Li Jin, Yang Cheng-Cheng, Tian Xin-Yuan, Li Yun-Xuan, Cui Ju, Chen Zhe, Deng Zhou-Lu, Chen Fu-Jun, Hayakawa Hiroshi, Sekiguchi Mutsuo, Cai Jian-Ping
Peking University Fifth School of Clinical Medicine, Beijing Hospital, Beijing, P.R. China.
School of Pharmacy, Wenzhou Medical University, Wenzhou, P.R. China.
Oncotarget. 2017 Nov 11;8(62):105714-105726. doi: 10.18632/oncotarget.22393. eCollection 2017 Dec 1.
MutT-related proteins, including MTH1, MTH2, MTH3 and NUDT5, can effectively degrade 8-oxoGua-containing nucleotides. The MTH1 expression is elevated in many types of human tumors and MTH1 overexpression correlates with the tumor pathological stage and poor prognosis. However, the expression of other MutT-related proteins in human cancers remains unknown. The present study systematically investigated the expression of MTH1, MTH2, MTH3 and NUDT5 in human colorectal cancer to establish its clinical significance.
Amounts of related mRNA and protein in CRC cell lines were assessed by qRT-PCR and Western blotting, respectively. Furthermore, the MutT-related protein expression was evaluated by immunohistochemical staining of tissue microarrays containing 87 paired CRC tissues and by Western blotting of 44 CRC tissue samples. Finally, the effect of knockdown of MutT-related proteins on CRC cell proliferation was investigated.
The expression of MTH1, MTH2, MTH3 and NUDT5 was significantly higher in CRC cells and CRC tissues than normal cells and tissues, and this phenomenon was significantly associated with AJCC stage and lymph node metastasis of CRC specimens. CRC patients with high expression of MTH1, MTH2 or NUDT5 had an extremely poor overall survival after surgical resection. Notably, NUDT5 was an independent prognostic factor of CRC patients. We found that knockdown of MutT-related proteins inhibited CRC cell proliferation.
We showed for the first time that MutT-related proteins play an important role in CRC progression and prognosis. Further investigations are needed to elucidate the role of these proteins in CRC progression and their potential use for therapeutic targets.
MutT相关蛋白，包括MTH1、MTH2、MTH3和NUDT5，可有效降解含8-氧代鸟嘌呤的核苷酸。MTH1在多种人类肿瘤中表达升高，且MTH1过表达与肿瘤病理分期及预后不良相关。然而，其他MutT相关蛋白在人类癌症中的表达情况仍不清楚。本研究系统地调查了MTH1、MTH2、MTH3和NUDT5在人类结直肠癌中的表达，以确定其临床意义。
分别通过qRT-PCR和蛋白质印迹法评估结直肠癌细胞系中相关mRNA和蛋白质的含量。此外，通过对包含87对结直肠癌组织的组织芯片进行免疫组织化学染色以及对44个结直肠癌组织样本进行蛋白质印迹法，评估MutT相关蛋白的表达。最后，研究敲低MutT相关蛋白对结直肠癌细胞增殖的影响。
MTH1、MTH2、MTH3和NUDT5在结直肠癌细胞和组织中的表达明显高于正常细胞和组织，且这种现象与结直肠癌标本的美国癌症联合委员会（AJCC）分期及淋巴结转移显著相关。MTH1、MTH2或NUDT5高表达的结直肠癌患者手术切除后的总生存期极差。值得注意的是，NUDT5是结直肠癌患者的独立预后因素。我们发现敲低MutT相关蛋白可抑制结直肠癌细胞增殖。
我们首次表明MutT相关蛋白在结直肠癌进展和预后中起重要作用。需要进一步研究以阐明这些蛋白在结直肠癌进展中的作用及其作为治疗靶点的潜在用途。
