FOSL1 ceRNA网络调控舌鳞癌Tumor Budding细胞侵袭转移的分子机制

In our previous study, we demonstrated that tumor budding was correlated with invasion and metastasis in tongue squamous cell carcinoma. However, the molecular mechanisms are still poorly understood during invasion and metastasis of tumor budding cells. In next study, we further revealed that FOSL1 could promote epithelial mesenchymal transtion of tumor budding cells by activating ZEB2, Snai2 and Vimentin at transcriptional level. We also found that miR-320 family may regulate invasion and metastasis by targeting FOSL1, ZEB2 and Vimentin. Then, bioinformatics analysis showed that FOSL1 shared many miRNA response elements with its targeted genes, MALAT1 and NEAT1. These results indicated FOSL1 may be regulated by its targeted gene and lncRNAs which functioned as a ceRNA. Based on these findings, we proposed that FOSL1 with its targeted genes and lncRNAs could form a novel regulatory circuit in tongue squamous cell carcinoma. In this project, we aim to screen FOSL1 ceRNA and identify its biological function, then establish FOSL1 ceRNA network to clarify the mechanism of FOSL1 and its ceRNA network in invasion and metastasis of tumor budding cells.

课题组前期研究证实Tumor budding代表一群恶性程度更高的癌细胞亚群，与舌鳞癌侵袭转移密切相关，但其分子调控机制仍不清楚。进一步研究揭示FOSL1可转录激活ZEB2、Snai2和Vimentin促进Tumor budding上皮间质转化；发现miR-320家族在Tumor budding中表达下调，并可能靶向抑制FOSL1、ZEB2和Vimentin调控舌鳞癌侵袭转移；生物信息学分析显示FOSL1与其转录激活的靶基因及MALAT1、NEAT1间存在多个共同miRNA结合位点；提示FOSL1与其靶基因和lncRNA可互为ceRNA形成调控网络。本课题拟在上述工作基础上，分析、筛选FOSL1相关ceRNAs，验证关键ceRNAs的生物学功能，明确FOSL1 ceRNAs表达网络，阐明FOSL1 ceRNAs网络调控舌鳞癌Tumor budding细胞侵袭转移的分子机制。

Tumor budding在舌及头颈鳞癌恶性进展中起着重要作用，但其分子调控机制尚不清楚。在本研究中，我们通过临床回顾性研究证实Tumor budding与舌鳞癌及头颈鳞癌颈淋巴结转移和预后密切相关，可作为患者独立的预后判断指标（J Oral Pathol Med, 2019; Head Neck, 2019）；结合Tumor budding及其周围组织炎性微环境和免疫微环境状态，揭示肿瘤浸润的CD8+ T细胞、NK细胞和巨噬细胞与口腔癌患者预后相关（J Oral Pathol Med, 2019）；并建立iBD模型，发现iBD模型可用于预测舌鳞癌患者预后（Histopathology, 2019）；同时，我们基于miRNA芯片和HTA2.0芯片分析获得Tumor buding特征性分子表达谱，证实miR-320a靶向抑制Suz12调控舌鳞癌Tumor budding细胞侵袭转移（Oncotarget, 2016）；揭示miR-204-5p-SNAI2/SUZ12/HDAC1/STAT3反馈环路促进tumor budding及头颈鳞癌侵袭转移和干性（Theranostics, 2020）；最后，我们围绕FOSL1及其分子调控网络，证实了FOSL1在舌及头颈鳞癌中tumor budding中表达上调，并可调控超级增强子（Super Enhancers, SEs）上调SNAI2、CD44和EPHA2表达，促进头颈鳞癌侵袭转移，相关研究结果在整理中，文章待发表。