title: Progression from cirrhosis to cancer is associated with early ubiquitin post-translational modifications: identification of new biomarkers of cirrhosis at risk of malignancy.
abstract: Cirrhosis is a lesion at risk of hepatocellular carcinoma (HCC). Identifying mechanisms associated with the transition from cirrhosis to HCC and characterizing biomarkers of cirrhosis at high risk of developing into cancer are crucial for improving early diagnosis and prognosis of HCC. We used MALDI imaging to compare mass spectra obtained from tissue sections of cirrhosis without HCC, cirrhosis with HCC, and HCC, and a top-down proteomics approach to characterize differential biomarkers. We identified a truncated form of monomeric ubiquitin lacking the two C-terminal glycine residues, Ubi(1-74), the level of which increased progressively, from cirrhosis without HCC to cirrhosis with HCC to HCC. We showed that kallikrein-related peptidase 6 (KLK6) catalysed the production of Ubi(1-74) from monomeric ubiquitin. Furthermore, we demonstrated that KLK6 was induced de novo in cirrhosis and increased in HCC in parallel with accumulation of Ubi(1-74). We investigated in vitro the possible consequences of Ubi(1-74) accumulation and demonstrated that Ubi(1-74) interferes with the normal ubiquitination machinery in what is likely to be a kinetic process. Our data suggest that de novo KLK6 expression during early liver carcinogenesis may induce production of Ubi(1-74) by post-translational modification of ubiquitin. Given the deleterious effect of Ubi(1-74) on protein ubiquitination and the major role of ubiquitin machinery in maintenance of cell homeostasis, Ubi(1-74) might severely impact a number of critical cellular functions during transition from cirrhosis to cancer. Ubi(1-74) and KLK6 may serve as markers of cancer risk in patients with cirrhosis.
authors: INSERM U773, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors: Samira
authors: S
authors: Laouirem
authors: Julie
authors: J
authors: Le Faouder
authors: Theodore
authors: T
authors: Alexandrov
authors: Denis
authors: D
authors: Mestivier
authors: Thibaut
authors: T
authors: Léger
authors: Xavier
authors: X
authors: Baudin
authors: Mouniya
authors: M
authors: Mebarki
authors: Valérie
authors: V
authors: Paradis
authors: Jean-Michel
authors: JM
authors: Camadro
authors: Pierre
authors: P
authors: Bedossa
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007610:Kallikreins / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011499:Protein Processing, Post-Translational; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D060388:Support Vector Machine; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D025801:Ubiquitin; C103551:KLK6 protein, human; D007610:Kallikreins
keywords: imaging mass spectrometry; kallikrein; liver carcinogenesis; ubiquitin