长链非编码RNA EGOT通过HuR/ITPR1促进乳腺癌细胞自噬的机制研究

Breast cancer is the most common cancer in women worldwide, and it is one of the main causes of death with complex pathogenesis. As reported, long noncoding RNA is an important regulator in the process of breast cancer development. EGOT is a long noncoding transcript from intron in antisense strand of ITPR1 which is an autophagy sensor. Besides the growth regulation of eosinophil granule, there was no report on the role of EGOT in malignancy diseases, including breast cancer. By whole genome high throughput sequencing, we found that long noncoding RNA EGOT was downregulated significantly in breast cancer and it is closely related to worse prognosis. In our previous study, EGOT promoted autophagy in breast cancer cell lines in vitro. Bioinformatics analysis indicated that EGOT and ITPR1 had special binding sequences of HuR which increases the target mRNA stability via binding these sequences and this prediction was validated by RIP assay. Therefore, we hypothesize that EGOT recruits HuR to ITPR1, increases its mRNA stability and translation, resulting in promoted autophagy. To validate this hypothesis, we will carry out a series of investigation from clinical samples, TCGA data, in vitro experiments and animal level. This study may elucidate the role of EGOT in regulation of autophagy in breast cancer from a new perspective, and provide a new idea for treatment of breast cancer.

乳腺癌是全球女性罹患和死亡最常见的肿瘤，其发病机理复杂。文献报道，长链非编码RNA（LncRNA）是调节乳腺癌发病的重要因素。EGOT是转录自ITPR1（自噬感受器）反义链内含子区的LncRNA，仅与嗜酸性颗粒发育有关。迄今，EGOT在肿瘤中的生物学功能尚无报道。我们通过全基因组测序发现EGOT在乳腺癌中表达显著降低，与不良预后相关；通过预实验，证实EGOT促进自噬；利用生物信息学分析和RIP实验，明确EGOT、ITPR1与HuR（mRNA稳定因子）物理结合，且三者存在胞浆中分布。结合前期工作基础，申请人提出科学假设：EGOT招募HuR，后者与ITPR1 mRNA结合，增加其稳定性，翻译增加，促进自噬。我们将利用临床乳腺癌样本、TCGA等公共数据及体内、外分子生物学实验手段多角度、多层面开展研究，最终从LncRNA的视角揭示EGOT调控乳腺癌细胞自噬的机制，为乳腺癌治疗提供新思路。

乳腺癌是全球女性罹患和死亡最常见的肿瘤，其发病机理复杂。文献报道，长链非编码RNA（LncRNA）是调节乳腺癌发病的重要因素。EGOT是转录自ITPR1（自噬感受器）反义链内含子区的LncRNA，仅与嗜酸性颗粒发育有关。迄今，EGOT在肿瘤中的生物学功能尚无报道。我们通过全基因组测序发现EGOT在乳腺癌中表达显著降低，与不良预后相关；通过实验，证实EGOT促进自噬；利用生物信息学分析和RIP实验，明确EGOT、ITPR1与hNRNPH1物理结合，且三者存在胞浆中分布EGOT招募hNRNPH1，后者与ITPR1 mRNA结合，增加选择性剪切，翻译增加，促进自噬。我们将利用临床乳腺癌样本、TCGA等公共数据及体内、外分子生物学实验手段多角度、多层面开展研究，最终从LncRNA的视角揭示EGOT调控乳腺癌细胞自噬的机制，为乳腺癌治疗提供新思路。