SREBF2-AS1调控SREBF2和胆固醇合成代谢在乳腺癌中作用及机制研究

Long non-coding RNA and cholesterol synthesis metabolism play an important role in breast cancer progression. However, the role of long non-coding RNA on the growth and metastasis of breast cancer through regulating cholesterol synthesis metabolism has not been reported. Pre-experiment of LncRNA microarray showed that SREBF2-AS1, a long non-coding RNA, was highly expressed in breast cancer; silencing of SREBF2-AS1 inhibited the growth and metastasis of breast cancer. Transcriptome sequencing of breast cancer cells with knocking down of SREBF2-AS1 revealed that the genes were mainly affected the cholesterol synthesis metabolism. Furthermore, our data shown that silencing of SREBF2-AS1 inhibited the growth and metastasis of breast cancer by regulating the SREBF2 and cholesterol synthesis metabolism. This study will evaluate the role of SREBF2-AS1 in the growth and metastasis of breast cancer. Mechanismly, SREBF2-AS1 recruits CRTC2, promotes CRTC2 to combine with CREB to form a transcriptional activation complex and then activates SREBF2 transcription and cholesterol synthesis metabolism, thereby regulating the growth and metastasis of breast cancer. This study provides a research basis for inhibiting the growth and metastasis of breast cancer, and provides a new intervention approach and candidate targets for clinical treatment of breast cancer. It has clinical significance.

长非编码RNA和胆固醇合成代谢在乳腺癌进展中起着重要作用。但是长非编码RNA调控胆固醇合成代谢进而调控乳腺癌生长和转移尚未有文献报道。预实验进行LncRNA芯片检测发现长非编码RNA--SREBF2-AS1在乳腺癌中高表达；沉默SREBF2-AS1后抑制乳腺癌生长和转移。转录组测序显示敲低SREBF2-AS1后主要影响胆固醇合成代谢通路。深入研究发现SREBF2-AS1通过调控SREBF2和胆固醇合成代谢进而影响乳腺癌生长和转移。本项目将进一步明确SREBF2-AS1在乳腺癌生长和转移中作用。分子机制方面，阐明SREBF2-AS1招募CRTC2，促进CRTC2与CREB结合形成转录激活复合体，激活SREBF2转录和胆固醇合成代谢，从而调控乳腺癌生长和转移。本研究为抑制乳腺癌生长和转移提供实验基础，同时为乳腺癌临床治疗提供新的干预途径和候选靶点，具有学术价值和临床意义。

乳腺癌是常见的肿瘤，其发病率在女性恶性肿瘤排第一。外科手术切除是治疗早期乳腺癌有效的方法。然而，仍可能存在一些癌症细胞,导致乳腺癌复发和转移。lncRNA (long non-coding RNA, lncRNA)是一类普遍存在于哺乳动物，长度大于200bp的非编码RNA，参与调控基因转录和翻译、蛋白质定位、细胞结构完整性、细胞周期和凋亡等，但是其在乳腺癌中作用尚未清楚。为此本项目设计相关实验并获得如下重要结果：（1）通过LncRNAs测序分析在乳腺癌中异常表达的LncRNAs，发现SREBF2-AS1在乳腺癌组织和乳腺癌细胞中高表达；（2）研究SREBF2-AS1在乳腺癌生长和转移中作用。通过MTT实验、凋亡实验和BrdU实验明确阻断SREBF2-AS1后抑制乳腺癌生长；通过Migration实验明确阻断SREBF2-AS1后抑制乳腺癌转移作用；通过乳腺癌原位种植瘤模型发现阻断SREBF2-AS1后抑制乳腺癌生长和延长其生存期。（3）探讨SREBF2-AS1调控SREBF2和胆固醇合成代谢进而调控乳腺癌细胞生长和转移分子机制。通过转录组测序和KEGG pathway分析，发现SREBF2-AS1调控胆固醇合成代谢信号通路和相关基因表达，然后通过正向实验和反向实验明确SREBF2-AS1通过调控SREBF2和胆固醇合成代谢进而调控乳腺癌的生长和转移。本项目在细胞模型和动物模型上研究SREBF2-AS1在乳腺癌生长和转移中作用，探讨SREBF2-AS1调控乳腺癌生长和转移的分子机制，为抑制乳腺癌生长和转移提供研究基础，同时为乳腺癌临床治疗提供新的干预途径和候选靶点，具有学术价值和临床意义。