Claudia Augello1, Federico Colombo2, Andrea Terrasi1, Elena Trombetta2, Marco Maggioni3, Laura Porretti2, Giorgio Rossi4, Silvana Guerneri5, Rosamaria Silipigni5, Silvano Bosari6, Valentina Vaira7. 1. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Divisions of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 2. Clinical Chemistry and Microbiology Laboratory, Flow Cytometry and Experimental Hepatology Service, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 3. Divisions of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 4. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; General Surgery and Liver Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 5. Laboratory of Medical Genetics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 6. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Divisions of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: silvano.bosari@unimi.it. 7. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Divisions of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: valentina.vaira@unimi.it.
Abstract
BACKGROUND: Intratumor heterogeneity of hepatocellular carcinoma (HCC) and, among HCC cell subsets, the cancer stem cell population (hCSC), is responsible for therapeutic resistance and disease relapse. AIMS: To characterize hCSC-enriched HCCs at the molecular level. METHODS: Side population (SP) was used to identify the hCSCs in multiple tumor sampling from different patients and primary HCCs cultures. FACS was used to immunoprofile cultures. miRNAs were profiled in samples and correlated to SP. The Cancer Genome Atlas (TCGA) HCC dataset was analyzed to search for signatures associated with C19MC miRNAs expression. Results were confirmed by immunohistochemistry. RESULTS: The miRNA cluster on chromosome 19 (C19MC) was enriched in SP and in HCCs with a high SP fraction. At the molecular level, an elevated C19MC was correlated with expression of precursor transcripts. In TCGA-HCC series, high C19MC expression identified a subset of patients with poorer prognosis, advanced disease and overexpression of the cancer-testis (CT) antigens. These data were confirmed in an independent cohort of HCCs and at the protein level. CONCLUSION: C19MC miRNAs and CT antigens overexpression represents a novel oncogenic pathway in a subset of hCSC-enriched HCCs with dismal prognosis. CT antigens are promising immunotherapy targets. Therefore, these molecular signatures could identify HCCs who could benefit from immunotherapy.
BACKGROUND: Intratumor heterogeneity of hepatocellular carcinoma (HCC) and, among HCC cell subsets, the cancer stem cell population (hCSC), is responsible for therapeutic resistance and disease relapse. AIMS: To characterize hCSC-enriched HCCs at the molecular level. METHODS: Side population (SP) was used to identify the hCSCs in multiple tumor sampling from different patients and primary HCCs cultures. FACS was used to immunoprofile cultures. miRNAs were profiled in samples and correlated to SP. The Cancer Genome Atlas (TCGA) HCC dataset was analyzed to search for signatures associated with C19MC miRNAs expression. Results were confirmed by immunohistochemistry. RESULTS: The miRNA cluster on chromosome 19 (C19MC) was enriched in SP and in HCCs with a high SP fraction. At the molecular level, an elevated C19MC was correlated with expression of precursor transcripts. In TCGA-HCC series, high C19MC expression identified a subset of patients with poorer prognosis, advanced disease and overexpression of the cancer-testis (CT) antigens. These data were confirmed in an independent cohort of HCCs and at the protein level. CONCLUSION: C19MC miRNAs and CT antigens overexpression represents a novel oncogenic pathway in a subset of hCSC-enriched HCCs with dismal prognosis. CT antigens are promising immunotherapy targets. Therefore, these molecular signatures could identify HCCs who could benefit from immunotherapy.
Authors: Bhuvana A Setty; Goodwin G Jinesh; Michael Arnold; Fredrik Pettersson; Chia-Ho Cheng; Ling Cen; Sean J Yoder; Jamie K Teer; Elsa R Flores; Damon R Reed; Andrew S Brohl Journal: PLoS Genet Date: 2020-04-20 Impact factor: 5.917
Authors: Goodwin G Jinesh; Marco Napoli; Marian T Smallin; Andrew Davis; Hayley D Ackerman; Payal Raulji; Nicole Montey; Elsa R Flores; Andrew S Brohl Journal: Sci Rep Date: 2021-06-16 Impact factor: 4.996
Authors: Goodwin G Jinesh; Marco Napoli; Hayley D Ackerman; Payal M Raulji; Nicole Montey; Elsa R Flores; Andrew S Brohl Journal: Sci Rep Date: 2020-07-23 Impact factor: 4.996
Authors: Alessandro Palleschi; Gabriella Gaudioso; Valeria Edefonti; Valeria Musso; Andrea Terrasi; Federico Ambrogi; Sara Franzi; Lorenzo Rosso; Paolo Tarsia; Letizia C Morlacchi; Stefano Ferrero; Mario Nosotti; Valentina Vaira Journal: Transplant Direct Date: 2020-04-09