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Splice switching an oncogenic ratio of SmgGDS isoforms as a strategy to diminish malignancy.

剪接切换SmgGDS亚型的致癌比率作为减少恶性肿瘤的策略。

  • 影响因子:8.58
  • DOI:10.1073/pnas.1914153117
  • 作者列表:"Brandt AC","McNally L","Lorimer EL","Unger B","Koehn OJ","Suazo KF","Rein L","Szabo A","Tsaih SW","Distefano MD","Flister MJ","Rigo F","McNally MT","Williams CL
  • 发表时间:2020-02-18
Abstract

:The chaperone protein SmgGDS promotes cell-cycle progression and tumorigenesis in human breast and nonsmall cell lung cancer. Splice variants of SmgGDS, named SmgGDS-607 and SmgGDS-558, facilitate the activation of oncogenic members of the Ras and Rho families of small GTPases through membrane trafficking via regulation of the prenylation pathway. SmgGDS-607 interacts with newly synthesized preprenylated small GTPases, while SmgGDS-558 interacts with prenylated small GTPases. We determined that cancer cells have a high ratio of SmgGDS-607:SmgGDS-558 (607:558 ratio), and this elevated ratio is associated with reduced survival of breast cancer patients. These discoveries suggest that targeting SmgGDS splicing to lower the 607:558 ratio may be an effective strategy to inhibit the malignant phenotype generated by small GTPases. Here we report the development of a splice-switching oligonucleotide, named SSO Ex5, that lowers the 607:558 ratio by altering exon 5 inclusion in SmgGDS pre-mRNA (messenger RNA). Our results indicate that SSO Ex5 suppresses the prenylation of multiple small GTPases in the Ras, Rho, and Rab families and inhibits ERK activity, resulting in endoplasmic reticulum (ER) stress, the unfolded protein response, and ultimately apoptotic cell death in breast and lung cancer cell lines. Furthermore, intraperitoneal (i.p.) delivery of SSO Ex5 in MMTV-PyMT mice redirects SmgGDS splicing in the mammary gland and slows tumorigenesis in this aggressive model of breast cancer. Taken together, our results suggest that the high 607:558 ratio is required for optimal small GTPase prenylation, and validate this innovative approach of targeting SmgGDS splicing to diminish malignancy in breast and lung cancer.

摘要

: 伴侣蛋白SmgGDS促进人乳腺癌和非小细胞肺癌的细胞周期进展和肿瘤发生。SmgGDS的剪接变异体,命名为SmgGDS-607 和SmgGDS-558,通过调节异戊烯化途径通过膜运输促进小gtp酶Ras和Rho家族致癌成员的激活。SmgGDS-607 与新合成的预异戊烯化小gtp酶相互作用,而SmgGDS-558 与异戊烯化小gtp酶相互作用。我们确定癌细胞具有SmgGDS-607:SmgGDS-558 的高比率 (607:558 比率),并且该升高的比率与乳腺癌患者的存活率降低相关。这些发现表明,靶向SmgGDS剪接以降低 607:558 的比率可能是抑制由小gtp酶产生的恶性表型的有效策略。在这里,我们报道了一种剪接转换寡核苷酸的开发,命名为SSO Ex5,它通过改变SmgGDS pre-mRNA (信使RNA) 中外显子 5 的内含物来降低 607:558 的比例。我们的结果表明,SSO Ex5 抑制Ras、Rho和Rab家族中多种小gtp酶的异戊烯化,抑制ERK活性,导致内质网 (ER) 应激,未折叠蛋白反应,并最终在乳腺癌和肺癌细胞系中凋亡细胞死亡。此外,在MMTV-PyMT小鼠中腹膜内 (i.p.) 递送SSO Ex5 在乳腺中重定向SmgGDS剪接,并减缓乳腺癌的这种侵袭性模型中的肿瘤发生。总之,我们的结果表明,最佳小gtp酶异戊烯化需要高 607:558 的比率,并验证了这种靶向SmgGDS剪接以减少乳腺癌和肺癌恶性肿瘤的创新方法.

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影响因子:6.93
发表时间:2020-01-15
DOI:10.1002/ijc.32532
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翻译标题与摘要 下载文献
影响因子:6.93
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DOI:10.1002/ijc.32530
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肺肿瘤方向

肺肿瘤,又叫支气管肺癌,是常见的恶性肿瘤之一。肺肿瘤的治疗为包括手术、中药、放疗、化疗及免疫等多学科的综合治疗。

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