长链非编码RNA LINC01883通过募集转录因子SRF上调SIX2表达促进胃癌干细胞的自我更新和化疗耐药的机制

我们前期研究通过lncRNA芯片及外部数据库发现LINC01883在胃癌标本中呈高表达状态，但是LINC01883作为新标记物在肿瘤中的作用及分子机制尚无研究报告。本项目通过qRT-PCR检测发现LINC01883在胃癌中高表达与患者复发转移及预后不良密切相关。过表达LINC01883能够明显提高胃癌细胞株的自我更新能力，侵袭转移能力及对化疗药物的抵抗性。进一步探讨发现 LINC01883能够直接结合转录因子SRF作用于临近下游基因SIX2的启动子位点，进而上调SIX2的表达。同时miR-660下调是胃癌中LINC01883高表达的重要原因之一。本项目将进一步通过体内外实验证实LINC01883的功能，阐明LINC01883通过募集SRF结合于SIX2启动子，上调癌基因SIX2的表达从而促进胃癌肿瘤干细胞的活性和化疗耐药的产生，为深入理解胃癌恶性进展的分子机制及治疗靶点的选择提供实验基础。

Our previous studies and external databases showed that LINC01883 was significantly up-regulated in human gastric cancer(GC), but the role and molecular mechanism of LINC01883 as a new biomarker in cancer has not been reported. In this project, we conducted qRT-PCR assay to detect that high expression of LINC01883 in GC was closely associated with tumor metastasis/recurrence and poor survival outcome. Functional study revealed that overexpression of LINC01883 could promote GC self-renewal ability, invasion/metastasis ability, and trigger chemoresistance. Furthermore, LINC01883 could recruit the transcription factor SRF to the promoter region of downstream gene SIX2, and thus enhance SIX2 expression. In addition, LINC01883 could be suppressed by miR-660 via directly targeting the miRNA-binding site in GC. In this project, we hope to elucidate the molecular mechanism by which LINC01883 targeted the SIX2 promoter region through directly interaction with SRF, thus promoting self-renewal ability and chemoresistance in GC, to provide the experimental basis for understanding the molecular mechanism underlying the progression of GC and the selection of therapy targets in GC.