Single-cell RNA sequencing highlights the functional role of human endogenous retroviruses in gallbladder cancer

Jinghan Wang; Meng Ren; Jundan Yu; Mingtai Hu; Xiaojing Wang; Wencong Ma; Xiaoqing Jiang; Jie Cui

doi:10.1016/j.ebiom.2022.104319

Single-cell RNA sequencing highlights the functional role of human endogenous retroviruses in gallbladder cancer

EBioMedicine. 2022 Nov:85:104319. doi: 10.1016/j.ebiom.2022.104319. Epub 2022 Oct 29.

Authors

Jinghan Wang¹, Meng Ren², Jundan Yu³, Mingtai Hu¹, Xiaojing Wang³, Wencong Ma¹, Xiaoqing Jiang⁴, Jie Cui⁵

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
² CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; Nanjing Advanced Academy of Life and Health, Nanjing 211135, China.
³ CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Department of Biliary Tract Surgery I, the Third Hospital of Naval Medical University, Shanghai 200438, China. Electronic address: jxq1225@sina.com.
⁵ CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; Nanjing Advanced Academy of Life and Health, Nanjing 211135, China. Electronic address: jcui@ips.ac.cn.

Abstract

Background: Gallbladder cancer (GBC), the most common malignancy of the biliary tract, shows late diagnosis and low survival rate and requires continued search for new diagnostic biomarkers and therapeutic targets. Human endogenous retroviruses (HERVs) are specifically prone to be reactivated in diverse cancers and are implicated in cancer progression and immunotherapy.

Methods: Single-cell RNA sequencing was performed on tumor tissues and paired adjacent tissues from 4 GBC patients. Dual-luciferase reporter assay was applied to measure enhancer activity of HERV sequences.

Findings: We dissected the cellular diversity and described the HERV transcriptomic landscape for GBC. We found that HERVs were transcribed in a cell type-specific manner and different HERV families were associated with diverse biological effects. HERVs could function as enhancers, presumably causing altered expression of neighboring genes. The transcription level of HERVH was gradually elevated with the malignant transformation of epithelial cells, suggesting HERVH may be a potential early diagnostic biomarker of GBC. HHLA2, a newly emerging immune checkpoint, was derived by HERVH, exhibited an expressional correlation with HERVH, and was identified as a promising target for immunotherapy.

Interpretation: Exploring the transcriptional landscape and potential functional impact of HERVs highlights the important role of HERVs in GBC and provides a fresh perspective on managing GBC.

Funding: This study was supported by the National Natural Science Foundation of China (31970176, 81972256) and the research grants from the Innovation Capacity Building Project of Jiangsu province (BM2020019).

Keywords: Enhancer; Gallbladder cancer; HERVH; Human endogenous retrovirus; Immune checkpoint; Single-cell RNA sequencing.

MeSH terms

Endogenous Retroviruses* / genetics
Exome Sequencing
Gallbladder Neoplasms* / diagnosis
Gallbladder Neoplasms* / genetics
Humans
Immunoglobulins / genetics
Immunotherapy
Sequence Analysis, RNA

Substances

HHLA2 protein, human
Immunoglobulins