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

 Jee San Lee  ;  Jeong Eun Yoo  ;  Haeryoung Kim  ;  Hyungjin Rhee  ;  Myoung Ju Koh  ;  Ji Hae Nahm  ;  Jin Sub Choi  ;  Kee-Ho Lee  ;  Young Nyun Park 
 PLOS ONE, Vol.12(3) : e0171922, 2017 
Journal Title
Issue Date
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*
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Koh, Myoung Ju(고명주)
Nahm, Ji Hae(남지해) ORCID logo https://orcid.org/0000-0003-0902-866X
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Yoo, Jeong Eun(유정은)
Rhee, Hyungjin(이형진) ORCID logo https://orcid.org/0000-0001-7759-4458
Choi, Jin Sub(최진섭)
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