病毒既可以引起肿瘤，也可以治疗肿瘤。溶瘤病毒是经过基因工程改造的病毒，局部或全身注射后，可以毒攻毒，感染并杀死肿瘤细胞，而且能够刺激人体产生抗肿瘤免疫反应。不过，肿瘤细胞自己也有免疫力，可能阻止溶瘤病毒感染。该免疫力的重要特征是能够控制细胞染色体遗传密码转录至信使核糖核酸并翻译为蛋白质，但是该免疫力对于溶瘤病毒的作用机制尚不明确。
2019年12月17日，美国《细胞》旗下《细胞报告》发表加拿大渥太华大学、东安大略儿童医院、麦吉尔大学、魁北克大学阿曼德弗拉皮耶学院、美国罗格斯大学新泽西医学院、英国爱丁堡大学、贝尔法斯特女王大学的研究报告，发现了乳腺癌细胞对溶瘤病毒感染免疫力的靶点。
该研究首先对感染三种临床最常用溶瘤病毒（单纯疱疹病毒、呼吸肠道孤儿病毒、牛痘病毒）耐药乳腺癌细胞4T1的全部信使核糖核酸进行分析。感染三种溶瘤病毒后，癌细胞基因的蛋白质翻译被阻断，其中均被阻断基因包括肌醇磷酸酶编码基因INPP5E，从该改变了脂质信号传导。感染溶瘤病毒可以改变INPP5E信使核糖核酸前导序列非编码区的上游可读框（上游开放读码区）从而不能进行有效的下游蛋白质翻译。此外，敲除癌细胞的INPP5E基因，可以增强溶瘤病毒的附着和感染。
因此，该研究结果表明，INPP5E有望成为溶瘤病毒治疗乳腺癌新靶点。
Cell Rep. 2019 Dec 17;29(12):4010-4023,e5.
Induction of an Alternative mRNA 5' Leader Enhances Translation of the Ciliopathy Gene Inpp5e and Resistance to Oncolytic Virus Infection.
Huy-Dung Hoang, Tyson E. Graber, Jian-Jun Jia, Nasana Vaidya, Victoria H. Gilchrist, Xiao Xiang, Wencheng Li, Kyle N. Cowan, Christos G. Gkogkas, Maritza Jaramillo, Seyed Mehdi Jafarnejad, Tommy Alain.
Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada; McGill University, Montreal, QC, Canada; Rutgers New Jersey Medical School, Newark, NJ, USA; University of Edinburgh, Edinburgh, UK; INRS Institut Armand-Frappier Research Centre, Laval, QC, Canada; Queen's University Belfast, Belfast, UK.
HIGHLIGHTS
Oncolytic virus infection decouples transcription and translation in cancer cells
Upstream ORFs (uORFs) repress translation of Inpp5e mRNA in uninfected cells
Infection favors a translationally active Inpp5e variant lacking intronic uORFs
Inpp5e knockout cells exhibit increased HSV1 attachment and infection
Residual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. Translational control of mRNA is an important feature of innate immunity, yet the identity of translationally regulated mRNAs functioning in host defense remains ill-defined. We report the translatomes of resistant murine "4T1" breast cancer cells infected with three of the most clinically advanced oncolytic viruses: herpes simplex virus 1, reovirus, and vaccinia virus. Common among all three infections are translationally de-repressed mRNAs, including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signaling. We find that viral infection induces the expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5' leader and is efficiently translated. Furthermore, we show that INPP5E contributes to antiviral immunity by altering virus attachment. These findings uncover a role for translational control through alternative 5' leader expression and assign an antiviral function to the ciliopathy gene Inpp5e.
KEYWORDS: oncolytic virus; ribosome profiling; translation; uORF; INPP5E; ciliopathy; RNA variant; isoform switch; alternative splicing; breast cancer
DOI: 10.1016/j.celrep.2019.11.072
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