Suh Dae-Shik, Park Si Eun, Jin Hanyong, Lee Kangseok, Bae Jeehyeon
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
School of Pharmacy, Chung-Ang University, Seoul, 06974, Korea.
Oncogenesis. 2018 Jan 23;7(1):3. doi: 10.1038/s41389-017-0019-1.
Although endometrial cancer is the most common type of gynecological malignancy in developed countries, its molecular etiology is not well understood. Leucine-rich repeat and immunoglobulin-like domain 2 (LRIG2) is an evolutionarily conserved gene, but its functions in the endometrium are unknown. In this study, we found that LRIG2 is highly downregulated in endometrial adenocarcinoma patients and that it functions as a tumor suppressor. LRIG2 induced the mitochondrion-mediated apoptotic pathways by regulating stoichiometric balance among BCL-2 family proteins, whereby pro-survival members, MCL-1 and BCL-xL, were downregulated and pro-apoptotic BAK and BAX were upregulated. LRIG2 also inhibited proliferation of the Hec-1A and Ishikawa endometrial adenocarcinoma cells by upregulating p21. LRIG2 induced BAX- and BAK-dependent cell death that was efficiently prevented by MCL-1 overexpression. Furthermore, we found that LRIG2 unexpectedly phosphor-activates phosphoinositide 3-kinase (PI3K)/AKT and epidermal growth factor receptor (EGFR), which are conventionally accepted as survival signaling cues in diverse types of cancer. We observed that PI3K/AKT and EGFR serve as key kinases that have roles as growth suppressors of Hec-1A endometrial cancer cells by mediating the LRIG2-induced modulation of the BCL-2 family of proteins and p21. In vivo delivery of antisense DNAs against LRIG2 promoted the Hec-1A endometrial tumor growth in a xenograft mouse model, and immunoblotting of these tumor extracts showed consistent modulation of AKT, EGFR, the BCL-2 family members, and p21. Thus, our results demonstrated that LRIG2 is a growth suppressor of endometrial adenocarcinoma cells.
尽管子宫内膜癌是发达国家最常见的妇科恶性肿瘤类型，但其分子病因尚未完全明确。富含亮氨酸重复序列和免疫球蛋白样结构域2（LRIG2）是一个进化上保守的基因，但其在子宫内膜中的功能尚不清楚。在本研究中，我们发现LRIG2在子宫内膜腺癌患者中高度下调，且其发挥肿瘤抑制作用。LRIG2通过调节BCL-2家族蛋白之间的化学计量平衡来诱导线粒体介导的凋亡途径，从而使促生存成员MCL-1和BCL-xL下调，促凋亡蛋白BAK和BAX上调。LRIG2还通过上调p21来抑制Hec-1A和Ishikawa子宫内膜腺癌细胞的增殖。LRIG2诱导依赖BAX和BAK的细胞死亡，而MCL-1过表达可有效阻止这种死亡。此外，我们意外地发现LRIG2可磷酸化激活磷脂酰肌醇3激酶（PI3K）/AKT和表皮生长因子受体（EGFR），而这两种蛋白在多种癌症类型中通常被认为是生存信号线索。我们观察到PI3K/AKT和EGFR作为关键激酶，通过介导LRIG2诱导的BCL-2家族蛋白和p21的调节，发挥Hec-1A子宫内膜癌细胞生长抑制因子的作用。在异种移植小鼠模型中，体内递送针对LRIG2的反义DNA可促进Hec-1A子宫内膜肿瘤生长，对这些肿瘤提取物进行免疫印迹分析显示AKT、EGFR、BCL-2家族成员和p21存在一致的调节。因此，我们的结果表明LRIG2是子宫内膜腺癌细胞的生长抑制因子。
