低氧是肿瘤微环境的重要特征，影响肿瘤生物学特性。我们前期已证实：癌相关成纤维细胞（CAF）是舌鳞癌微环境中主要细胞，分泌SDF1促进肿瘤生长转移。舌鳞癌标本中HIF1α表达与CAF数量均增加，与患者预后相关；此外，低氧环境可诱导CAF活化。那么，低氧对CAF活化的调控机制是什么？预实验发现，低氧促进成纤维细胞自噬激活，HIF1α、lncRNA-HOTTIP与ATG4上调，miR-101下降；同时，miR-101与HOTTIP、ATG4均有特异结合位点。据此我们提出假设：低氧激活HIF1α并上调HOTTIP，后者作为ceRNA竞争性结合miR-101，导致ATG4升高、自噬激活、CAF活化。本项目拟干预HOTTIP表达，在体外模型中探索HOTTIP对低氧激活自噬、活化CAF的调控功能，阐明HOTTIP与ATG4的作用机理，检测HOTTIP与临床病理、患者预后的关系，为舌鳞癌的治疗提供新靶点。

Hypoxia is an important feature of tumor microenvironment, which determines its biological characteristics. We have previously demonstrated that cancer associated fibroblast (CAF) is the major component of tumor microenvironment in tongue squamous cell carcinoma (TSCC). CAF promotes tumor growth and metastasis via SDF1 secretion. In addition, both HIF1α expression and CAF amount are increased in TSCC, which are correlated to the poor prognosis of TSCC patients. Hypoxia activates normal fibroblast into CAF. However, the mechanism underlying hypoxia regulating CAF activation remains obscue. Our preliminary experiment data indicated that hypoxia activates autophagy in normal fibroblast, as well as increased expression of HIF1α, lncRNA-HOTTIP and ATG4, but decreased miR-101 expression. Target gene prediction software further demonstrated that miR-101 is specific binding with both HOTTIP and ATG4 segment. Accordingly, we propose a scientific hypothesis: hypoxia activates HIF1α and up-regulates HOTTIP expression, which competes with miR-101 and further activates ATG4 mediated autophagy, leading to CAF activation. In this project, we intend to interfere HOTTIP expression, investigate its function in regulating autophagy activation and CAF activation, and explore the molecular mechanism of HOTTIP interaction with ATG4 in vitro and in vivo. Then we will correlate expression of HOTTIP with clinical pathology and prognosis of TSCC patients. This project will provide a new target for the treatment of TSCC.