Comprehensive analysis identifies long non-coding RNA RNASEH1-AS1 as a potential prognostic biomarker and oncogenic target in hepatocellular carcinoma

Jin Sun; Yingnan Li; Hongwei Tian; Haiyan Chen; Jun Li; Zongfang Li

doi:10.62347/JPHF4071

Comprehensive analysis identifies long non-coding RNA RNASEH1-AS1 as a potential prognostic biomarker and oncogenic target in hepatocellular carcinoma

Am J Cancer Res. 2024 Mar 15;14(3):996-1014. doi: 10.62347/JPHF4071. eCollection 2024.

Authors

Jin Sun^{1

2

3}, Yingnan Li³, Hongwei Tian^{1

2

3}, Haiyan Chen^{1

4}, Jun Li^{1

2

3}, Zongfang Li^{5

1

2

3}

Affiliations

¹ National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Xi'an Jiaotong University Xi'an, Shaanxi, China.
² Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an, Shaanxi, China.
³ Center for Tumor and Immunology, The Precision Medical Institute, Xi'an Jiaotong University Xi'an, Shaanxi, China.
⁴ Core Research Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an, Shaanxi, China.
⁵ Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an, Shaanxi, China.

Abstract

RNASEH1-AS1, a long non-coding RNA (lncRNA) divergently transcribed from the antisense strand of its neighboring protein-coding gene ribonuclease H1 (RNASEH1), has recently been demonstrated to be involved in tumor progression. However, the association between RNASEH1-AS1 and hepatocellular carcinoma (HCC) remains unclear. In the present study, first, the expression of RNASEH1-AS1 in HCC and its correlation with clinicopathological features, prognosis, diagnosis, immune cell infiltration of HCC patients was inspected using relevant R packages based on The Cancer Genome Atlas (TCGA) data. RNASEH1-AS1 was found to be up-regulated in most cancer types, including HCC, and its overexpression was significantly associated with histologic grade and AFP level as well as poor prognosis, and was an independent risk factor affecting overall survival with good diagnostic and prognostic values for HCC. RNASEH1-AS1 was inversely associated with the infiltration of most immune cell types, including plasmacytoid dendritic cells (pDC), B cells and neutrophils. Second, a total of 1109 positively co-expressed genes (PCEGs) of RNASEH1-AS1 were screened out in HCC by correlation analysis in batches (|Spearman's r| >0.4 and adjusted P value <0.01). GO and KEGG enrichment analysis indicated that PCEGs of RNASEH1-AS1 were mainly related to RNA processing, ribosome biogenesis, transcription and histone acetylation. The top 10 hub genes (EIF4A3, WDR43, WDR12, DKC1, NAT10, UTP18, DDX18, BYSL, DDX10, PDCD11) were identified by constructing the protein-protein interaction (PPI) network, and they were all highly expressed in HCC and positively correlated with histological grade. Third, a risk model was constructed based on four RNASEH1-AS1-related hub genes (EIF4A3, WDR12, DKC1, and NAT10) with good prognostic predictive potential via univariate Cox and the least absolute selection operator (LASSO) regression analysis. Fourth, experimental validation revealed that RNASEH1-AS1 was significantly elevated in HCC tissues and several cell lines, and its knockdown could suppress the proliferation, migration, and invasion of HCC cells. Finally, mechanistic studies demonstrated that the stability of RNASEH1-AS1 could be regulated by DKC1 via their direct interaction. Taken together, RNASEH1-AS1 may serve as a potential prognostic and diagnostic biomarker and oncogenic lncRNA for HCC.

Keywords: Hepatocellular carcinoma; RNASEH1-AS1; diagnosis; prognosis.