Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, No. 241 West Huaihai Road, Shanghai, 200030, China.
Shanghai Changzheng Hospital Affiliated to the Second Military Medical University, Shanghai, China.
Cell Commun Signal. 2019 Aug 13;17(1):92. doi: 10.1186/s12964-019-0415-6.
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.
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.
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).
These findings indicate the oncogenic role of RasGRP4 in DLBCL, suggesting it as a prognostic biomarker and potential therapeutic target in DLBCL.
本研究旨在证实阻断 RasGRP4 可有效减缓体外和体内 DLBCL 的生长，并确定 RasGRP4 在 DLBCL 临床预后中的作用。
检测良性组织和淋巴瘤中的 RasGRP4 表达水平。为了验证 RasGRP4 基因是否存在体细胞突变，对 DLBCL 患者进行 cDNA 测序。通过敲低 RasGRP4 来测量 RasGRP4 依赖性细胞增殖、线粒体膜电位、氧化应激水平和信号通路变化。在异种移植淋巴瘤模型中监测肿瘤生长。收集临床数据以确认 RasGRP4 在 DLBCL 中的作用。
RasGRP4 在 DLBCL 中表达显著升高，而在 DLBCL 患者中未检测到该基因的体细胞突变。RasGRP4 表达降低显著通过同时减少有丝分裂和促进细胞凋亡来抑制细胞增殖，并增加氧化应激水平。在 SUDHL-4 细胞中，RasGRP4 表达降低降低了 ERK，而增加了 JNK 的表达。RasGRP4 的敲低也显著抑制了体内肿瘤的形成。此外，RasGRP4 表达水平在具有较大 DLBCL 病变的患者中显著升高（P=0.0004），高危国际预后指数评分组（P=0.0042），并且其表达与 DLBCL 中的最大标准化摄取值呈正相关（P=0.0004）。
这些发现表明 RasGRP4 在 DLBCL 中具有致癌作用，表明其作为 DLBCL 的预后生物标志物和潜在治疗靶点。
