Expression of oncogenic HRAS in human Rh28 and RMS-YM rhabdomyosarcoma cells leads to oncogene-induced senescence.
Expression of oncogenic HRAS in human Rh28 and RMS-YM rhabdomyosarcoma cells leads to oncogene-induced senescence.
复制标题
DOI：
10.1038/s41598-021-95355-2
复制
发表时间：
2021-08-13
影响因子：
4.6
通讯作者：
Linardic CM
中科院分区：
文献类型：
--
作者：
Li JJ;Kovach AR;DeMonia M;Slemmons KK;Oristian KM;Chen C;Linardic CM
横纹肌肉瘤是小儿最常见的软组织肉瘤。RMS的两种主要的组织学类型，胚胎型和腺泡型横纹肌肉瘤（分别为eRMS和aRMS），具有非常不同的肿瘤。虽然eRMS与中等预后相关，但aRMS的5年生存率低于30%。RMS亚型在分子水平上也是不同的-eRMS经常有多种遗传改变，包括RAS和TP 53突变，而aRMS经常有染色体易位，导致PAX 3-FOXO 1或PAX 7-FOXO 1融合，但在其他方面有一个“安静”的基因组。有趣的是，RAS突变很少在aRMS中发现。在这项研究中，我们探讨了致癌RAS在aRMS中的作用。我们发现，虽然异位致癌HRAS表达在人RAS驱动的eRMS细胞系RD中是耐受的，但它对人aRMS细胞系Rh 28中的细胞生长和增殖是有害的。生长抑制是由癌基因诱导的衰老介导的，并与RB途径活性增加和细胞周期蛋白依赖性激酶抑制剂p16和p21的表达相关。出乎意料的是，人eRMS细胞系RMS-YM（RAS野生型eRMS细胞系）也以与aRMS Rh 28细胞相似的方式表现出对致癌HRAS的响应的生长抑制。这项工作表明，致癌RAS在RMS中以上下文依赖的方式表达，并可能为RMS亚型的差异起源和治疗机会提供见解。
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.
登录
查看更多内容
影响因子：
11.2
作者：
Dolgikh, Nadezda;Hugle, Manuela;Fulda, Simone
通讯作者：
Fulda, Simone
DOI：
10.1158/1541-7786.mcr-12-0456
发表时间：
2013-04
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Burns TF;Dobromilskaya I;Murphy SC;Gajula RP;Thiyagarajan S;Chatley SN;Aziz K;Cho YJ;Tran PT;Rudin CM
通讯作者：
Rudin CM
影响因子：
3.7
作者：
Chen, YY;Takita, J;Hayashi, Y
通讯作者：
Hayashi, Y
DOI：
10.1073/pnas.93.24.13742
发表时间：
1996-11-26
影响因子：
11.1
作者：
Alcorta, DA;Xiong, Y;Barrett, JC
通讯作者：
Barrett, JC
影响因子：
--
作者：
Barr, FG;Nauta, LE;Hollows, JC
通讯作者：
Hollows, JC