Proteo-genomic characterization of virus-associated liver cancers reveals potential subtypes and therapeutic targets

Abstract

Primary liver cancer is a heterogeneous disease in terms of its etiology, histology, and therapeutic response. Concurrent proteomic and genomic characterization of a large set of clinical liver cancer samples can help elucidate the molecular basis of heterogeneity and thus serve as a valuable resource for personalized liver cancer treatment. In this study, we perform proteomic profiling of ~300 proteins on 259 primary liver cancer tissues with reverse-phase protein arrays, mutational analysis using whole genome sequencing and transcriptional analysis with RNA-Seq. Patients are of Japanese ethnic background and mainly HBV or HCV positive, providing insight into this important liver cancer subtype. Unsupervised classification of tumors based on protein expression profiles reveal three proteomic subclasses R1, R2, and R3. The R1 subclass is immunologically hot and demonstrated a good prognosis. R2 contains advanced proliferative tumor with TP53 mutations, high expression of VEGF receptor 2 and the worst prognosis. R3 is enriched with CTNNB1 mutations and elevated mTOR signaling pathway activity. Twenty-two proteins, including CDK1 and CDKN2A, are identified as potential prognostic markers. The proteomic classification presented in this study can help guide therapeutic decision making for liver cancer treatment.

Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets

“…In the following section of this review, we report the results of a survey performed through an extensive literature search ( Table 2 and Table 3 ). Of particular interest in this regard is the proteomic work performed in [ 64 ], which also revealed as-of-yet unclassified molecules potentially useful as therapeutic targets.…”

“…There is evidence that the VEGF/VEGFR autocrine signal axis is present in HCC cancer cells, with the overexpression of both promoting their growth and progression [ 157 , 162 , 163 , 164 , 165 ]. Recently, a large set of virus-associated liver cancers was classified according to proteomic profiling, whole-genome sequencing, and transcriptional analysis [ 64 ]. Among the three proteomic subclasses defined (R1, R2, and R3), the R2 subclass contains advanced proliferative tumors with TP53 mutations, high expression of VEGF receptor 2, and the worst prognosis but also four known targets of multikinase inhibitors: VEGFR2, CRAF, BRAF, and c-Kit, where c-Kit represents an as-of-yet underexplored target.…”

“…Among the three proteomic subclasses defined (R1, R2, and R3), the R2 subclass contains advanced proliferative tumors with TP53 mutations, high expression of VEGF receptor 2, and the worst prognosis but also four known targets of multikinase inhibitors: VEGFR2, CRAF, BRAF, and c-Kit, where c-Kit represents an as-of-yet underexplored target. VEGFR2 was overexpressed in HCC classified as R2 (the most aggressive cancer type) in [ 64 ], while VEGFR1-HIF1A was found to be selectively upregulated in the R3 proteomic class. The latter class corresponded to smaller and less aggressive tumors enriched with CTNNB1 mutations and possessing elevated mTOR-signaling-pathway activity.…”

“…However, the RAS/MAPK pathway is activated in 50–100% of human HCCs and is correlated with a poor prognosis [ 265 , 266 ]. CRAF and BRAF activation were confirmed to be altered in HCC [ 64 , 267 ], and CRAF overexpression is considered as a marker of poor prognosis in HCC [ 265 , 268 ].…”

KHDRBS1 as a novel prognostic signaling biomarker influencing hepatocellular carcinoma cell proliferation, migration, immune microenvironment, and drug sensitivity

“…Transcriptomic analyses have unveiled bulk and single-cell RNA expression profiles in HCC, aiding in understanding tumor behavior and molecular mechanisms ( 10 – 12 ). Proteomic approaches allow the analysis of protein levels in HCC, including expression, modification, and interactions ( 13 , 14 ). Metabolomics plays a significant role in studying tumor metabolic reprogramming, aiding in exploring metabolic pathways associated with HCC occurrence, progression, and drug resistance ( 15 – 17 ).…”