PIWI-interacting RNA-YBX1 inhibits proliferation and metastasis by the MAPK signaling pathway via YBX1 in triple-negative breast cancer. PIWI-interacting RNA-YBX1 inhibits proliferation and metastasis by the MAPK signaling pathway via YBX1 in triple-negative breast cancer

Breast cancer is the second leading cause of death in women worldwide, with triple-negative breast cancer (TNBC) having the worst prognosis. Although there are numerous studies on TNBC, there is no effective treatment for it, and it is still a major problem today. Studies on PIWI-interacting RNAs (piRNAs) are increasing and investigating the mechanism of piRNAs in the proliferation and metastasis of TNBC may lead to new potential treatment targets. Here, we identified a novel piRNA, piR-YBX1, which was downregulated in TNBC compared to matched normal breast tissue. Overexpression of piR-YBX1 significantly inhibited the proliferation, migration, invasion ability of TNBC cells both in vivo and in vitro. Mechanistically, piR-YBX1 could bind directly to mRNA of YBX1 and overexpression of piR-YBX1 downregulated YBX1 in both mRNA and protein levels, while the function of piR-YBX1 could be partly rescued by overexpression of YBX1. In addition, YBX1 could bind to RAF1 which is the key molecule in the MAPK signaling pathway, and overexpression of piR-YBX1 inhibited the p-MEK and p-ERK1/2 which can be reverted by YBX1. In conclusion, our findings discovered that the piR-YBX1/YBX1/MAPK axis suppresses the proliferation and metastasis of TNBC and therefore piR-YBX1 has the potential to be an effective therapeutic agent for breast cancer. Overall design: 3 pairs of TNBC tissue and matched adjacent normal breast tissue were collected to obtain profiles of differentially expressed piRNAs using piRNA microarray

乳腺癌是全球女性第二大主要死亡原因，其中三阴性乳腺癌（triple-negative breast cancer, TNBC）的预后最差。尽管针对TNBC的研究层出不穷，但目前仍缺乏有效的治疗手段，至今仍是临床亟待攻克的重大难题。PIWI互作RNA（PIWI-interacting RNAs, piRNAs）相关研究日益增多，探究其在TNBC增殖与转移过程中的作用机制，有望为该疾病发掘全新的潜在治疗靶点。本研究鉴定出一种新型piRNA——piR-YBX1，相较于配对的正常乳腺组织，其在TNBC组织中呈显著低表达。体内外实验均证实，过表达piR-YBX1可显著抑制TNBC细胞的增殖、迁移与侵袭能力。机制研究表明，piR-YBX1可直接结合YBX1的mRNA，过表达piR-YBX1可在mRNA与蛋白水平同时下调YBX1的表达；而通过过表达YBX1，可部分逆转piR-YBX1的抗肿瘤功能。此外，YBX1可结合MAPK（丝裂原活化蛋白激酶）信号通路关键分子RAF1；过表达piR-YBX1可抑制p-MEK与p-ERK1/2的活性，该效应可被YBX1过表达所逆转。综上，本研究发现piR-YBX1/YBX1/MAPK轴可抑制TNBC的增殖与转移，因此piR-YBX1有望成为乳腺癌的有效治疗制剂。整体实验设计：收集3对TNBC组织及配对的癌旁正常乳腺组织，通过piRNA微阵列技术筛选并获取差异表达piRNA的表达谱。