CoChat
Sign Up
Cited by 53Pancreatic and Hepatic Oncology ResearchPancreatitis Pathology and TreatmentSignaling Pathways in Disease

PIM-1 contributes to the malignancy of pancreatic cancer and displays diagnostic and prognostic value

Open access
Xu, Jianwei, Xiong, Guangbing, Cao, Zhe, Huang, Hua, Wang, Tianxiao, You, Lei, Zhou, Li, Zheng, Lianfang +3 more·2016·Journal of Experimental & Clinical Cancer Research
DOI 10.1186/s13046-016-0406-zPMC PMC5011911
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: The effects of PIM-1 on the progression of pancreatic cancer remain unclear, and the prognostic value of PIM-1 levels in tissues is controversial. Additionally, the expression levels and clinical value of PIM-1 in plasma have not been reported. METHODS: The effects of PIM-1 on biological behaviours were analysed. PIM-1 levels in tissues and plasma were detected, and the clinical value was evaluated. RESULTS: We found that PIM-1 knockdown in pancreatic cancer cells suppressed proliferation, induced cell cycle arrest, enhanced apoptosis, resensitized cells to gemcitabine and erlotinib treatment, and inhibited ABCG2 and EZH2 mRNA expression. Our results indicated that PIM-1 and the EGFR pathway formed a positive feedback loop. We also found that PIM-1 expression in pancreatic cancer tissues was significantly upregulated and that a high level of expression was negatively associated with prognosis (P = 0.025, hazard ratio [HR] =2.113, 95 % confidence interval: 1.046-4.266). Additionally, we found that plasma PIM-1 levels in patients with pancreatic cancer were significantly increased and could be used in the diagnosis of pancreatic cancer. High plasma PIM-1 expression was an independent adverse prognostic factor for pancreatic cancer (P = 0.037, HR = 1.87, 95 % CI: 1.04-3.35). CONCLUSION: Our study suggests that PIM-1 contributes to malignancy and has diagnostic and prognostic value in pancreatic cancer.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s13046-016-0406-z

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The IL-6-STAT3-Pim kinase axis is involved in the development and cell growth of pancreatic cancer.

    “The IL-6–STAT3–Pim kinase axis is involved in the development and cell growth of pancreatic cancer (128, 129).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [129]

    The Discussion says PIM kinases contribute to pancreatic cancer development and progression, and reports that PIM-1 knockdown inhibited cancer-cell proliferation. It also lists increased phosphorylated STAT3 as a possible effect of PIM-3. Neither the Discussion nor a search for IL-6 supports the specific IL-6–STAT3–Pim kinase axis claimed. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 46 · Cited by 53

