Cellular senescence throws new insights into patient classification and pharmacological interventions for clinical management of hepatocellular carcinoma.

Abstract

Cellular senescence, a state of stable growth arrest, is intertwined with human cancers. However, characterization of cellular senescence-associated phenotypes in hepatocellular carcinoma (HCC) remains unexplored. To address this issue, we delineated cellular senescence landscape across HCC. We enrolled two HCC datasets, TCGA-LIHC and International Cancer Genome Consortium (ICGC). Unsupervised clustering was executed to probe tumor heterogeneity based upon cellular senescence genes. Least absolute shrinkage and selection operator algorithm were utilized to define a cellular senescence-relevant scoring system. TRNP1 expression was measured in HCCs and normal tissues through immunohistochemistry, immunoblotting and quantitative real-time polymerase chain reaction. The influence of TMF-regulated nuclear protein (TRNP)1 on HCC senescence and growth was proven via a series of experiments. TCGA-LIHC patients were classified as three cellular senescence subtypes, named C1-3. The robustness and reproducibility of these subtypes were proven in the ICGC cohort. C2 had the worst overall survival, C1 the next, and C3 the best. C2 presented the highest levels of immune checkpoints, abundance of immune cells, and immunogenetic indicators. Thus, C2 might possibly respond to immunotherapy. C2 had the lowest somatic mutation rate, while C1 presented the highest copy number variations. A cellular senescence-relevant gene signature was generated, which can predict patient survival, and chemo- or immunotherapeutic response. Experimentally, it was proven that TRNP1 presented the remarkable upregulation in HCCs. TRNP1 knockdown induced apoptosis and senescence of HCC cells and attenuated tumor growth. These findings provide a systematic framework for assessing cellular senescence in HCC, which decode the tumor heterogeneity and tailor the pharmacological interventions to improve clinical management.