title: Tumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma.
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.
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.|BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.|Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jee San
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Yoo
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea.
authors.forename: Haeryoung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.|BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.|Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Rhee
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Myoung Ju
authors.initials: MJ
authors.lastname: Koh
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Nahm
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jin Sub
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea.
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.|BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.|Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea.|Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000375:Aging; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000401:mortality / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000150:complications / Q000401:mortality / Q000473:pathology*; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000473:pathology; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000473:pathology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D015850:Interleukin-6