TREM2 acts as a tumor suppressor in hepatocellular carcinoma by targeting the PI3K/Akt/β-catenin pathway
TREM2 acts as a tumor suppressor in hepatocellular carcinoma by targeting the PI3K/Akt/β-catenin pathway
复制标题
TREM2 通过靶向 PI3K/Akt/β-catenin 通路作为肝细胞癌的肿瘤抑制因子
DOI：
10.1038/s41389-018-0115-x
复制
发表时间：
2019-01-25
期刊：
影响因子：
6.2
通讯作者：
Xia, Jinglin
中科院分区：
文献类型：
--
作者：
Tang, Wenqing;Lv, Bei;Xia, Jinglin
触发髓系细胞上表达的受体2(TREM2)参与了非恶性病理过程。然而，TREM2的S在恶性疾病中的作用，尤其是在肝细胞癌中的作用尚不清楚。在本研究中，我们报道了TREM2是一种新的肝细胞癌肿瘤抑制因子。TREM2在肝癌细胞(尤其是转移性肝癌细胞)和大多数人肝癌组织(尤其是肝外转移性肿瘤)中的表达明显降低。肿瘤TREM2表达降低与肝细胞癌患者预后不良、侵袭性病理特征(BCLC分期、肿瘤大小、肿瘤包膜、血管侵犯和肿瘤分化)相关。在体外和体内，TREM2基因敲除显著促进了细胞的生长、迁移和侵袭，而过表达TREM2则产生了相反的效果。TREM2通过抑制上皮-间充质转化抑制肝癌转移，并伴有上皮和间质标志物的异常表达。进一步的研究表明，肝癌中TREM2的下调受miR-31-5p的调控。此外，通过直接与β-连环素相互作用，TREM2通过抑制Akt和GSK3β磷酸化，激活β-连环素来减弱肿瘤和转移行为。TREM2通过靶向PI3K/Akt/β-catenin通路抑制肝癌的发生和转移。因此，我们认为TREM2可能是恶性疾病的候选预后生物标志物，TREM2修复可能是肝癌治疗的一种有前景的策略。
Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in nonmalignant pathological processes. However, TREM2's function in malignant diseases, especially in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that TREM2 is a novel tumor suppressor in HCC. TREM2 expression was obviously decreased in hepatoma cells (especially metastatic HCC cells), and in most human HCC tissues (especially extrahepatic metastatic tumors). Reduced tumor TREM2 expression was correlated with poor prognosis of HCC patients, and with aggressive pathological features (BCLC stage, tumor size, tumor encapsulation, vascular invasion, and tumor differentiation). TREM2 knockdown substantially promoted cell growth, migration, and invasion in vitro and in vivo, while TREM2 overexpression produced the opposite effect. TREM2 suppressed HCC metastasis by inhibiting epithelial-mesenchymal transition, accompanied by abnormal expression of epithelial and mesenchymal markers. Further study revealed that downregulation of TREM2 in HCC was regulated by miR-31-5p. Moreover, by directly interacting with beta-catenin, TREM2 attenuated oncogenic and metastatic behaviors by inhibiting Akt and GSK3 beta phosphorylation, and activating beta-catenin. TREM2 suppressed carcinogenesis and metastasis in HCC by targeting the PI3K/Akt/beta-catenin pathway. Thus, we propose that TREM2 may be a candidate prognostic biomarker in malignant diseases and TREM2 restoration might be a prospective strategy for HCC therapy.