title: PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis.
abstract: BACKGROUND
  Mounting epidemiological evidence supports a role for phosphatase and tensin homologue (PTEN)-T cell leukaemia 1 (Tcl1) signalling deregulation in hepatocarcinogenesis.
  
  
  OBJECTIVE
  To determine the molecular and biochemical mechanisms by which the PTEN/Tcl1 axis regulates the pentose phosphate pathway (PPP) in hepatocellular carcinoma (HCC).
  
  
  METHODS
  We compared levels of PTEN and glucose-6-phosphate dehydrogenase (G6PD) mRNA in human HCC and healthy liver tissue. We measured PPP flux, glucose consumption, lactate production, nicotinamide adenine dinucleotide phosphate (NADPH) levels and lipid accumulation. We investigated the PTEN/Tcl1 axis using molecular biology, biochemistry and mass spectrometry analysis. We assessed proliferation, apoptosis and senescence in cultured cells, and tumour formation in mice.
  
  
  RESULTS
  We showed that PTEN inhibited the PPP pathway in human liver tumours. Through the PPP, PTEN suppressed glucose consumption and biosynthesis. Mechanistically, the PTEN protein bound to G6PD, the first and rate-limiting enzyme of the PPP and prevented the formation of the active G6PD dimer. Tcl1, a coactivator for Akt, reversed the effects of PTEN on biosynthesis. Tcl1 promoted G6PD activity and also increased G6PD pre-mRNA splicing and protein expression in a heterogeneous nuclear ribonucleoprotein (hnRNPK)-dependent manner. PTEN also formed a complex with hnRNPK, which inhibited G6PD pre-mRNA splicing. Moreover, PTEN inactivated Tcl1 via glycogen synthase kinase-3β (GSK3β)-mediated phosphorylation. Importantly, Tcl1 knockdown enhanced the sensitivity of HCC to sorafenib, whereas G6PD knockdown inhibited hepatocarcinogenesis.
  
  
  CONCLUSIONS
  These results establish the counteraction between PTEN and Tcl1 as a key mechanism that regulates the PPP and suggest that targeting the PTEN/Tcl1/hnRNPK/G6PD axis could open up possibilities for therapeutic intervention and improve the prognosis of patients with HCC.
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Xuehui
authors.initials: X
authors.lastname: Hong
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Cardiovascular Medicine and Department of Emergence, Baoan Hospital, Southern Medical University, ShenZhen, China.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Song
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Tongsen
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jiabei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Gerontology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Qi
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Song
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, University of Medicine & Dentistry of New Jersey, New Brunswick, New Jersey, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010427:Pentose Phosphate Pathway / Q000502:physiology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics*; D012326:RNA Splicing; D012261:Ribonucleoproteins / Q000378:metabolism*
chemical_list: D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D011518:Proto-Oncogene Proteins; D012322:RNA Precursors; D012261:Ribonucleoproteins; C090851:TCL1A protein, human; C072074:HNRNPK protein, human; D005954:Glucosephosphate Dehydrogenase; D006006:Glycogen Synthase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D005947:Glucose
keywords: GLUCOSE METABOLISM; HEPATOCELLULAR CARCINOMA; LIVER METABOLISM; MOLECULAR BIOLOGY; MOLECULAR MECHANISMS