Novel tumour suppressor roles for GZMA and RASGRP1 in Theileria annulata-transformed macrophages and human B-lymphoma cells.,Cellular Microbiology

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Novel tumour suppressor roles for GZMA and RASGRP1 in Theileria annulata-transformed macrophages and human B-lymphoma cells.
Cellular Microbiology ( IF 2.6 ) Pub Date : 2020-08-24 , DOI: 10.1111/cmi.13255
Zineb Rchiad _{1,

2,

3,

4} , Malak Haidar _{1,

2,

3} , Hifzur Rahman Ansari _{1,

5} , Shahin Tajeri _{2,

3} , Sara Mfarrej ₁ , Fathia Ben Rached ₁ , Abhinav Kaushik ₁ , Gordon Langsley _{2,

3} , Arnab Pain _{1,

6}

Affiliation

Theileria annulata is a tick‐transmitted apicomplexan parasite that infects and transforms bovine leukocytes into disseminating tumours that cause a disease called tropical theileriosis. Using comparative transcriptomics we identified genes transcriptionally perturbed during Theileria‐induced leukocyte transformation. Dataset comparisons highlighted a small set of genes associated with Theileria‐transformed leukocyte dissemination. The roles of Granzyme A (GZMA) and RAS guanyl‐releasing protein 1 (RASGRP1) were verified by CRISPR/Cas9‐mediated knockdown. Knocking down expression of GZMA and RASGRP1 in attenuated macrophages led to a regain in their dissemination in Rag2/γC mice confirming their role as dissemination suppressors in vivo. We further evaluated the roles of GZMA and RASGRP1 in human B lymphomas by comparing the transcriptome of 934 human cancer cell lines to that of Theileria‐transformed bovine host cells. We confirmed dampened dissemination potential of human B lymphomas that overexpress GZMA and RASGRP1. Our results provide evidence that GZMA and RASGRP1 have a novel tumour suppressor function in both T. annulata‐infected bovine host leukocytes and in human B lymphomas.

中文翻译：

GZMA 和 RASGRP1 在环形泰勒虫转化的巨噬细胞和人 B 淋巴瘤细胞中的新型肿瘤抑制作用。

环形泰勒虫是一种蜱传播的顶复体寄生虫，它感染牛白细胞并将其转化为传播性肿瘤，从而导致一种称为热带泰勒虫病的疾病。使用比较转录组学，我们鉴定了泰勒虫诱导的白细胞转化过程中转录受到干扰的基因。数据集比较突出了与泰勒氏菌转化的白细胞传播相关的一小组基因。颗粒酶 A ( GZMA ) 和 RAS鸟苷释放蛋白 1 ( RASGRP1 ) 的作用通过 CRISPR/Cas9 介导的敲低得到验证。抑制GZMA和RASGRP1 的表达在减毒的巨噬细胞中，它们在 Rag2/γC 小鼠中的传播重新开始，证实了它们在体内作为传播抑制因子的作用。我们通过将 934 种人类癌细胞系的转录组与泰勒氏杆菌转化的牛宿主细胞的转录组进行比较，进一步评估了GZMA和RASGRP1在人类 B 淋巴瘤中的作用。我们证实过表达GZMA和RASGRP1的人 B 淋巴瘤的传播潜力减弱。我们的结果提供证据表明GZMA和RASGRP1在T. annulata感染的牛宿主白细胞和人 B 淋巴瘤中都具有新的肿瘤抑制功能。

更新日期：2020-08-24

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