Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, 200001, China.
J Exp Clin Cancer Res. 2019 Apr 12;38(1):159. doi: 10.1186/s13046-019-1143-x.
Tripartite motif 47 (TRIM47), a member of the TRIM family proteins, plays a key role in many types of cancers including colorectal cancer (CRC). We found that levels of TRIM47 mRNA and protein were increased significantly in colorectal tumors compared with nontumor tissues and the increased levels were associated with advanced tumor stage and poor outcome.
We used quantitative polymerase chain reaction and western blot to measure levels of TRIM47 mRNA and protein in human colorectal cancer and paired normal tissues. TRIM47 was knocked down and overexpressed in colorectal cancer cells, and the effects on cell proliferation, migration and growth of xenograft tumors in nude mice were assessed. The signaling pathways were examined by western blot and immunoprecipitation assays.
TRIM47 promoted CRC proliferation and metastasis in vitro and in vivo as an oncogene. Mechanistically, TRIM47 interacted physically with SMAD4, increasing its ubiquitination and degradation. Loss of SMAD4 leaded to up-regulation of CCL15 expression and caused growth and invasion in human CRC cells through the CCL15-CCR1 signaling. Moreover, TRIM47 overexpression played a role in CRC chemoresistance in response to 5-FU therapy.
Our study demonstrated a functional role of the TRIM47-SMAD4-CCL15 axis in CRC progression and suggested a potential target for CRC therapy.
三结构域蛋白 47（TRIM47）是 TRIM 家族蛋白的成员，在包括结直肠癌（CRC）在内的多种癌症中发挥关键作用。我们发现，与非肿瘤组织相比，结直肠肿瘤中 TRIM47 mRNA 和蛋白水平显著升高，且升高水平与肿瘤晚期和预后不良相关。
我们使用定量聚合酶链反应和 Western blot 检测了人结直肠癌和配对正常组织中 TRIM47 mRNA 和蛋白的水平。在结直肠癌细胞中敲低和过表达 TRIM47，并评估其对裸鼠异种移植肿瘤生长和转移的影响。通过 Western blot 和免疫沉淀实验检测信号通路。
TRIM47 作为一种癌基因，在体外和体内促进 CRC 的增殖和转移。机制上，TRIM47 与 SMAD4 发生物理相互作用，增加其泛素化和降解。SMAD4 的缺失导致 CCL15 表达上调，并通过 CCL15-CCR1 信号通路导致人 CRC 细胞的生长和侵袭。此外，TRIM47 的过表达在 CRC 对 5-FU 治疗的化疗耐药中发挥作用。
本研究证实了 TRIM47-SMAD4-CCL15 轴在 CRC 进展中的功能作用，并提示该轴可能成为 CRC 治疗的潜在靶点。