Research works printed but not linked: 45

  1. [1]Siegel R Ma J Zou Z Jemal A Cancer statistics, 2014 CA Cancer J Clin 2014 64 1 9 29 10.3322/caac.21208 24399786 · DOI · Paper page
  2. [2]Wang Z Li Y Ahmad A Banerjee S Azmi AS Kong D Sarkar FH Pancreatic cancer: understanding and overcoming chemoresistance Nat Rev Gastroenterol Hepatol 2011 8 1 27 33 10.1038/nrgastro.2010.188 21102532 · DOI
  3. [3]Gao Y Zhu Y Zhang Z Zhang C Huang X Yuan Z Clinical significance of pancreatic circulating tumor cells using combined negative enrichment and immunostaining-fluorescence in situ hybridization J Exp Clin Cancer Res 2016 35 66 10.1186/s13046-016-0340-0 27066900 PMC4828870 · DOI
  4. [4]Liu Q Li Y Niu Z Zong Y Wang M Yao L Lu Z Liao Q Zhao Y Atorvastatin (Lipitor) attenuates the effects of aspirin on pancreatic cancerogenesis and the chemotherapeutic efficacy of gemcitabine on pancreatic cancer by promoting M2 polarized tumor associated macrophages J Exp Clin Cancer Res 2016 35 33 10.1186/s13046-016-0304-4 26879926 PMC4754966 · DOI
  5. [5]Blanco-Aparicio C Carnero A Pim kinases in cancer: diagnostic, prognostic and treatment opportunities Biochem Pharmacol 2013 85 5 629 43 10.1016/j.bcp.2012.09.018 23041228 · DOI
  6. [6]Xu D Allsop SA Witherspoon SM Snider JL Yeh JJ Fiordalisi JJ White CD Williams D Cox AD Baines AT The oncogenic kinase Pim-1 is modulated by K-Ras signaling and mediates transformed growth and radioresistance in human pancreatic ductal adenocarcinoma cells Carcinogenesis 2011 32 4 488 95 10.1093/carcin/bgr007 21262926 PMC3066419 · DOI
  7. [7]Xu D Cobb MG Gavilano L Witherspoon SM Williams D White CD Taverna P Bednarski BK Kim HJ Baldwin AS Inhibition of oncogenic Pim-3 kinase modulates transformed growth and chemosensitizes pancreatic cancer cells to gemcitabine Cancer Biol Ther 2013 14 6 492 501 10.4161/cbt.24343 23760491 PMC3813565 · DOI
  8. [8]Yamanaka Y Friess H Kobrin MS Buchler M Beger HG Korc M Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness Anticancer Res 1993 13 3 565 9 8317885
  9. [9]Lemoine NR Hughes CM Barton CM Poulsom R Jeffery RE Kloppel G Hall PA Gullick WJ The epidermal growth factor receptor in human pancreatic cancer J Pathol 1992 166 1 7 12 10.1002/path.1711660103 1538276 · DOI
  10. [10]Nedaeinia R Avan A Manian M Salehi R Ghayour-Mobarhan M EGFR as a potential target for the treatment of pancreatic cancer: dilemma and controversies Curr Drug Targets 2014 15 14 1293 301 10.2174/1389450115666141125123003 25429712 · DOI
  11. [11]Reiser-Erkan C Erkan M Pan Z Bekasi S Giese NA Streit S Michalski CW Friess H Kleeff J Hypoxia-inducible proto-oncogene Pim-1 is a prognostic marker in pancreatic ductal adenocarcinoma Cancer Biol Ther 2008 7 9 1352 9 10.4161/cbt.7.9.6418 18708761 · DOI
  12. [12]Matsuda Y Kure S Ishiwata T Nestin and other putative cancer stem cell markers in pancreatic cancer Med Mol Morphol 2012 45 2 59 65 10.1007/s00795-012-0571-x 22718289 · DOI
  13. [13]van Vlerken LE Kiefer CM Morehouse C Li Y Groves C Wilson SD Yao Y Hollingsworth RE Hurt EM EZH2 is required for breast and pancreatic cancer stem cell maintenance and can be used as a functional cancer stem cell reporter Stem Cells Transl Med 2013 2 1 43 52 10.5966/sctm.2012-0036 23283488 PMC3659740 · DOI
  14. [14]Xu J Zhang T Wang T You L Zhao Y PIM kinases: an overview in tumors and recent advances in pancreatic cancer Future Oncol 2014 10 5 865 76 10.2217/fon.13.229 24799066 · DOI
  15. [15]Li YY Popivanova BK Nagai Y Ishikura H Fujii C Mukaida N Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in human pancreatic cancer and phosphorylates bad to block bad-mediated apoptosis in human pancreatic cancer cell lines Cancer Res 2006 66 13 6741 7 10.1158/0008-5472.CAN-05-4272 16818649 · DOI
  16. [16]Liang C Yu XJ Guo XZ Sun MH Wang Z Song Y Ni QX Li HY Mukaida N Li YY MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine Oncotarget 2015 6 16 14440 55 10.18632/oncotarget.3885 25971209 PMC4546478 · DOI
  17. [17]Chen XY Wang Z Li B Zhang YJ Li YY Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells Biochem Biophys Res Commun 2016 473 1 296 302 10.1016/j.bbrc.2016.03.099 27016481 · DOI
  18. [18]Wang C Li HY Liu B Huang S Wu L Li YY Pim-3 promotes the growth of human pancreatic cancer in the orthotopic nude mouse model through vascular endothelium growth factor J Surg Res 2013 185 2 595 604 10.1016/j.jss.2013.06.004 23845873 · DOI
  19. [19]Liu B Wang Z Li HY Zhang B Ping B Li YY Pim-3 promotes human pancreatic cancer growth by regulating tumor vasculogenesis Oncol Rep 2014 31 6 2625 34 24789328
  20. [20]Siu A Virtanen C Jongstra J PIM kinase isoform specific regulation of MIG6 expression and EGFR signaling in prostate cancer cells Oncotarget 2011 2 12 1134 44 10.18632/oncotarget.386 22193779 PMC3282072 · DOI
