文章：

SGPL1321突变：儿童肺泡横纹肌肉瘤侵袭性的一个主要触发因素

SGPL1321 mutation: one main trigger for invasiveness of pediatric alveolar rhabdomyosarcoma

原文发布日期：2019-08-27 

英文摘要：

Sphingosine-1-phosphate (S1P), a sphingolipid with second messenger properties, is a main regulator of various cellular processes including lymphocyte cell trafficking, angiogenesis, cell proliferation, and survival. High S1P concentrations and deficiencies in S1P degradation have been associated with cancer cell progression, their directed chemoattraction and promotion of chemo-resistance mechanism. The endoplasmic reticulum (ER) membrane localized enzyme sphingosine-1-phosphate lyase (SGPL1) has a key role in prevention of S1P overstimulation in tumor cells by its irreversible S1P degradation activity. In this paper we demonstrated a SGPL1 overexpression and mislocalization in pediatric alveolar rhabdomyosarcoma (RMA) cells. Moreover, a homozygous point mutation from A to G at position 321 in the coding sequence was obvious, which interferes with the S1P degradation activity and correct localization in the ER-membrane. By complementation with the native SGPL1 variant, the ER localization was restored in RMA cells. More importantly, the SGPL1 restauration prevents the S1P induced migration and colony formation of RMA cells, significantly. This observation opens new highways for the treatment of pediatric RMA by gene therapeutic SGPL1 renewal and recommends the detection of specific SGPL1 mutations as pathological, molecular metastasis marker. 

摘要翻译： 

鞘氨醇-1-磷酸（S1P）是一种具有第二信使特性的鞘脂，主要调控淋巴细胞运输、血管生成、细胞增殖和存活等多种细胞过程。S1P浓度升高及其降解缺陷与癌细胞进展、定向化学趋化及化疗耐药机制的促进密切相关。内质网（ER）膜定位酶——鞘氨醇-1-磷酸裂解酶（SGPL1）通过其不可逆的S1P降解活性，在防止肿瘤细胞中S1P过度刺激方面起关键作用。本研究发现在儿童肺泡型横纹肌肉瘤（RMA）细胞中存在SGPL1过表达与错误定位现象，且编码序列第321位点存在明显的A→G纯合点突变，该突变会干扰S1P降解活性及酶在内质网膜的正确定位。通过回补天然SGPL1变体，成功恢复了RMA细胞中该酶的内质网定位。更重要的是，SGPL1功能恢复可显著抑制S1P诱导的RMA细胞迁移和集落形成。这一发现为通过基因治疗手段恢复SGPL1功能来治疗儿童肺泡型横纹肌肉瘤开辟了新途径，并提示特定SGPL1突变可作为病理学分子转移标志物进行检测。

原文链接：

SGPL1321 mutation: one main trigger for invasiveness of pediatric alveolar rhabdomyosarcoma