周期性色氨酸蛋白PWP1调控核糖体合成促进结直肠癌生长的分子机制研究

核糖体合成异常激活与恶性肿瘤发生发展密切相关。前期研究中，通过数据库及组织芯片分析，申请人发现周期性色氨酸蛋白Periodic tryptophan protein 1（PWP1）作为核糖体合成相关分子，在结直肠癌中表达显著升高，且高表达提示不良预后。体内外实验表明敲降PWP1显著抑制结直肠癌生长，且明显抑制新生rRNA合成。通过TMT标记定量蛋白质谱，发现敲降PWP1对DNA复制、错配修复通路相关基因的蛋白水平影响显著大于其他通路；而敲降PWP1对上述基因的mRNA水平未见明显影响，这提示PWP1-核糖体合成途径调控蛋白翻译可能存在选择性。之后申请人将利用核糖体印记测序、rRNA测序、ChIP-seq等技术深入探究PWP1-核糖体合成途径通过影响核糖体异质性，进而选择性翻译mRNAs，实现对下游信号通路的精准调控，最终促进结直肠癌生长的分子机制，为结直肠癌诊疗提供新思路。

Aberrant activation of ribosome biosynthesis is closely related to the development of malignant tumors. In this study, through data analysis of public database and tissue microarray, we found that Periodic tryptophan protein 1 (PWP1), as a molecule related to ribosome synthesis, was significantly higher in colorectal cancer (CRC) than in adjacent tissues, which indicated poor prognosis of CRC. In vitro and in vivo experiments showed that PWP1 knockdown significantly inhibits CRC growth and newborn rRNA synthesis. Through TMT marked quantitative protein profiling, it was found that PWP1 knockdown had a greater effect on the protein levels of genes related to DNA replication and mismatch repair pathways than other pathways, while PWP1 knockdown had no significant effect on the mRNA levels of those genes, which suggested that PWP1-ribosome biosynthesis pathway had a selectivity in protein translation. Afterwards, we will conduct ribosome profiling, rRNA profiling, ChIP-seq to explore underlying mechanism by which PWP1-ribosome biosynthesis pathway regulates ribosome heterogeneity thus selectively translates mRNAs to precise regulation of downstream signaling pathways and ultimately promotes CRC growth, which provides new horizon for the diagnosis and treatment of colorectal cancer.