Li Chunxue, Luo Xuelian, Huang Bin, Wang Xiangfeng, Deng Yi, Zhong Zhaoyang
Department of General Surgery, Gastric and Colorectal Surgery Division, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China.
Cancer Center, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China.
Ann Transl Med. 2020 Mar;8(6):301. doi: 10.21037/atm.2020.02.154.
ADAMTS12, a member of the ADAMTS family, is reported to be associated with the clinic outcome of colorectal cancer (CRC) patients. However, the functions and precise mechanism in CRC progression have yet to be fully understood.
By analyzing The Cancer Genome Atlas (TCGA) database, we examined the mRNA level of ADAMTS12 and assessed the prognostic value of ADAMTS12 in CRC patients using a tissue microarray containing 41 CRC patient samples. Cell Counting Kit-8 (CCK-8), colony formation, and transwell assays were used to quantify the impact of ADAMTS12 on cell proliferation and migration in ADAMTS12-overexpressing and ADAMTS12-deficient cell lines. The signaling pathways that ADAMTS12 mediated were identified by dual-luciferase reporter assays, and confirmed by western blotting and quantitative teal-time polymerase chain reaction (qRT-PCR).
The ADAMTS12 mRNA level was upregulated in CRC tissues, and CRC patients with a high level of ADAMTS12 showed worse prognosis when compared with the patients with a low level of ADAMTS12. functional assays demonstrated that overexpression of ADAMTS12 significantly boosted cell proliferation and migration while ADAMTS12 deficiency remarkably impaired both tumor cell behaviors. Mechanical studies further verified that ADAMTS12 overexpression enhanced the transcriptional activity of β-catenin in the Wnt/β-catenin signaling pathway. In the ADAMTS12-deficient context, the downstream gene expression of myc and cyclin D1 was significantly reduced compared with that in wild-type cancer cells.
ADAMTS12 fulfills the tumor-promotor role by activating Wnt/β-catenin signaling pathway in colon cells and may represent a new option in CRC target treatment.
ADAMTS12是ADAMTS家族的一员，据报道与结直肠癌（CRC）患者的临床结局相关。然而，其在CRC进展中的功能和确切机制尚未完全明确。
通过分析癌症基因组图谱（TCGA）数据库，我们检测了ADAMTS12的mRNA水平，并使用包含41例CRC患者样本的组织芯片评估ADAMTS12在CRC患者中的预后价值。采用细胞计数试剂盒-8（CCK-8）、集落形成和Transwell实验来量化ADAMTS12对ADAMTS12过表达和ADAMTS12缺陷细胞系中细胞增殖和迁移的影响。通过双荧光素酶报告基因实验确定ADAMTS12介导的信号通路，并通过蛋白质免疫印迹和定量实时聚合酶链反应（qRT-PCR）进行验证。
CRC组织中ADAMTS12的mRNA水平上调，与低水平ADAMTS12的患者相比，ADAMTS12水平高的CRC患者预后更差。功能实验表明，ADAMTS12的过表达显著促进细胞增殖和迁移，而ADAMTS12缺陷则明显损害这两种肿瘤细胞行为。机制研究进一步证实，ADAMTS12过表达增强了Wnt/β-连环蛋白信号通路中β-连环蛋白的转录活性。在ADAMTS12缺陷的情况下，与野生型癌细胞相比，myc和细胞周期蛋白D1的下游基因表达显著降低。
ADAMTS12通过激活结肠细胞中的Wnt/β-连环蛋白信号通路发挥肿瘤促进作用，可能代表CRC靶向治疗的新选择。
