Colorectal cancer (CRC) is the third most prevalent cancer worldwide causing an estimated 700 000 deaths annually. Different types of treatment are available for patients with advanced metastatic colorectal cancer, including targeted biological agents, such as cetuximab, a monoclonal antibody that targets EGFR. We have previously reported a study indicating multiple levels of interaction between metallopeptidase inhibitor 1 (TIMP-1) and the epidermal growth factor (EGF) signaling axis, which could explain how TIMP-1 levels can affect the antitumor effects of EGFR inhibitors. We also reported an association between TIMP-1-mediated cell invasive behavior and KRAS status. To gain insight into the molecular mechanisms underlying the effects of TIMP-1 in CRC, we examined by transcriptomics, proteomics, and kinase activity profiling a matched pair of isogenic human CRC isogenic DLD-1 CRC cell clones, bearing either an hemizygous KRAS wild-type allele or KRAS G13D mutant allele, exposed, or not, to TIMP-1. Omics analysis of the two cell lines identified the receptor tyrosine kinase c-Kit, a proto-oncogene that can modulate cell proliferation and invasion in CRC, as a target for TIMP-1. We found that exposure of DLD-1 CRC cells to exogenously added TIMP-1 promoted phosphorylation of c-Kit, indicative of a stimulatory effect of TIMP-1 on the c-Kit signaling axis. In addition, TIMP-1 inhibited c-Kit shedding in CRC cells grown in the presence of exogenous TIMP-1. Given the regulatory roles that c-Kit plays in cell proliferation and migration, and the realization that c-Kit is an important oncogene in CRC, it is likely that some of the biological effects of TIMP-1 overexpression in CRC may be exerted through its effect on c-Kit signaling.

中文翻译：

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金属肽酶抑制剂1（TIMP-1）促进结直肠癌中的受体酪氨酸激酶c-Kit信号传导。

结肠直肠癌（CRC）是全球第三大流行癌症，估计每年导致70万人死亡。晚期转移性结直肠癌患者可以使用不同类型的治疗方法，包括靶向生物制剂，例如西妥昔单抗（一种靶向EGFR的单克隆抗体）。我们之前已经报道过一项研究，表明金属肽酶抑制剂1（TIMP-1）和表皮生长因子（EGF）信号转导轴之间存在多种相互作用水平，这可以解释TIMP-1水平如何影响EGFR抑制剂的抗肿瘤作用。我们还报道了TIMP-1介导的细胞侵袭行为与KRAS状态之间的关联。为了深入了解TIMP-1在CRC中发挥作用的分子机制，我们通过转录组学，蛋白质组学，和激酶活性，对配对的一对同基因人类CRC同基因DLD-1 CRC细胞克隆进行分析，这些克隆包含一个半合子KRAS野生型等位基因或KRAS G13D突变等位基因，是否暴露于TIMP-1。两种细胞系的组学分析表明，受体酪氨酸激酶c-Kit是TIMP-1的靶标，它是一种原癌基因，可以调节CRC中的细胞增殖和侵袭。我们发现，将DLD-1 CRC细胞暴露于外源添加的TIMP-1可以促进c-Kit的磷酸化，这表明TIMP-1对c-Kit信号轴有刺激作用。另外，TIMP-1抑制在外源TIMP-1存在下生长的CRC细胞中的c-Kit脱落。鉴于c-Kit在细胞增殖和迁移中起着调节作用，并认识到c-Kit是CRC中重要的癌基因，