Tumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma

PLoS One. 2017 Mar 8;12(3):e0171922. doi: 10.1371/journal.pone.0171922. eCollection 2017.

Abstract

Senescence secretome was recently reported to promote liver cancer in an obese mouse model. Steatohepatitic hepatocellular carcinoma (SH-HCC), a new variant of HCC, has been found in metabolic syndrome patients, and pericellular fibrosis, a characteristic feature of SH-HCC, suggests that alteration of the tumor stroma might play an important role in SH-HCC development. Clinicopathological characteristics and tumor stroma showing senescence and senescence-associated secretory phenotype (SASP) were investigated in 21 SH-HCCs and 34 conventional HCCs (C-HCCs). The expression of α-smooth muscle actin (α-SMA), p21Waf1/Cif1, γ-H2AX, and IL-6 was investigated by immunohistochemistry or immunofluorescence. SH-HCCs were associated with older age, higher body mass index, and a higher incidence of metabolic syndrome, compared to C-HCC (P <0.05, all). The numbers of α-SMA-positive cancer-associated fibroblasts (CAFs) (P = 0.049) and α-SMA-positive CAFs co-expressing p21Waf1/Cif1 (P = 0.038), γ-H2AX (P = 0.065), and IL-6 (P = 0.048) were greater for SH-HCCs than C-HCCs. Additionally, non-tumoral liver from SH-HCCs showed a higher incidence of non-alcoholic fatty liver disease and a higher number of α-SMA-positive stellate cells expressing γ-H2AX and p21Waf1/Cif1 than that from C-HCCs (P <0.05, all). In conclusion, SH-HCCs are considered to occur more frequently in metabolic syndrome patients. Therein, senescent and damaged CAFs, as well as non-tumoral stellate cells, expressing SASP including IL-6 may contribute to the development of SH-HCC.

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Aged
  • Aging*
  • Carcinoma, Hepatocellular / complications
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Disease-Free Survival
  • Female
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Immunohistochemistry
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Kaplan-Meier Estimate
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / complications
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology*
  • Male
  • Metabolic Syndrome / complications
  • Metabolic Syndrome / pathology
  • Microscopy, Fluorescence
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / pathology*

Substances

  • ACTA2 protein, human
  • Actins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histones
  • Interleukin-6

Grants and funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MISP) (Grant number: NRF-2012M3A9B6055350, to PYN). We declare that the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.