Transforming growth factor-β-induced plasticity causes a migratory stemness phenotype in hepatocellular carcinoma.
As part of its potential pro-tumorigenic actions, Transforming Growth Factor-(TGF)-β induces epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells. Whether EMT induces changes in tumor cell plasticity has not been fully explored yet. Here, we analyze the effects of TGF-β on the EMT and stem-related properties of HCC cells and the potential correlation among those processes. The translational aim of the study was to propose a TGF-β/EMT/stem gene signature that would help in recognizing HCC patients as good candidates for anti-TGF-β therapy. Results indicate that when TGF-β induces EMT in HCC cells, a switch in the expression of stem genes is observed and their stemness potential and migratory/invasive capacity are enhanced. However, TGF-β may induce a partial EMT in some epithelial HCC cells, increasing the expression of mesenchymal genes and CD44, but maintaining epithelial gene expression. Epithelial cells show higher stemness potential than the mesenchymal ones, but respond to TGF-β increasing their migratory and invasive capacity. In HCC patient samples, TGFB1 expression most frequently correlates with a partial EMT, increase in mesenchymal genes and CD44 expression, as well as maintenance or over-expression of epithelial-related genes.
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
Andrea
A
Malfettone
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
Jitka
J
Soukupova
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
Esther
E
Bertran
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
Eva
E
Crosas-Molist
Department of Surgery, Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain.
Raquel
R
Lastra
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
Joan
J
Fernando
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
Petra
P
Koudelkova
Department of Biomedical Sciences and Human Oncology, University of Bari, Medical School, Bari, Italy.
Bhavna
B
Rani
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
Ángels
Á
Fabra
Pathological Anatomy Service, University Hospital of Bellvitge, Barcelona, Spain.
Teresa
T
Serrano
Department of Surgery, Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain.
Emilio
E
Ramos
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
Wolfgang
W
Mikulits
National Institute of Gastroenterology IRCCS "S. De Bellis" Castellana Grotte Bari, Italy.
Gianluigi
G
Giannelli
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain; Department of Physiological Sciences, School of Medicine, University of Barcelona, Barcelona, Spain. Electronic address: ifabregat@idibell.cat.
Isabel
I
Fabregat
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000066670:Cell Plasticity / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D059467:Transcriptome; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
CD44; EMT; HCC; Stem; TGF-beta