Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma
Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma
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核糖核苷酸还原酶大亚基M1在甲状腺乳头状癌和未分化甲状腺癌侵袭转移中发挥不同作用
DOI：
10.1007/s13277-015-4175-7
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发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Shao, Jimin
中科院分区：
文献类型：
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作者：
Fang, Zejun;Song, Rui;Shao, Jimin
据报道，核糖核苷酸还原酶（RR）与多种癌症相关，然而其在甲状腺癌（TC）中的表达及作用尚未得到研究。在此，我们首先通过免疫组织化学方法检测了146例甲状腺乳头状癌（PTC）和12例未分化甲状腺癌（UTC）患者样本中三种RR亚基蛋白（RRM1、RRM2和RRM2B）的表达水平。结果显示，在146例PTC样本中，95.2%的癌组织中RRM1表达高于其癌旁正常组织。PTC患者中，RRM1的表达水平与T分期、淋巴结转移（LNM）、甲状腺外侵犯（ETI）及TNM分期呈正相关。然而，在12例UTC样本中，6例RRM1呈低表达。为进一步明确RRM1在甲状腺癌中的生物学作用，我们分别在高分化甲状腺癌细胞系TPC - 1和低分化甲状腺癌细胞系SW579中进行RRM1的异位表达或siRNA介导的敲低实验。在TPC - 1和SW579细胞中，RRM1的过表达及siRNA敲低实验表明，如EdU掺入实验和细胞活力检测所示，RRM1在这两种细胞系中均促进DNA合成和细胞增殖。然而，如伤口愈合实验和Transwell实验所示，RRM1增强了TPC - 1细胞的迁移和侵袭能力，但抑制了SW579细胞的迁移和侵袭能力。此外，我们还发现，在低分化甲状腺癌细胞中，RRM1以一种不依赖RR活性的方式促进PTEN表达并降低Akt磷酸化水平，而在高分化甲状腺癌细胞中则无此作用。相比之下，RRM2在PTC和UTC患者样本中均高表达，这与其在其他癌症中的致癌作用相符。因此，我们认为RRM1作为RR的组成部分促进甲状腺癌增殖，但可能通过非RR途径在不同分化程度的甲状腺癌侵袭和转移中发挥不同作用，这对于使用RR抑制剂精准治疗甲状腺癌具有重要意义。
Ribonucleotide reductase (RR) has been reported to be associated with several types of cancer while the expression and role of RR in thyroid carcinoma (TC) has not been investigated. Here, we first examined the expression level of three RR subunit proteins (RRM1, RRM2, and RRM2B) in papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinoma (UTC) patient samples by immunohistochemistry. The results showed that RRM1 was higher expressed in 95.2 % cancer tissues compared with their adjacent normal tissues in 146 PTC samples. The expression level of RRM1 was positively correlated with T stage, lymph node metastasis (LNM), extrathyroidal invasion (ETI), and TNM stage in PTC patients. However, in 12 UTC samples, RRM1 expression was negatively expressed in six cases. To further determine the biological role of RRM1 in TC, ectopic expression or siRNA-mediated knockdown of RRM1 were carried out in the high-differentiated thyroid carcinoma cell line TPC-1 and the poor-differentiated thyroid carcinoma cell line SW579, respectively. In TPC-1 and SW579 cells, overexpression and siRNA knockdown of RRM1 demonstrated that RRM1 promoted DNA synthesis and proliferation in both cell lines as shown by EdU incorporation and cell viability assays. However, RRM1 enhanced cell migration and invasion in TPC-1 cells but inhibited that in SW579 cells as shown by wound healing and transwell assays. Moreover, we also found that RRM1 promoted PTEN expression and reduced Akt phosphorylation in a RR-activity-independent manner in the low-differentiated TC cells but not in the high-differentiated TC cells. In contrast, RRM2 expression was higher expressed in both PTC and UTC patient samples, consisting with its oncogenic role in other cancers. Therefore, we suggest that RRM1 promotes thyroid carcinoma proliferation as a component of RR but may play a different role in the invasion and metastasis of differently differentiated thyroid carcinomas through a non-RR pathway, which could be meaningful to precision treatment of thyroid carcinoma with RR inhibitors.