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Epigenetically Silenced miR-1224 Suppresses the Proliferation of Human Hepatocellular Carcinoma via the CREB-Mediated YAP Signaling Pathway

41 Pages Posted: 18 Dec 2018

See all articles by Shikun Yang

Shikun Yang

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Chao Yang

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Gefengqiang Shen

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Hu Yuan Chang

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation; Nanjing Medical University - Hepatobiliary Center

Keyan Chen

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Chengyu Shi

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Qiang Zhu

Nanjing Medical University

Feng Cheng

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Feng Zhang

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Xue-Hao Wang

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Ling Lu

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Jianhua Rao

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

More...

Abstract

Background: MicroRNAs (miRNAs) are involved in a range of biological processes and their dysregulation have emerged as a critical regulatory mechanism in the progression of multiple human cancers, including hepatocellular carcinoma (HCC). Mounting evidence indicates that miR-1224 is commonly down-regulated in various malignant tumors including glioma and metastatic colorectal cancer, and acts as a tumor suppressor by inhibiting cell proliferation, invasion and by promoting apoptosis. However, the function and mechanisms responsible for the role of miR-1224 in HCC are still unknown.

Methods: miR-1224 expression levels were detected in HCC cells and tissues by quantitative real-time PCR (qPCR) and fluorescent in situ hybridization (FISH). Bisulfite sequencing PCR (BSP) was used for DNA methylation analysis. miR-1224 shRNAs and an overexpression vector were transfected into HCC cells in order to down-regulate or up-regulate the expression of miR-1224. In vitro and in vivo assays were performed to investigate the functional role of miR-1224 in the cell cycle progression of HCC cells. Dual-luciferase reporter assays were also used to determine the underlying targets and mechanisms regulated by miR-1224.

Results: miR-1224 was down-regulated in human HCC tissues. The methylation status of CpG islands was also found to be involved in the modulation of miR-1224 expression. Additionally, we found that the overexpression of miR-1224 induced HCC cells to arrest in G0/G1 phase and suppressed the proliferation of HCC cells while knockdown of miR-1224 promoted HCC cell proliferation both in vitro and in vivo. Moreover, mechanistic investigation showed that miR-1224 could repress YAP transcription and induce the HIPPO signaling pathway via binding with cAMP-response element binding protein (CREB).

Conclusions: Taken together, these findings show that miR-1224 not only inhibits the proliferation of HCC cells in vitro, but also inhibits the proliferation of these cells in vivo, at least in part, by suppressing the activation of Hippo/YAP signaling by targeting CREB.  

Funding Statement: This study was supported by the Foundation of Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, the Priority Academic Program Development of Jiangsu Higher Education Institutions, the National Natural Science Foundation of China (81871259), Six talent peaks project in Jiangsu Province (WSW-019).

Declaration of Interests: The authors declare that they have no conflict of interest.

Ethics Approval Statement: This study was approved by the Ethics Committee of Nanjing Medical University and written informed consent was obtained from all enrolled patients prior to surgery. The recorded data did not contain any information that could identify individual patients.

Keywords: miR-1224, HCC, proliferation, Hippo/YAP signaling

Suggested Citation

Yang, Shikun and Yang, Chao and Shen, Gefengqiang and Yuan Chang, Hu and Chen, Keyan and Shi, Chengyu and Zhu, Qiang and Cheng, Feng and Zhang, Feng and Wang, Xue-Hao and Lu, Ling and Rao, Jianhua, Epigenetically Silenced miR-1224 Suppresses the Proliferation of Human Hepatocellular Carcinoma via the CREB-Mediated YAP Signaling Pathway (December 12, 2018). Available at SSRN: https://ssrn.com/abstract=3301614

Shikun Yang

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Nanjing
China

Chao Yang

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Gefengqiang Shen

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Hu Yuan Chang

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Keyan Chen

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Chengyu Shi

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Qiang Zhu

Nanjing Medical University ( email )

300 Guangzhou Road
Nanjing, Jiangsu 210029
China

Feng Cheng

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Feng Zhang

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Xue-Hao Wang

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Ling Lu

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Jianhua Rao (Contact Author)

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

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