lancet-header

Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com.

NNMT Involvement in CD44v3 Regulation Induced by Hepatic Stellate Cells Contributes to the Metastasis of Hepatocarcinoma Cells

37 Pages Posted: 10 Jan 2019

See all articles by Jie Li

Jie Li

Xiamen University

Song You

Xiamen University

Qing Hu

Xiamen Xianyue Hospital

Fuqiang Wang

Xiamen University - Department of Hepatobiliary Surgery

Sheng Zhang

Xiamen University

Xiaoqin Chi

Xiamen University

Wenxiu Zhao

Xiamen University

Chengrong Xie

Xiamen University

Changmao Zhang

Xiamen University

Yaqi Yu

Xiamen University

Jianmin Liu

Xiamen University

Yue Zhao

Xiamen University

Pingguo Liu

Xiamen University

Yi Zhang

Xiamen University

Xujin Wei

Xiamen University

Qiu Li

Xiamen University

Xiaomin Wang

Xiamen University - Department of Hepatobiliary Surgery

Zhenyu Yin

Xiamen University - Department of Hepatobiliary Surgery

More...

Abstract

The crosstalk between hepatic stellate cells (HSCs) and hepatic carcinoma cells contributes to hepatocellular carcinoma (HCC) progression, although the underlying mechanism is largely unknown. We found that activated HSCs upregulated nicotinamide (NAM) N-methyltransferase (NNMT) expression in hepatoma cells. NNMT regulates multiple metabolic pathways in the liver, and aberrantly high levels of NNMT in the HCC tissues were positively correlated with vascular invasion, serum HBV levels and distant metastasis in our study. Functional assays showed that NNMT promoted cell migration, invasion and metastasis in vitro and in vivo. Mechanistically, NNMT regulated the intracellular methylation potential which in turn altered histone H3K27 methylation pattern, resulting in the transcriptional activation of CD44. NNMT-mediated m6A modification of the CD44 mRNA resulted in the formation of the CD44v3 splice variant, while its product 1-MNA stabilized CD44 protein by preventing ubiquitin-mediated degradation. Finally, NNMT was also a target of statins which inhibited the metastatic ability of hepatoma cells. Taken together, our study provides evidence for the first time on the potential role of the NNMT/CD44v3 axis in regulating HCC metastasis, and presents NNMT as a promising prognostic biomarker and therapeutic target for HCC.

Funding Statement: This study was supported by the National Natural Science Foundation of China (No.81672418 and 81871961, to Zhenyu Yin. No. 81802344,to Jie Li. No. 81572335,to Wenxiu Zhao) and the Xiamen Science and Technology Project of People-benefit (No. 3502Z20174089, to J.L.).

Declaration of Interests: All of the authors have declared that no competing interests exist.

Ethics Approval Statement: Specimen collection was performed after obtaining informed consent from each patient, and the utilization of the tumor materials for research purposes was carried out in accordance with the approved guidelines and approved by the Ethics Committee (No: 20111008) of Zhong Shan Hospital Xiamen University

Keywords: hepatocellular carcinoma, hepatic stellate cells , NNMT, CD44, m6A, metastasis

Suggested Citation

Li, Jie and You, Song and Hu, Qing and Wang, Fuqiang and Zhang, Sheng and Chi, Xiaoqin and Zhao, Wenxiu and Xie, Chengrong and Zhang, Changmao and Yu, Yaqi and Liu, Jianmin and Zhao, Yue and Liu, Pingguo and Zhang, Yi and Wei, Xujin and Li, Qiu and Wang, Xiaomin and Yin, Zhenyu, NNMT Involvement in CD44v3 Regulation Induced by Hepatic Stellate Cells Contributes to the Metastasis of Hepatocarcinoma Cells (June 1, 2019). Available at SSRN: https://ssrn.com/abstract=3311838 or http://dx.doi.org/10.2139/ssrn.3311838

Jie Li

Xiamen University

Xiamen, Fujian 361005
China

Song You

Xiamen University

Xiamen, Fujian 361005
China

Qing Hu

Xiamen Xianyue Hospital

Xiamen
China

Fuqiang Wang

Xiamen University - Department of Hepatobiliary Surgery

No.201, Hubinnan Rd
Xiamen, 361000
China

Sheng Zhang

Xiamen University

Xiamen, Fujian 361005
China

Xiaoqin Chi

Xiamen University

Xiamen, Fujian 361005
China

Wenxiu Zhao

Xiamen University

Xiamen, Fujian 361005
China

Chengrong Xie

Xiamen University

Xiamen, Fujian 361005
China

Changmao Zhang

Xiamen University

Xiamen, Fujian 361005
China

Yaqi Yu

Xiamen University

Xiamen, Fujian 361005
China

Jianmin Liu

Xiamen University

Xiamen, Fujian 361005
China

Yue Zhao

Xiamen University

Xiamen, Fujian 361005
China

Pingguo Liu

Xiamen University

Xiamen, Fujian 361005
China

Yi Zhang

Xiamen University

Xiamen, Fujian 361005
China

Xujin Wei

Xiamen University

Xiamen, Fujian 361005
China

Qiu Li

Xiamen University

Xiamen, Fujian 361005
China

Xiaomin Wang (Contact Author)

Xiamen University - Department of Hepatobiliary Surgery ( email )

No.201, Hubinnan Rd
Xiamen, 361000
China

Zhenyu Yin

Xiamen University - Department of Hepatobiliary Surgery ( email )

No.201, Hubinnan Rd
Xiamen, 361000
China

Click here to go to TheLancet.com

Paper statistics

Downloads
28
Abstract Views
335
PlumX Metrics