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Background  Hepatocellular carcinoma (HCC) is one of the most lethal human tumors with extensive intratumor heterogeneity (ITH). Serine protease 3 (PRSS3) is an indispensable member of the trypsin family and has been implicated in the pathogenesis of several malignancies, including HCC. However, the paradoxical effects of  PRSS3  on carcinogenesis due to an unclear molecular basis impede the utilization of its biomarker potential. We hereby explored the contribution of  PRSS3  transcripts to tumor functional heterogeneity by systematically dissecting the expression of four known splice variants of  PRSS3  ( PRSS3-SVs, V1~V4 ) and their functional relevance to HCC.    Methods  The expression and DNA methylation of  PRSS3  transcripts and their associated clinical relevance in HCC were analyzed using several publicly available datasets and validated using qPCR-based assays. Functional experiments were performed in gain- and loss-of-function cell models, in which  PRSS3  transcript constructs were separately transfected after deleting  PRSS3  expression by CRISPR/Cas9 editing.    Results   PRSS3  was aberrantly differentially expressed toward bipolarity from very low ( PRSS3 Low  ) to very high ( PRSS3 High  ) expression across HCC cell lines and tissues. This was attributable to the disruption of  PRSS3-SVs , in which  PRSS3-V2  and/or  PRSS3-V1  were dominant transcripts leading to  PRSS3  expression, whereas  PRSS3-V3  and  -V4  were rarely or minimally expressed. The expression of  PRSS3-V2  or  -V1  was inversely associated with site-specific CpG methylation at the  PRSS3  promoter region that distinguished HCC cells and tissues phenotypically between hypermethylated low-expression (m PRSS3-SV Low  ) and hypomethylated high-expression (um PRSS3-SV High  ) groups.  PRSS3-SVs  displayed distinct functions from oncogenic  PRSS3-V2  to tumor-suppressive  PRSS3-V1 ,  -V3  or  PRSS3-V4  in HCC cells. Clinically, aberrant expression of  PRSS3-SVs  was translated into divergent relevance in patients with HCC, in which significant epigenetic downregulation of  PRSS3-V2  was seen in early HCC and was associated with favorable patient outcome.    Conclusions  These results provide the first evidence for the transcriptional and functional characterization of  PRSS3  transcripts in HCC. Aberrant expression of divergent  PRSS3-SVs  disrupted by site-specific CpG methylation may integrate the effects of oncogenic  PRSS3-V2  and tumor-suppressive  PRSS3-V1 , resulting in the molecular diversity and functional plasticity of  PRSS3  in HCC. Dysregulated expression of  PRSS3-V2  by site-specific CpG methylation may have potential diagnostic value for patients with early HCC.

frontiers in oncology

CpG Site-Specific Methylation-Modulated Divergent Expression of PRSS3 Transcript Variants Facilitates Nongenetic Intratumor Heterogeneity in Human Hepatocellular Carcinoma