title: E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2.
abstract: As the ribonucleotide reductase small subunit, the high expression of ribonucleotide reductase small subunit M2 (RRM2) induces cancer and contributes to tumor growth and invasion. In several colorectal cancer (CRC) cell lines, we found that the expression levels of RRM2 were closely related to the transcription factor E2F1. Mechanistic studies were conducted to determine the molecular basis. Ectopic overexpression of E2F1 promoted RRM2 transactivation while knockdown of E2F1 reduced the levels of RRM2 mRNA and protein. To further investigate the roles of RRM2 which was activated by E2F1 in CRC, CCK-8 assay and EdU incorporation assay were performed. Overexpression of E2F1 promoted cell proliferation in CRC cells, which was blocked by RRM2 knockdown attenuation. In the migration and invasion tests, overexpression of E2F1 enhanced the migration and invasion of CRC cells which was abrogated by silencing RRM2. Besides, overexpression of RRM2 reversed the effects of E2F1 knockdown partially in CRC cells. Examination of clinical CRC specimens demonstrated that both RRM2 and E2F1 were elevated in most cancer tissues compared to the paired normal tissues. Further analysis showed that the protein expression levels of E2F1 and RRM2 were parallel with each other and positively correlated with lymph node metastasis (LNM), TNM stage and distant metastasis. Consistently, the patients with low E2F1 and RRM2 levels have a better prognosis than those with high levels. Therefore, we suggest that E2F1 can promote CRC proliferation, migration, invasion and metastasis by regulating RRM2 transactivation. Understanding the role of E2F1 in activating RRM2 transcription will help to explain the relationship between E2F1 and RRM2 in CRC and provide a novel predictive marker for diagnosis and prognosis of the disease.
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors.forename: Zejun
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
authors.forename: Chaoju
authors.initials: C
authors.lastname: Gong
authors.affiliation: Zhejiang Normal University - Jinhua People's Hospital Joint Center for Biomedical Research, Jinhua, Zhejiang, 321004, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors.forename: Lingming
authors.initials: L
authors.lastname: Mei
authors.affiliation: Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS), School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, 100005, China.
authors.forename: Mintao
authors.initials: M
authors.lastname: Song
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors.forename: Shuchai
authors.initials: S
authors.lastname: Luo
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors.forename: Ronghui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors.forename: Hongqian
authors.initials: H
authors.lastname: Gu
authors.affiliation: Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China. Electronic address: sychenxiang@126.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
mesh_terms: D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D050687:E2F1 Transcription Factor / Q000502:physiology*; D006801:Humans; D012262:Ribonucleoside Diphosphate Reductase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase
keywords: Colorectal cancer; E2F1; Ribonucleotide reductase small subunit M2; Transactivation