OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma
OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma
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DOI：
10.1002/hep4.1361
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发表时间：
2019-07-01
影响因子：
5.1
通讯作者：
Ohtsuka, Masayuki
中科院分区：
文献类型：
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作者：
Ashizawa, Yosuke;Kuboki, Satoshi;Ohtsuka, Masayuki
嗅觉调节素4（OLFM 4）通过抑制信号转导和转录激活因子3（STAT 3）的强抑制基因GRIM 19（GRIM 19）而激活STAT 3，但OLFM 4调控GRIM 19-STAT 3级联反应的机制尚不清楚。采用从111例HCC患者或2个HCC细胞系中收集的手术标本，在体外评估OLFM 4、GRIM 19和STAT 3激活在HCC进展中的功能和调节。此外，研究了由富含亮氨酸重复序列的G蛋白偶联受体5（LGR 5）（称为肠干细胞标志物）介导的OLFM 4的癌干细胞样性质。与癌旁肝组织相比，肝细胞癌中OLFM 4表达增加。多因素分析显示OLFM 4高表达是预后不良的独立因素。在HCC中，OLFM 4表达与GRIM 19表达呈负相关，与STAT 3激活呈正相关，从而增加细胞周期进程。在HCC细胞中，OLFM 4敲低增加GRIM 19表达并抑制STAT 3活化;然而，在GRIM 19和OLFM 4双敲低后，由OLFM 4敲低降低的STAT 3活化再次增加。OLFM 4敲低增加细胞凋亡，抑制细胞增殖，并抑制肝癌细胞中的癌干细胞样性质。OLFM 4高表达的肝癌患者血行性复发的发生率较高，提示OLFM 4增强了肝癌的抗失巢凋亡能力。在临床病例中，HCC中LGR 5表达和CD 133表达与OLFM 4表达相关，导致患者预后不良。在体外，LGR 5通过Wnt信号通路上调OLFM 4增强了癌症干细胞样性质。结论：OLFM 4由LGR 5-Wnt信号通路诱导，并通过调节STAT 3诱导的肿瘤细胞增殖和癌干细胞样性质与HCC中的侵袭性肿瘤进展和不良预后密切相关。因此，OLFM 4是一种新的预后预测因子，也是HCC患者潜在的治疗靶点。
Olfactomedin 4 (OLFM4) induces signal transducer and activator of transcription 3 (STAT3) activation by inhibiting gene associated with retinoid-interferon-induced mortality 19 (GRIM19), a strong STAT3 suppressor gene; however, the mechanisms of OLFM4 for regulating GRIM19-STAT3 cascade in hepatocellular carcinoma (HCC) remain unclear. The functions and regulations of OLFM4, GRIM19, and STAT3 activation in HCC progression were evaluated using surgical specimens collected from 111 HCC patients or 2 HCC cell lines in vitro. Moreover, the cancer stem cell-like property of OLFM4 mediated by leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), known as an intestinal stem cell marker, was investigated. OLFM4 was increased in HCC compared with adjacent liver tissue. The multivariate analysis revealed that high OLFM4 expression was an independent factor for poor prognosis. OLFM4 expression was negatively correlated with GRIM19 expression and positively correlated with STAT3 activation in HCC, thereby increasing cell cycle progression. OLFM4 knockdown in HCC cells increased GRIM19 expression and inhibited STAT3 activation; however, after double knockdown of GRIM19 and OLFM4, STAT3 activation decreased by OLFM4 knockdown was increased again. OLFM4 knockdown increased cell apoptosis, inhibited cell proliferation, and suppressed cancer stem cell-like property in HCC cells. The incidence of hematogenous recurrence was higher in HCC patients with high OLFM4 expression, suggesting that anoikis resistance of HCC was enhanced by OLFM4. In clinical cases, LGR5 expression and CD133 expression was correlated with OLFM4 expression in HCC, leading to poor patient prognosis. In vitro, LGR5 enhanced cancer stem cell-like property by up-regulating OLFM4 through the Wnt signaling pathway. Conclusion: OLFM4 is induced by the LGR5-Wnt signaling pathway and is strongly associated with aggressive tumor progression and poor prognosis in HCC by regulating STAT3-induced tumor cell proliferation and cancer stem cell-like property. Therefore, OLFM4 is a novel prognostic predictor and a potential therapeutic target for patients with HCC.