The critical role of RasGRP4 in the growth of diffuse large B cell lymphoma

Cell Communication and Signaling

Ning Qu¹  Junling Liu²  Yuxuan Zhang³  Yongxin Xiao⁴  Chunyan Xia⁴  Jing Liu⁴  Liyu Huang⁴  Kai Nie⁴  Lin Zhu⁵  Hong Yu⁵  Yinan Chen⁵  Lin Wu⁶ 

[1] Fudan University Shanghai Cancer Center;School of Medicine, Shanghai Jiao Tong University;School of Pharmacy, Queen’s University Belfast Medical Biology Centre;Shanghai Changzheng Hospital Affiliated to the Second Military Medical University;Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University;Shanghai General Hospital Affiliated to Shanghai Jiaotong University;

关键词: RasGRP4;    DLBCL;    MAPK;    Proliferation;    Prognosis;   

DOI  :  10.1186/s12964-019-0415-6

来源: DOAJ

【 摘 要 】

Abstract Background This study aimed to confirm that blocking RasGRP4 can effectively slow down the growth of DLBCL both in vitro and in vivo and ascertain the role of RasGRP4 in the prognosis of DLBCL clinically. Methods RasGRP4 expression levels were examined in benign tissues and lymphomas. In order to verify somatic mutation in RasGRP4 gene, cDNA sequencing was performed in DLBCL patients. RasGRP4-dependent cell proliferation, mitochondrial membrane potential, oxidative stress levels and signaling pathway changes were measured by knockdown of RasGRP4. Tumor growth was monitored in xenografted lymphoma model. Clinical data were collected to confirm the role of RasGRP4 in DLBCL. Results RasGRP4 expression was significantly elevated in DLBCL while no somatic mutations were detected of this gene in DLBCL patients. Decreased RasGRP4 significantly inhibited cell proliferation by simultaneously reducing mitosis and promoting apoptosis and increased the oxidative stress levels. Mechanistically, reduced expression of RasGRP4 decreased ERK while increased JNK expression in SUDHL-4 cells. Knockdown of RasGRP4 also significantly inhibited tumor formation in vivo. Furthermore, RasGRP4 expression levels were significantly higher in patients with larger DLBCL lesions (P = 0.0004), high-risk international prognostic index score groups (P = 0.0042), and its expression was positively correlated with maximum standardized uptake value in DLBCL (P = 0.0004). Conclusions These findings indicate the oncogenic role of RasGRP4 in DLBCL, suggesting it as a prognostic biomarker and potential therapeutic target in DLBCL.

【 授权许可】

Unknown