Significance of Liver Zonation in Hepatocellular Carcinoma

Shizhe Yu; Jie Gao; Haoren Wang; Long Liu; Xudong Liu; Yuantong Xu; Jihua Shi; Wenzhi Guo; Shuijun Zhang

doi:10.3389/fcell.2022.806408

Significance of Liver Zonation in Hepatocellular Carcinoma

Front Cell Dev Biol. 2022 Jun 23:10:806408. doi: 10.3389/fcell.2022.806408. eCollection 2022.

Authors

Shizhe Yu^{1

2

3}, Jie Gao^{1

2

3}, Haoren Wang⁴, Long Liu^{1

2

3}, Xudong Liu^{1

2

3}, Yuantong Xu⁵, Jihua Shi^{1

2

3}, Wenzhi Guo^{1

2

3}, Shuijun Zhang^{1

2

3}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Henan Engineering Technology Research Center for Organ Transplantation, Zhengzhou, China.
³ Open and Key Laboratory for Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.
⁴ Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁵ Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Kunming, Calmette Hospital, Kunming, China.

Abstract

Liver zonation is fundamental to normal liver function, and numerous studies have investigated the microstructure of normal liver lobules. However, only a few studies have explored the zonation signature in hepatocellular carcinoma (HCC). In this study, we investigated the significance of liver zonation in HCC with the help of single-cell RNA sequencing (scRNA-seq) and multicolor immunofluorescence staining. Liver zonation-related genes were extracted from the literature, and a three-gene model was established for HCC prognosis. The model reliability was validated using bulk RNA and single-cell RNA-level data, and the underlying biological mechanism was revealed by a functional enrichment analysis. The results showed that the signaling pathways of high-risk groups were similar to those of perivenous zones in the normal liver, indicating the possible regulating role of hypoxia in HCC zonation. Furthermore, the co-staining results showed that the low-grade tumors lost their zonation features whereas the high-grade tumors lost the expression of zonation-related genes, which supported the results obtained from the sequencing data.

Keywords: ALAD; FTCD; PON1; hepatocellular carcinoma; liver zonation; multiplex immunofluorescence; single-cell RNA sequence; tumor dedifferentiation.