Kim Min Soo, Suh Kwang Wook, Hong Suntaek, Jin Wook
Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon 406-840, Korea.
Department of Surgery, Ajou University School of Medicine, Yeongto-gu, Suwon 443-380, Korea.
Oncotarget. 2017 Jun 20;8(25):41319-41333. doi: 10.18632/oncotarget.17289.
The current work reveals that TrkC receptor is crucial to many aspects of tumorigenicity and metastasis of cancer. However, with only a few exceptions, such as colorectal cancer (CRC), where suppressing tumorigenic and metastatic ability via expression of TrkC as tumor suppressor have been proposed. These diverse lines of evidence led us to investigate whether TrkC is involved in CRC progression. By using mouse models and molecular biology analyses, we demonstrate that TrkC acts as an activator in tumorigenicity and metastasis of colorectal cancer. In this study, TrkC was frequently overexpressed in CRC cells, patients' tumor samples and an azoxymethane/dextran sulphate sodium-induced mouse model of colitis-associated CRCs. TrkC expression was associated with a high-grade CRC phenotype, leading to significantly poorer survival. Also, TrkC expression promoted the acquisition of motility and invasiveness in CRC. Moreover, TrkC increased the ability to form tumor spheroids, a property associated with cancer stem cells. Importantly, knockdown of TrkC in malignant mouse or human CRC cells inhibited tumor growth and metastasis in a mouse xenograft model. Furthermore, TrkC enhanced metastatic potential and induced proliferation by aberrant gain of AKT activation and suppression of transforming growth factor (TGF)-β signalling. Interestingly, TrkC not only modulated the actions of TGF-β type II receptor, but also attenuated expression of this receptor. These findings reveal an unexpected physiological role of TrkC in the pathogenesis of CRC. Therefore, TrkC is a potential target for designing effective therapeutic strategies for CRC development.
当前的研究表明，TrkC受体在癌症的致瘤性和转移的许多方面都至关重要。然而，仅有少数例外情况，如结直肠癌（CRC），在结直肠癌中曾有人提出通过表达作为肿瘤抑制因子的TrkC来抑制其致瘤性和转移能力。这些不同的证据线索促使我们研究TrkC是否参与结直肠癌的进展。通过使用小鼠模型和分子生物学分析，我们证明TrkC在结直肠癌的致瘤性和转移中起激活剂的作用。在本研究中，TrkC在结直肠癌细胞、患者肿瘤样本以及由氧化偶氮甲烷/葡聚糖硫酸钠诱导的结肠炎相关结直肠癌小鼠模型中经常过度表达。TrkC表达与高级别结直肠癌表型相关，导致生存率显著降低。此外，TrkC表达促进了结直肠癌的运动性和侵袭性。而且，TrkC增加了形成肿瘤球体的能力，这是一种与癌症干细胞相关的特性。重要的是，在恶性小鼠或人结直肠癌细胞中敲低TrkC可在小鼠异种移植模型中抑制肿瘤生长和转移。此外，TrkC通过异常增加AKT激活和抑制转化生长因子（TGF）-β信号传导来增强转移潜能并诱导增殖。有趣的是，TrkC不仅调节TGF-β II型受体的作用，还减弱该受体的表达。这些发现揭示了TrkC在结直肠癌发病机制中意想不到的生理作用。因此，TrkC是设计有效的结直肠癌治疗策略的潜在靶点。
