LTA4H在喉鳞状细胞癌中对CD44可变剪接的调控作用及机制

喉鳞状细胞癌是最常见的头颈部恶性肿瘤之一，LTA4H作为多种癌症中的关键因子逐渐成为肿瘤化疗药物的新靶点，最近有研究表明LTA4H在LSCC中具有显著的高表达，促进癌细胞的增殖、迁徙和转移，但其作用机制目前仍不清楚。我们前期研究发现LTA4H富集性结合CD44的mRNA，CD44的不同剪接亚型在LSCC中与癌细胞的增殖和转移有关，我们推测LTA4H可能通过结合CD44的mRNA调控其可变剪接，从而促进LSCC的发生和发展。为验证假说，本课题拟从RNA调控角度出发，研究LTA4H在LSCC细胞中调控CD44可变剪接的作用和功能；通过RIP-PCR等实验研究LTA4H调控CD44可变剪接的机制；在小鼠模型中证实该调控轴在LSCC发生发展中的作用并在临床样本中研究与LSCC肿瘤进展的关系。本研究预期阐明LTA4H在LSCC中调控CD44可变剪接的机制，为LSCC的靶向治疗研究提供新的思路。

Laryngeal squamous cell carcinoma (LSCC) is one of the most common type of head and neck malignancy. LTA4H is an emerging target of natural products for cancer chemoprevention and chemotherapy. Recent studies have shown that LTA4H is upregulated in LSCC and promotes tumor proliferation, migration and metastasis without clear mechanism. Our previous studies have found that LTA4H significantly binding the intron and CDS region of CD44 mRNA, which regulates tumor cell migration, proliferation and survival with variant splicing isoforms. Therefore, we speculate that LTA4H may play an important role in the occurrence and development of LSCC by binding the mRNA of CD44, regulating the variable splicing of CD44. To test the hypothesis, this project intends to study the cell biological functions of LTA4H in LSCC cells from the perspective of RNA regulation and the regulation mechanism of LTA4H on alternative splicing of CD44 through RIP-PCR and other experiments. Then we intend to confirm the function of LTA4H in the occurrence and development of LSCC by regulating the variable splicing of CD44 was confirmed in the mouse model, as well as the specific manifestations of this regulatory mechanism in LSCC patients in Xinjiang. This study is expected to clarify the regulatory effect and mechanism of LTA4H on CD44 alternative splicing in LSCC, providing a new idea for clinical targeted therapy of LSCC.