口腔鳞癌微环境内LncUCA1诱导CAF形成并活化CCL2趋化通路的研究

Tumor microenvironment (TME) can induce residental normal fibroblasts (NF) to transform into cancer associated fibroblasts (CAF), recruiting immunosuppressive myeloid-derived suppressor cell (MDSC). However, the Key regulator and mechanism of NF/CAF transformation remain unknown. It has been reported that abnormal expression of long noncoding RNAs (LncRNAs) is associated with tumor progression. Our preliminary study in primary oral squamous cell carcinoma (OSCC) patients demonstrated that LncUCA1 was highly expressed in CAF. Bioinformatics analysis revealed that LncUCA1 was positively co-expressed with chemokine 2 (CCL2) which could recruit MDSC into TME. We also found that MDSC increased in OSCC TME. Consequently, this study will focus on identification of relation between lncUCA1 and OSCC progress; analysis of function of LncUCA1 during NF/CAF transformation ; demonstration the the mechanism that LncUCA1 in NF/CAF recruit MDSC infiltration through CCL2; evaluation of the anti-tumor efficiency of targeting LncUCA1/CCL2 in vivo though the regulation of MDSC.

肿瘤微环境可使定居的正常成纤维细胞（NF）转化为肿瘤相关成纤维细胞（CAF），募集免疫抑制功能的髓样起源抑制细胞（MDSC），但调控NF向CAF转化的关键分子及机制未知。据报道异常表达的长链非编码RNAs(LncRNAs)与肿瘤进程相关。我们发现口腔鳞状细胞癌（OSCC）组织来源CAF内 LncUCA1高表达；生物信息学发现LncUCA1与趋化因子2（CCL2）存在共表达调节关系；而CCL2可趋化MDSC。我们也发现OSCC微环境中MDSC增加。推测：LncUCA1调控NF向CAF转化并分泌CCL2募集MDSC,参与肿瘤进程。因此，本研究拟聚焦于①分析OSCC LncUCA1与OSCC进程的关系②明确LncUCA1对NF向CAF转化的关键作用及机制③探讨CAF通过调控 CCL2募集MDSC的作用④体内阐明LncUCA1通过调控NF向CAF转化分泌CCL2募集MDSC促进肿瘤进展的机制。

摘要：肿瘤微环境可使定居的正常成纤维细胞（NF）转化为肿瘤相关成纤维细胞（CAF），募集免疫抑制功能的髓样起源抑制细胞（MDSC），但调控NF向CAF转化的关键分子及机制未知。据报道异常表达的长链非编码RNAs(LncRNAs)与肿瘤进程相关。我们发现口腔鳞状细胞癌（OSCC）组织来源CAF内 LncUCA1、EREG、LG3BPCD68高表达；生物信息学发现LncUCA1与趋化因子2（CCL2）等存在共表达调节关系。因此，本研究研究了①分析OSCC LncUCA1与OSCC进程的关系②明确LncUCA1、EREG、CD68、LG3BP对NF向CAF转化的关键作用及机制③探讨CAF通过调JAK/STAT3通路调控肿瘤微环境的作用④体内阐明LncUCA1通过调控NF向CAF促进肿瘤进展的机制。