inhibitor type1 (PAI-1) in the head and neck squamous cell carcinoma (HNSCC) cell line CAL27 with recombination human EGF (10ng/ml) and TFE3 siRNA treated in hypoxia culture condition at
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in humans, with about 450,000 newly diagnosed cases worldwide every year [1]. Hypoxia inducible factor (HIF) plays a key role in tumor, and it is correlated with short disease-free survival by upregulating hypoxia-related factors, such as transforming growth factor-β (TGF-β) and plasminogen activator inhibitor type (PAI-1), which play an important role in antiapoptotic and angiogenic factors and cancer stem cell initiation [5]. Despite its uPA-inhibiting function, PAI1 has been demostrated by numerous clinical studies to have a strong correlation with poor HNSCC prognosis[9]. This paradoxical finding may be explained by further biological functions of PAI-1 in promoting migration and angiogenesis and in inhibiting apoptosis of tumor cells [10, 11]. Our previous study suggeted that inhibition of EGFR may reduce HIF-1α in a preclinical mouse HNSCC model[14]
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