Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers

Abstract

Background and Aims Vascular invasion (VI) is a critical risk factor for HCC recurrence and poor survival. The molecular drivers of vascular invasion in HCC are open for investigation. Deciphering the molecular landscape of invasive HCC will help identify therapeutic targets and noninvasive biomarkers. Approach and Results To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with VI using the multiplatform cancer genome atlas (The Cancer Genome Atlas; TCGA) data (n = 373). In the TCGA Liver Hepatocellular Carcinoma cohort, macrovascular invasion was present in 5% (n = 17) of tumors and microvascular invasion in 25% (n = 94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA, and proteomic changes in VI. We performed comparative proteomic analyses of invasive human HCC and MYC‐driven murine HCC and identified fibronectin to be a proteomic biomarker of invasive HCC (mouse fibronectin 1 [Fn1], P = 1.7 × 10−11; human FN1, P = 1.5 × 10−4) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n = 153; P < 0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n = 35; mean = 307.7 μg/mL; SEM = 35.9) when compared to cirrhosis (n = 10; mean = 41.8 μg/mL; SEM = 13.3; P < 0.0001). Conclusions Our study evaluates the molecular landscape of tumors with VI, identifying distinct transcriptional, epigenetic, and proteomic changes driven by the MYC oncogene. We show that MYC up‐regulates fibronectin expression, which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising noninvasive proteomic biomarker of VI in HCC.

USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells

“…Patients with HCC usually do not cause any symptoms in the early stages of the disease process, thereby losing the chance of possible cure. In addition, patients with advanced HCC usually show tumor metastasis and invasion, and are prone to treatment resistance [ 2 – 4 ]. Indeed, although many tyrosine kinase inhibitors, such as regorafenib, sorafenib, and lenvatinib, have been developed and used clinically to treat the locally advanced or metastatic HCC, they can only extend survival by a few months [ 3 , 5 , 6 ].…”

CircC16orf62 promotes hepatocellular carcinoma progression through the miR-138-5p/PTK2/AKT axis

“…Early detection and treatment lead to a better prognosis. For that, finding an effective novel biomarker and exploring HCC pathogenesis-related signaling pathways is vital 22 , 23 .…”

HCG18 Participates in Vascular Invasion of Hepatocellular Carcinoma by Regulating Macrophages and Tumor Stem Cells

“…mRNA stability is improved by recruiting the mRNA stability maintenance factor ELAVL1 ( Chen et al, 2019 , 2000 ), which is a component of a CRD-mediated complex that promotes MYC mRNA stability ( Weidensdorfer et al, 2009 ). Recent genomic and proteomic studies of HCC have identified MYC as a key protein involved in vascular invasion that plays a critical role in gene-edited mice ( Krishnan et al, 2020 ). In addition, YBX1 also regulates selective splicing of pre-mRNA by controlling interactions between mRNA and eukaryotic initiation factors ( Raffetseder et al, 2003 ).…”