基于lncRNA HCG11调控UBR5表达研究姜黄素衍生物EF24抑制三阴性乳腺癌生长及转移的作用机制

EF24是一种具有更高水溶性和生物利用率的姜黄素衍生物，可诱导三阴性乳腺癌（TNBC）细胞周期阻滞和细胞凋亡，但其抑制TNBC发展及生长转移的作用机制尚不清楚。前期实验发现EF24可显著下调TNBC细胞中lncRNA HCG11的表达，而HCG11与乳腺癌预后不良及三阴性状态有关，提示EF24可能通过控制HCG11表达抑制TNBC进展。转录因子Sp1和E3泛素连接酶UBR5均可促进TNBC生长和转移。我们在TNBC细胞中干扰HCG11可下调Sp1水平，而干扰Sp1可下调UBR5表达。因此推测，HCG11可能通过Sp1上调UBR5表达而促进TNBC生长和转移，而EF24则通过下调HCG11抑制TNBC生长转移。本研究从临床、细胞和模式动物水平研究姜黄素衍生物EF24抑制TNBC生长转移的作用机制及HCG11在其中的关键作用，为姜黄素等抗癌中药在TNBC临床治疗及改善预后中的应用提供重要依据。

EF24 is one of the curcumin analogs with better water solubility and bioavailability than curcumin. It has been proven that EF24 induces cell cycle arrest and apoptosis in the triple-negative breast cancer (TNBC), while the underlying mechanism that EF24 suppresses the development, growth, and metastasis has not been clarified. In TNBC cells, our preliminary study revealed that EF24 markedly down-regulated the expression of the long non-coding RNA (lncRNA) HCG11, which has been found to be associated with the poor prognosis of breast cancer and the triple negative status. It can be speculated that EF24 may repress the progression of TNBC through controlling the level of HCG11. It is known that both the transcriptional factor Sp1 and the E3 ubiquitin ligase UBR5 promote the growth and metastasis of TNBC. We also noted that interference of HCG11 down-regulated the level of Sp1 in TNBC cells, and the silence of Sp1 contributed to the down-regulation of UBR5. Taken together, we proposed the hypothesis that HCG11 might promote the growth and metastasis of TNBC by up-regulating UBR5 expression via Sp1, but EF24 suppressed TNBC growth and metastasis through targeting HCG11. The present study will be performed at the levels of clinical, cellular, and animal model, to explore the action mechanism of curcumin analog EF24 inhibiting the growth and metastasis of TNBC, and to investigate the key role of HCG11 in this process. Accomplish of this study may provide a significant basis for the application of curcumin and other traditional Chinese anticancer drugs in the clinical treatment and the prognosis improvement of TNBC.