DANCR deletion retards the initiation and progression of hepatocellular carcinoma based on gene knockout and patient-derived xenograft in situ hepatoma mice model

Xiaojie Gan; Dongyang Ding; Mengchao Wang; Yuan Yang; Dapeng Sun; Wen Li; Wenbin Ding; Fu Yang; Weiping Zhou; Shengxian Yuan

doi:10.1016/j.canlet.2022.215930

DANCR deletion retards the initiation and progression of hepatocellular carcinoma based on gene knockout and patient-derived xenograft in situ hepatoma mice model

Cancer Lett. 2022 Dec 1:550:215930. doi: 10.1016/j.canlet.2022.215930. Epub 2022 Sep 29.

Authors

Xiaojie Gan¹, Dongyang Ding¹, Mengchao Wang¹, Yuan Yang¹, Dapeng Sun¹, Wen Li¹, Wenbin Ding¹, Fu Yang², Weiping Zhou³, Shengxian Yuan⁴

Affiliations

¹ The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China.
² The Department of Medical Genetics, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, China. Electronic address: [email protected].
³ The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China. Electronic address: [email protected].
⁴ The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China. Electronic address: [email protected].

PMID: 36183859
DOI: 10.1016/j.canlet.2022.215930

Abstract

Our previous study has demonstrated that the expression level of long noncoding RNA (lncRNA)-differentiation antagonizing non-protein coding RNA (DANCR) increases in hepatocellular carcinoma (HCC), contributing to the initiation and aggravation of such kind of malignant tumor, which is recognized as a promising therapeutic target for patients with HCC. To further investigate the effect of DANCR on HCC in preclinical models, we generated a Dancr knockout (KO) mice model by Cas9/gRNA technology and a patient-derived xenograft (PDX) in situ hepatoma mice model using immunodeficient mice and utilized adeno-associated virus 8 (AAV8) delivery DANCR-shRNA system to silence the expression of DANCR in xenograft tumor. Here, we reported that Dancr expression mainly occurred in hepatocytes and its depletion significantly alleviated hepatic fibrosis in mice and showed a prospective result with smaller tumor size and fewer number of tumors in HCC preclinical mice model. Additionally, we found that the expression of Dancr in mice cirrhotic liver was positively correlated with the content of Dancr in serum. Overall, DANCR KO can inhibit the occurrence and development of HCC and is a target worthy of further study in patients with HCC.

Keywords: AAV; DANCR; Gene knockout; Hepatocellular carcinoma; PDX.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / pathology
Cell Line, Tumor
Cell Proliferation / genetics
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
Heterografts
Humans
Liver Neoplasms* / genetics
Liver Neoplasms* / pathology
Mice
MicroRNAs* / genetics
Prospective Studies
RNA, Guide, CRISPR-Cas Systems
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
RNA, Small Interfering

Substances

MicroRNAs
RNA, Long Noncoding
RNA, Small Interfering