PDF(Pubmed)
Abstract：
VAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (OSCC) cells. Here, we demonstrate that VAV2 also regulates ribosome biogenesis in those cells, a program associated with poor prognosis of human papilloma virus-negative (HPV-) OSCC patients. Mechanistically, VAV2 regulates this process in a catalysis-dependent manner using a conserved pathway comprising the RAC1 and RHOA GTPases, the PAK and ROCK family kinases, and the c-MYC and YAP/TAZ transcription factors. This pathway directly promotes RNA polymerase I activity and synthesis of 47S pre-rRNA precursors. This process is further consolidated by the upregulation of ribosome biogenesis factors and the acquisition of the YAP/TAZ-dependent undifferentiated cell state. Finally, we show that RNA polymerase I is a therapeutic Achilles\' heel for both keratinocytes and OSCC patient-derived cells endowed with high VAV2 catalytic activity. Collectively, these findings highlight the therapeutic potential of modulating VAV2 and the ribosome biogenesis pathways in both preneoplastic and late progression stages of OSCC.
摘要：
VAV2是RHOGTP酶的激活剂，可促进和维持正常角质形成细胞和口腔鳞状细胞癌（OSCC）细胞的再生增殖样状态。这里,我们证明VAV2还调节这些细胞中的核糖体生物发生，与人乳头瘤病毒阴性（HPV-）OSCC患者预后不良相关的项目。机械上,VAV2使用包含RAC1和RHOAGTP酶的保守途径以催化依赖性方式调节该过程，PAK和ROCK家族激酶,以及c-MYC和YAP/TAZ转录因子。该途径直接促进RNA聚合酶I活性和47S前rRNA前体的合成。核糖体生物发生因子的上调和YAP/TAZ依赖性未分化细胞状态的获得进一步巩固了该过程。最后,我们显示RNA聚合酶I是角质形成细胞和OSCC患者来源的细胞的治疗性致命弱点，具有高VAV2催化活性。总的来说，这些发现强调了在OSCC的肿瘤前期和晚期进展阶段调节VAV2和核糖体生物发生途径的治疗潜力.
