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N6-Methyladenosine Modification of the TRIM7 Positively Regulates Tumorigenesis and Chemoresistance in Osteosarcoma Through Ubiquitination of BRMS1

38 Pages Posted: 20 May 2020

See all articles by Chenliang Zhou

Chenliang Zhou

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Zhichang Zhang

Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital

Guowei Qian

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Yan Zhou

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Yong Sun

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Wenxi Yu

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Jiahui Wang

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Haiyang Lu

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Feng Lin

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Zan Shen

Shanghai Jiao Tong University (SJTU) - Department of Oncology

Shuier Zheng

Shanghai Jiao Tong University (SJTU) - Department of Oncology

More...

Abstract

Background: Metastasis is the leading cause of death in patients with osteosarcoma. Some of these patients fail to respond to chemotherapy and die of metastasis within a short period. Therefore, it is important to identify novel biomarkers to improve the diagnosis and treatment of osteosarcoma. TRIM7 is a member of the tripartite motif (TRIM) family protein that is involved in various pathological conditions including cancer; however, its role in osteosarcoma remains elusive.

Methods: Cell proliferation, invasion and migration were measured by CCK-8 and Transwell. Immunoprecipitation and mass spectrometry analysis were used to identify candidate proteins associated with TRIM7. Immunoprecipitation, immunofluorescence, pull down and ubiquitination assay were performed to examine the regulation between TRIM7 and its candidate protein. m6A modification of TRIM7 was measured by RNA immunoprecipitation.

Findings: TRIM7 expression was upregulated in osteosarcoma tissues and was an independent risk factor in predicting poor prognosis. TRIM7 regulates osteosarcoma cell migration and invasion through ubiquitination of breast cancer metastasis suppressor 1 (BRMS1). Moreover, chemoresistance was readily observed in osteosarcoma cells and in patient-derived xenograft (PDX) mice with higher TRIM7 levels. Loss of TRIM7 m6A modification was observed in osteosarcoma tissues. METTL3 and YTHDF2 were the main factors involved in the aberrant m6A modification of TRIM7.

Interpretation: Overall, our findings show that TRIM7 plays a key role in regulating metastasis and chemoresistance in osteosarcoma through ubiquitination of BRMS1.

Funding Statement: This work was financially supported by grants of NSFC (81001192, 81672658 and 81972521) and National Key Research Project of Science and Technology Ministry (2016YFC0106204).

Declaration of Interests: The authors declare that they have no competing interests.

Ethics Approval Statement: The study was approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital.

Animal experiments were approved by the Animal Care and Use Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital.

Keywords: osteosarcoma; TRIM7; BRMS1; metastasis; ubiquitination; chemoresistance; m6A methylation

Suggested Citation

Zhou, Chenliang and Zhang, Zhichang and Qian, Guowei and Zhou, Yan and Sun, Yong and Yu, Wenxi and Wang, Jiahui and Lu, Haiyang and Lin, Feng and Shen, Zan and Zheng, Shuier, N6-Methyladenosine Modification of the TRIM7 Positively Regulates Tumorigenesis and Chemoresistance in Osteosarcoma Through Ubiquitination of BRMS1 (3/25/2020). EBioMedicine, Volume 47, September 2019, Pages 195-207, https://doi.org/10.1016/j.ebiom.2019.07.068, Available at SSRN: https://ssrn.com/abstract=3562445 or http://dx.doi.org/10.2139/ssrn.3562445

Chenliang Zhou

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Zhichang Zhang

Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Guowei Qian

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Yan Zhou

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

135, Xingang Xi Road
Guangzhou, Guangdong 510275
China

Yong Sun

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

135, Xingang Xi Road
Guangzhou, Guangdong 510275
China

Wenxi Yu

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Jiahui Wang

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Haiyang Lu

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Feng Lin

Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Zan Shen (Contact Author)

Shanghai Jiao Tong University (SJTU) - Department of Oncology ( email )

Shanghai, 200233
China

Shuier Zheng

Shanghai Jiao Tong University (SJTU) - Department of Oncology ( email )

Shanghai, 200233
China

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