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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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Tumor Biology

Abstract

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.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81572384, 81372138, 30873094, and 81090421), the 863 National High Technology Research and Development Program of China (2012AA020206), Zhejiang Medical Association Clinical Research Fund (2013ZYC-A144), and Taizhou Science and Technology Plan (1301ky55).

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    Authors and Affiliations

    1. Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, China

      Zejun Fang, Rui Song, Chaoju Gong, Yuexia Chen & Jimin Shao

    2. Sanmen People’s Hospital of Zhejiang, Sanmen, 317100, China

      Zejun Fang, Xiaomin Zhang, Lanlan Qiu, Lingming Mei, Ronghui Zhang & Xiang Chen

    3. Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

      Guoping Ren

    4. Department of Pathology, The Second Affiliated hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China

      Jinfan Li & Xueping Xiang

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    1. Zejun Fang
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    Correspondence to Xiang Chen or Jimin Shao.

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    Zejun Fang and Rui Song contributed equally to this work.

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    Fang, Z., Song, R., Gong, C. et al. Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma. Tumor Biol. 37, 3515–3526 (2016). https://doi.org/10.1007/s13277-015-4175-7

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