Chen Jianjun, Luo Yang, Zhou Yong, Qin Shaolan, Qiu Yier, Cui Ran, Yu Minhao, Qin Jun, Zhong Ming
Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of General Surgery, Shanghai Jiading District Hospital of Chinese medicine, Shanghai, China.
Cell Physiol Biochem. 2018;46(4):1693-1703. doi: 10.1159/000489245. Epub 2018 Apr 20.
BACKGROUND/AIMS: ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are a family of extracellular proteases that have been related to both oncogenic and tumor-suppressive functions. The aim of the present study was to investigate: 1) the mutation, copy-number alterations, and expression profile of ADAMTSs in colorectal cancer and 2) whether ADAMTSs participate in colorectal cancer (CRC) progression and invasion.
The mutation, copy-number alterations, and expression profile of ADAMTSs in CRC were analyzed in the TCGA cohort using cBioportal. ADAMTS4 expression in tumor tissues and cell lines were determined by immunostaining and real-time quantitative PCR. The role of ADAMTS-4 in CRC progression and the underlying mechanisms were studied by using short hairpin RNA-mediated knockdown of ADAMTS4. The effects of ADAMTS4 in cell proliferation and invasion were determined by clone formation assay and transwell migration assay, respectively. Macrophages were depleted by liposomal clodronate in immune-competent BALB/c mice and tumor growth was analyzed.
ADAMTS4 was differentially expressed in CRC and predicted a poor prognosis. Elevated ADAMTS4 expression was closely associated with larger tumor size, enhanced TNM stage, and a poor clinical outcome in patients with CRC. ADAMTS4 knockdown had no inhibitory implications on cell proliferation and invasion in vitro, but significantly attenuated tumor growth in vivo. Mechanistically, we revealed that ADAMTS4 was associated macrophages infiltration and polarization in the tumor microenvironment of CRC. Macrophage depletion largely abolished the promotive effect of ADAMTS4 on tumor growth in the immune competent BALB/c mice.
ADAMTS4 seemed to be a promising prognostic indicator in CRC. The novel link between ADAMTS4 and macrophages mirrors the potential regulatory roles of ADAMTSs in the inflammatory microenvironment of cancers.
背景/目的：含血小板反应蛋白基序的解聚素和金属蛋白酶（ADAMTSs）是一类细胞外蛋白酶家族，其与致癌和肿瘤抑制功能均有关联。本研究的目的是探究：1）ADAMTSs在结直肠癌中的突变、拷贝数改变及表达谱；2）ADAMTSs是否参与结直肠癌（CRC）的进展和侵袭。
使用cBioportal在TCGA队列中分析CRC中ADAMTSs的突变、拷贝数改变及表达谱。通过免疫染色和实时定量PCR测定肿瘤组织和细胞系中ADAMTS4的表达。利用短发夹RNA介导的ADAMTS4敲低研究ADAMTS-4在CRC进展中的作用及潜在机制。分别通过克隆形成试验和Transwell迁移试验确定ADAMTS4对细胞增殖和侵袭的影响。在具有免疫活性的BALB/c小鼠中，用脂质体氯膦酸盐清除巨噬细胞，并分析肿瘤生长情况。
ADAMTS4在CRC中差异表达，且预示预后不良。ADAMTS4表达升高与CRC患者的肿瘤体积较大、TNM分期增加及临床结局较差密切相关。ADAMTS4敲低对体外细胞增殖和侵袭无抑制作用，但显著减弱体内肿瘤生长。机制上，我们发现ADAMTS4与CRC肿瘤微环境中的巨噬细胞浸润和极化有关。巨噬细胞清除在很大程度上消除了ADAMTS4对具有免疫活性的BALB/c小鼠肿瘤生长的促进作用。
ADAMTS4似乎是CRC中一个有前景的预后指标。ADAMTS4与巨噬细胞之间的新联系反映了ADAMTSs在癌症炎症微环境中的潜在调节作用。
