Duke University School of Medicine, Durham, NC, USA.
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
Sci Rep. 2021 Aug 13;11(1):16505. doi: 10.1038/s41598-021-95355-2.
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. The two predominant histologic variants of RMS, embryonal and alveolar rhabdomyosarcoma (eRMS and aRMS, respectively), carry very different prognoses. While eRMS is associated with an intermediate prognosis, the 5-year survival rate of aRMS is less than 30%. The RMS subtypes are also different at the molecular level-eRMS frequently has multiple genetic alterations, including mutations in RAS and TP53, whereas aRMS often has chromosomal translocations resulting in PAX3-FOXO1 or PAX7-FOXO1 fusions, but otherwise has a "quiet" genome. Interestingly, mutations in RAS are rarely found in aRMS. In this study, we explored the role of oncogenic RAS in aRMS. We found that while ectopic oncogenic HRAS expression was tolerated in the human RAS-driven eRMS cell line RD, it was detrimental to cell growth and proliferation in the human aRMS cell line Rh28. Growth inhibition was mediated by oncogene-induced senescence and associated with increased RB pathway activity and expression of the cyclin-dependent kinase inhibitors p16 and p21. Unexpectedly, the human eRMS cell line RMS-YM, a RAS wild-type eRMS cell line, also exhibited growth inhibition in response to oncogenic HRAS in a manner similar to aRMS Rh28 cells. This work suggests that oncogenic RAS is expressed in a context-dependent manner in RMS and may provide insight into the differential origins and therapeutic opportunities for RMS subtypes.
横纹肌肉瘤 (RMS) 是最常见的小儿软组织肉瘤。RMS 的两种主要组织学变异型，胚胎性横纹肌肉瘤 (eRMS) 和肺泡横纹肌肉瘤 (aRMS)，具有非常不同的预后。虽然 eRMS 与中等预后相关，但 aRMS 的 5 年生存率小于 30%。RMS 亚型在分子水平上也不同-eRMS 经常有多种遗传改变，包括 RAS 和 TP53 的突变，而 aRMS 经常有染色体易位导致 PAX3-FOXO1 或 PAX7-FOXO1 融合，但其他方面具有“安静”的基因组。有趣的是，RAS 突变在 aRMS 中很少见。在这项研究中，我们探讨了致癌性 RAS 在 aRMS 中的作用。我们发现，虽然异位致癌性 HRAS 在人类 RAS 驱动的 eRMS 细胞系 RD 中可以耐受，但它对人类 aRMS 细胞系 Rh28 的细胞生长和增殖有害。生长抑制是由癌基因诱导的衰老介导的，并与 RB 途径活性的增加和细胞周期蛋白依赖性激酶抑制剂 p16 和 p21 的表达有关。出乎意料的是，人类 eRMS 细胞系 RMS-YM，一种 RAS 野生型 eRMS 细胞系，也表现出对致癌性 HRAS 的生长抑制，其方式类似于 aRMS Rh28 细胞。这项工作表明，致癌性 RAS 在 RMS 中以依赖于上下文的方式表达，这可能为 RMS 亚型的不同起源和治疗机会提供启示。
