title: Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma.
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.
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.|Sanmen People's Hospital of Zhejiang, Sanmen, 317100, China.
authors.forename: Zejun
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
authors.forename: Chaoju
authors.initials: C
authors.lastname: Gong
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, 317100, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Ren
authors.affiliation: Department of Pathology, The Second Affiliated hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
authors.forename: Jinfan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, 317100, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, 317100, China.
authors.forename: Lingming
authors.initials: L
authors.lastname: Mei
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, 317100, China.
authors.forename: Ronghui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The Second Affiliated hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Xiang
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, 317100, China. sychenxiang@126.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, China. shaojimin@zju.edu.cn.
authors.forename: Jimin
authors.initials: J
authors.lastname: Shao
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000473:pathology*; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000502:physiology; D012262:Ribonucleoside Diphosphate Reductase / Q000502:physiology; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D025521:Tumor Suppressor Proteins; C093713:ribonucleotide reductase M2; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Papillary thyroid carcinoma; Ribonucleotide reductase large subunit M1; Undifferentiated thyroid carcinoma