HIF-1α和STAT3异常激活能介导肿瘤细胞参与乏氧耐受和侵袭转移。我们前期工作发现ZIP4在头颈部鳞状细胞癌（HNSCC）侵袭前缘表达增高并与EGFR共定位；ZIP4可能受HIF-1α和STAT3调控但具体机制不明。据此，我们提出“乏氧微环境中HIF-1α/STAT3转录激活ZIP4促进HNSCC侵袭转移”的科学假说。本项目拟开展：在HNSCC侵袭前缘肿瘤细胞中研究HIF-1α/STAT3与ZIP4/EGFR表达特征；在细胞系和动物模型中证明乏氧条件下HIF-1α/STAT3转录激活ZIP4；探究受ZIP4调节的下游靶基因；明确不同浓度锌离子对ZIP4/EGFR相互作用影响。预期结果阐明乏氧应激刺激下HIF-1α/STAT3调节ZIP4/EGFR参与肿瘤侵袭前缘形成的分子机制，为建立以ZIP4为核心针对HIF-1α/STAT3/EGFR通路治疗HNSCC新策略提供实验和理论依据。

Abnormal activation of HIF-1α and STAT3 can mediate hypoxia resistance and invasion or metastasis in cancer cell. Our preliminary study indicated that ZIP4 was highly expressed in invasive front and co-localized with EGFR in HNSCC tumor samples. ZIP4 could be regulated by HIF-1α and STAT3 and the underling mechanism is still unclear. Thus, we propose the research hypothesis that HIF-1α/STAT3 triggers ZIP4 transcription to promote invasion and metastasis in HNSCC under hypoxia stress. In the current research program, we will study as follows: the expression character of HIF-1α/STAT3 and ZIP4/EGFR in the invasive front of HNSCC; the mechanism that HIF-1α/STAT3 triggers ZIP4 transcription; the downstream target genes regulated by ZIP4; the interaction mechanism between ZIP4 and EGFR under different Zn2+ concentration in vitro and in vivo. Expected research results will elucidate that HIF-1α/STAT3 triggers ZIP4 transcription to form cancer invasive front in HNSCC under hypoxia stress and provide novel strategy based on targeting HIF-1α/STAT3/EGFR to treat HNSCC.