Analysis of human endogenous retrovirus in hepatocellular carcinomas using HERV-Fcount

Human endogenous retroviruses (HERVs) are important in the development of human diseases, including cancers, and comprehensive study for hepatocellular carcinoma (HCC) is lacking.

We analyzed the impacts of HERVs on 254 HCC patients using total RNA sequencing (RNA-seq) and a new approach based on featureCounts (we call it HERV-Fcount), and then evaluated the alterations of HERVs in an HCC cell line after TP53 knockdown and alternative splicing (AS)-related small molecules treatment. We also compared the differences in HERVs detection between the Telescope and HERV-Fcount.

In all, 206 HERVs with differential expression are correlated with patient survival and there are 299 genes located near the 206 survival-related differentially expressed (DE) HERVs. There are 14 HERVs whose expression is in the same direction as their nearby genes and also have survival significance. Among these, 11 are positive regulators, with 7 detected by both methods and 4 unique to HERV-Fcount, and 3 are negative regulators, with 2 detected by both methods and 1 unique to HERV-Fcount. Knockdown of TP53 results in dysregulation of survival-related DE HERVs and their nearby genes. The molecule modulating AS can influence the expressions of HERVs by regulating the host genes near HERVs.

HERV-Fcount detects HERVs faster than the Telescope. In addition to total RNA-seq, which increases the detection of HERVs and their nearby genes, this phenomenon can also be observed with HERV-Fcount. HERVs activation results in dysregulation of nearby genes that could be associated with HCC development and prognosis.