Differential alternative splicing between hepatocellular carcinoma with normal and elevated serum alpha-fetoprotein

Abstract

Background Serum alpha-fetoprotein (AFP) is the approved serum marker for hepatocellular carcinoma (HCC) screening. However, not all HCC patients show high (≥ 20 ng/mL) serum AFP, and the molecular mechanisms of HCCs with normal (< 20 ng/mL) serum AFP remain to be elucidated. Therefore, we aimed to identify biological features of HCCs with normal serum AFP by investigating differential alternative splicing (AS) between HCCs with normal and high serum AFP. Methods We performed a genome-wide survey of AS events in 249 HCCs with normal (n = 131) and high (n = 118) serum AFP levels using RNA-sequencing data obtained from The Cancer Genome Atlas. Results In group comparisons of RNA-seq profiles from HCCs with normal and high serum AFP levels, 161 differential AS events (125 genes; ΔPSI > 0.05, FDR < 0.05) were identified to be alternatively spliced between the two groups. Those genes were enriched in cell migration or proliferation terms such as “the cell migration and growth-cone collapse” and “regulation of insulin-like growth factor (IGF) transport and uptake by IGF binding proteins”. Most of all, two AS genes (FN1 and FAM20A) directly interact with AFP; these relate to the regulation of IGF transport and post-translational protein phosphorylation. Interestingly, 42 genes and 27 genes were associated with gender and vascular invasion (VI), respectively, but only eighteen genes were significant in survival analysis. We especially highlight that FN1 exhibited increased differential expression of AS events (ΔPSI > 0.05), in which exons 25 and 33 were more frequently skipped in HCCs with normal (low) serum AFP compared to those with high serum AFP. Moreover, these events were gender and VI dependent. Conclusion We found that AS may influence the regulation of transcriptional differences inherent in the occurrence of HCC maintaining normal rather than elevated serum AFP levels.

Regulation of secretory pathway kinase or kinase-like proteins in human cancers

“…FAM20A is associated with poor survival of HCC. Further experimental investigation on FAM20A should be performed to evaluate its potential as a diagnostic biomarker for the early diagnosis of HCC in a high-risk population ( 82 ). Interestingly, FN1 was co-screened with FAM20A in the above two articles, and FN1 was also found to act as a substrate of FAM20C and is essential in the development of glioma ( 18 ).…”

The International Conference on Intelligent Biology and Medicine (ICIBM) 2020: Data-driven analytics in biomedical genomics

“…In the study of "Differential alternative splicing (AS) between hepatocellular carcinoma with normal and elevated serum alpha-fetoprotein", Jin et al [5] reported an investigation of differential AS events in hepatocellular carcinoma (HCC) patients with high and normal serum alpha-fetoprotein (AFP) levels. Using RNA-seq data extracted from TCGA, they identified a set of AS events for genes that are enriched for cell migration or proliferation, and some of these genes are associated with gender and vascular invasion.…”