title: PIM1 regulates glycolysis and promotes tumor progression in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is characteristically one of the most rapidly proliferating tumors which outgrows functional blood supply and results in regional oxygen deprivation. Overexpression of PIM1, a serine/threonine kinase, has been identified recently in human cancers. Knowledge on PIM1 in HCC is however, scarce. By immunohistochemical analysis on 56 human primary HCC samples, we observed overexpression of PIM1 in 39% of the cases. In two independent cohorts of paired primary and extra-hepatic metastatic HCC tissues, PIM1 expression was higher (p=0.002) in the extra-hepatic metastatic HCC tissues as compared with the corresponding primary HCCs. PIM1 was markedly up-regulated in multiple HCC cell lines in hypoxic condition (1% O2) versus normoxia (20% O2). Silencing of PIM1 suppressed HCC cell invasion in vitro as compared to non-target control, and decreased HCC cell proliferation in vitro and tumor growth and metastatic potential in vivo. Knockdown of PIM1 significantly reduced glucose uptake by HCC cells and was associated with decreased levels of p-AKT and key molecules in the glycolytic pathway. Taken together, PIM1 is up-regulated by hypoxia in HCC and promotes tumor growth and metastasis through facilitating cancer cell glycolysis. Targeting PIM1 may have potential role in the management of HCC.
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Carmen Oi-ning
authors.initials: CO
authors.lastname: Leung
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Carmen Chak-lui
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Dorothy Ngo-yin
authors.initials: DN
authors.lastname: Fan
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Alan Ka-lun
authors.initials: AK
authors.lastname: Kai
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Edmund Kwok-kwan
authors.initials: EK
authors.lastname: Tung
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Iris Ming-jing
authors.initials: IM
authors.lastname: Xu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Irene Oi-lin
authors.initials: IO
authors.lastname: Ng
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Regina Cheuk-lam
authors.initials: RC
authors.lastname: Lo
mesh_terms: D021581:Active Transport, Cell Nucleus; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C496634:PIM1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D046988:Proteasome Endopeptidase Complex
keywords: HCC; PIM1; metastasis
references.citation: Biochem Biophys Res Commun. 2001 Mar 2;281(3):663-9
references.pmid: 11237709
references.citation: Nature. 2001 Aug 23;412(6849):822-6
references.pmid: 11518967
references.citation: Cell. 2001 Oct 5;107(1):43-54
references.pmid: 11595184
references.citation: Cancer Res. 2004 Apr 1;64(7):2627-33
references.pmid: 15059920
references.citation: Cell. 1989 Feb 24;56(4):673-82
references.pmid: 2537153
references.citation: Br J Cancer Suppl. 1996 Jul;27:S247-51
references.pmid: 8763890
references.citation: Cancer Res. 1996 Dec 1;56(23):5522-8
references.pmid: 8968110
references.citation: Semin Radiat Oncol. 1998 Jul;8(3):143-50
references.pmid: 9634491
references.citation: J Endocrinol. 2004 Oct;183(1):145-54
references.pmid: 15525582
references.citation: J Biol Chem. 2004 Nov 12;279(46):48319-28
references.pmid: 15319445
references.citation: World J Gastroenterol. 2005 Mar 21;11(11):1705-8
references.pmid: 15786555
references.citation: Mol Cancer Res. 2005 Mar;3(3):170-81
references.pmid: 15798097
references.citation: Mol Cancer Ther. 2007 Jan;6(1):163-72
references.pmid: 17218638
references.citation: World J Gastroenterol. 2007 Jun 21;13(23):3176-82
references.pmid: 17589895
references.citation: Cell. 2007 Jun 29;129(7):1261-74
references.pmid: 17604717
references.citation: Mol Cancer Res. 2007 Sep;5(9):909-22
references.pmid: 17855660
references.citation: Nat Rev Cancer. 2008 Jan;8(1):51-6
references.pmid: 18046334
references.citation: Mol Cell. 2008 May 23;30(4):393-402
references.pmid: 18498744
references.citation: Cancer Cell. 2008 Jun;13(6):472-82
references.pmid: 18538731
references.citation: Cancer Res. 2008 Jul 1;68(13):5076-85
references.pmid: 18593906
references.citation: Nat Rev Cancer. 2008 Sep;8(9):705-13
references.pmid: 19143055
references.citation: J Clin Invest. 2009 Feb;119(2):362-75
references.pmid: 19147983
references.citation: Semin Cancer Biol. 2009 Feb;19(1):25-31
references.pmid: 19130886
references.citation: Am J Pathol. 2009 Apr;174(4):1544-52
references.pmid: 19286567
references.citation: Am J Pathol. 2009 Jul;175(1):400-11
references.pmid: 19528349
references.citation: Oncogene. 2009 Jul 16;28(28):2581-92
references.pmid: 19483729
references.citation: Exp Hematol. 2009 Nov;37(11):1284-94
references.pmid: 19703513
references.citation: Expert Opin Ther Targets. 2009 Dec;13(12):1411-27
references.pmid: 19874261
references.citation: Anticancer Res. 2009 Nov;29(11):4451-5
references.pmid: 20032391
references.citation: Curr Opin Genet Dev. 2010 Feb;20(1):51-6
references.pmid: 19942427
references.citation: Future Oncol. 2010 Sep;6(9):1461-78
references.pmid: 20919829
references.citation: Clin Cancer Res. 2010 Dec 15;16(24):5928-35
references.pmid: 20962028
references.citation: Nat Rev Cancer. 2011 Feb;11(2):85-95
references.pmid: 21258394
references.citation: Future Oncol. 2011 Oct;7(10):1149-67
references.pmid: 21992728
references.citation: Cell. 2012 Feb 3;148(3):399-408
references.pmid: 22304911
references.citation: Oncogene. 2012 Feb 16;31(7):918-28
references.pmid: 21743487
references.citation: Biochim Biophys Acta. 2012 Dec;1826(2):370-84
references.pmid: 22750268
references.citation: J Biol Chem. 2013 Feb 1;288(5):3048-58
references.pmid: 23209281
references.citation: Leukemia. 2014 Feb;28(2):293-301
references.pmid: 23748345
references.citation: Hepatology. 2014 Nov;60(5):1645-58
references.pmid: 25048396
references.citation: Cancer Lett. 2015 Jan 28;356(2 Pt A):156-64
references.pmid: 24732809