肿瘤相关成纤维细胞调控舌癌细胞中PTEN活性促进舌癌转移的研究

Tongue squamous cell carcinoma (TSCC) is the most common oral cancer with high incidence and poor prognosis. Metastasis is one of the main reasons of death. So, the prevention and therapy for metastasis are urgent problems for tongue cancer clinical and basic research. Current treatments and researches generally target the tumor cells, however, increasing studies have shown that besides the tumor cells, the tumor microenvironment also plays important roles in tumor metastasis. It has been reported that both the cancer-associated fibroblasts (CAF) and the tumor-associated macrophages (TAM) show a correlation with tumor metastasis. So illustrating the mechanism and significance of tumor microenvironment-induced tongue cancer metastasis is important for tongue cancer therapy. We have previously reported that phosphorylation and acetylation could regulate PTEN membrane-translocation (activation) in tumor cells, furthermore our pretest study found that CAF could promote PTEN membrane-translocation in tongue cancer cells, but the mechanism is still unknown. This project aims to reveal the mechanism of CAF inducing PTEN membrane-translocation and the corresponding significance in tongue cancer metastasis. Our study will provide theoretical basis for tongue cancer therapy targeting both cancer cell and tumor microenvironment.

舌癌是最常见的口腔癌，发病率高，预后差，转移是舌癌患者死亡的主要原因之一，因此转移的预防和治疗是舌癌研究亟待解决的问题。现在的临床治疗和基础研究主要针对舌癌细胞本身，但越来越多的证据证实肿瘤微环境在肿瘤的转移中起着重要作用，肿瘤微环境中肿瘤相关成纤维细胞、肿瘤相关巨噬细胞都与肿瘤转移关系密切。因此，研究肿瘤微环境在舌癌转移中的作用，对舌癌转移的预防和治疗具有重要的意义。申请者前期工作研究发现了磷酸化与乙酰化对PTEN膜转位的调控，预实验结果提示肿瘤相关成纤维细胞可以下调舌癌细胞中PTEN膜转位，但具体机制和意义尚不明了。本项目拟通过探讨肿瘤相关成纤维细胞调控舌癌细胞中PTEN膜转位的机制及其在舌癌转移中的作用，进一步认识肿瘤微环境对舌癌转移的重要调控作用，为将肿瘤细胞和肿瘤微环境共同作为治疗靶点，设计新的舌癌治疗方法提供理论依据。

口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）是头颈部最常见的恶性肿瘤之一，发病率逐年上升，病死率较高，转移是OSCC不良预后的主要原因之一，明确OSCC转移的机制，对预判OSCC转移并制定个性化的治疗策略具有重要意义。肿瘤相关成纤维细胞（cancer-associated fibroblasts，CAFs）在肿瘤发生发展中起着重要作用，但在OSCC中，CAFs调控肿瘤转移的作用和机制尚未完全明确。本项目研究发现CAFs通过外泌体途径将miR-382-5p转运至OSCC细胞中，下调PTEN表达，进而促进OSCC细胞迁移和侵袭；并进一步对OSCC细胞激活CAFs的机制作了初步探讨，发现OSCC细胞中PVT1通过TGF-β，介导OSCC细胞与CAFs细胞相互作用，促进CAFs细胞增殖。此外，在本项目的资助下，我们在OSCC中发现了一系列融合基因，并发现融合基因TRIM52-RACK1促进OSCC细胞增殖、迁移和侵袭。项目资助已发表SCI收录论文6篇，待发表2篇。培养研究生3名，其中1名已经取得博士学位，2名硕士研究生在读。项目投入经费19.0000万元，支出11.8413万元，各项支出基本与预算相符。剩余经费7.1587万元，剩余经费计划用于本项目研究后续支出。