  21. [21]Grundler R Brault L Gasser C Bullock AN Dechow T Woetzel S Pogacic V Villa A Ehret S Berridge G Dissection of PIM serine/threonine kinases in FLT3-ITD-induced leukemogenesis reveals PIM1 as regulator of CXCL12-CXCR4-mediated homing and migration J Exp Med 2009 206 9 1957 70 10.1084/jem.20082074 19687226 PMC2737164 · DOI
  22. [22]Mochizuki T Kitanaka C Noguchi K Muramatsu T Asai A Kuchino Y Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway J Biol Chem 1999 274 26 18659 66 10.1074/jbc.274.26.18659 10373478 · DOI
  23. [23]Bachmann M Kosan C Xing PX Montenarh M Hoffmann I Moroy T The oncogenic serine/threonine kinase Pim-1 directly phosphorylates and activates the G2/M specific phosphatase Cdc25C Int J Biochem Cell Biol 2006 38 3 430 43 10.1016/j.biocel.2005.10.010 16356754 · DOI
  24. [24]Wang Z Bhattacharya N Mixter PF Wei W Sedivy J Magnuson NS Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase Biochim Biophys Acta 2002 1593 1 45 55 10.1016/S0167-4889(02)00347-6 12431783 · DOI
  25. [25]Morishita D Katayama R Sekimizu K Tsuruo T Fujita N Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels Cancer Res 2008 68 13 5076 85 10.1158/0008-5472.CAN-08-0634 18593906 · DOI
  26. [26]Aho TL Sandholm J Peltola KJ Mankonen HP Lilly M Koskinen PJ Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site FEBS Lett 2004 571 1–3 43 9 10.1016/j.febslet.2004.06.050 15280015 · DOI · Paper page
  27. [27]Gu JJ Wang Z Reeves R Magnuson NS PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis Oncogene 2009 28 48 4261 71 10.1038/onc.2009.276 19749799 PMC2788665 · DOI
  28. [28]Zhang F Beharry ZM Harris TE Lilly MB Smith CD Mahajan S Kraft AS PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells Cancer Biol Ther 2009 8 9 846 53 10.4161/cbt.8.9.8210 19276681 · DOI
  29. [29]Xie Y Xu K Linn DE Yang X Guo Z Shimelis H Nakanishi T Ross DD Chen H Fazli L The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells J Biol Chem 2008 283 6 3349 56 10.1074/jbc.M707773200 18056989 · DOI
  30. [30]Xie Y Burcu M Linn DE Qiu Y Baer MR Pim-1 kinase protects P-glycoprotein from degradation and enables its glycosylation and cell surface expression Mol Pharmacol 2010 78 2 310 8 10.1124/mol.109.061713 20460432 PMC11037423 · DOI
  31. [31]Niero EL Rocha-Sales B Lauand C Cortez BA de Souza MM Rezende-Teixeira P Urabayashi MS Martens AA Neves JH Machado-Santelli GM The multiple facets of drug resistance: one history, different approaches J Exp Clin Cancer Res 2014 33 37 10.1186/1756-9966-33-37 24775603 PMC4041145 · DOI
  32. [32]Peltola K Hollmen M Maula SM Rainio E Ristamaki R Luukkaa M Sandholm J Sundvall M Elenius K Koskinen PJ Pim-1 kinase expression predicts radiation response in squamocellular carcinoma of head and neck and is under the control of epidermal growth factor receptor Neoplasia 2009 11 7 629 36 10.1593/neo.81038 19568408 PMC2697349 · DOI
  33. [33]Shen J Xia W Khotskaya YB Huo L Nakanishi K Lim SO Du Y Wang Y Chang WC Chen CH EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2 Nature 2013 497 7449 383 7 10.1038/nature12080 23636329 PMC3717558 · DOI
  34. [34]Arteaga CL The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia J Clin Oncol 2001 19 18 Suppl 32s 40 11560969
  35. [35]Foley J Nickerson NK Nam S Allen KT Gilmore JL Nephew KP Riese DJ 2nd EGFR signaling in breast cancer: bad to the bone Semin Cell Dev Biol 2010 21 9 951 60 10.1016/j.semcdb.2010.08.009 20813200 PMC2991402 · DOI
  36. [36]Tong Y Stewart KD Thomas S Przytulinska M Johnson EF Klinghofer V Leverson J McCall O Soni NB Luo Y Isoxazolo[3,4-b]quinoline-3,4(1H,9H)-diones as unique, potent and selective inhibitors for Pim-1 and Pim-2 kinases: chemistry, biological activities, and molecular modeling Bioorg Med Chem Lett 2008 18 19 5206 8 10.1016/j.bmcl.2008.08.079 18790640 · DOI
  37. [37]Blanco-Aparicio C Collazo AM Oyarzabal J Leal JF Albaran MI Lima FR Pequeno B Ajenjo N Becerra M Alfonso P Pim 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition Cancer Lett 2011 300 2 145 53 10.1016/j.canlet.2010.09.016 21051136 · DOI
  38. [38]Yang Q Chen LS Neelapu SS Gandhi V Combination of Pim kinase inhibitor SGI-1776 and bendamustine in B-cell lymphoma Clin Lymphoma Myeloma Leuk 2013 13 Suppl 2 S355 62 10.1016/j.clml.2013.05.024 24290221 PMC3951504 · DOI
  39. [39]Keeton EK McEachern K Dillman KS Palakurthi S Cao Y Grondine MR Kaur S Wang S Chen Y Wu A AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia Blood 2014 123 6 905 13 10.1182/blood-2013-04-495366 24363397 PMC3916880 · DOI
  40. [40]Natarajan K Bhullar J Shukla S Burcu M Chen ZS Ambudkar SV Baer MR The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1-dependent and -independent mechanisms Biochem Pharmacol 2013 85 4 514 24 10.1016/j.bcp.2012.12.006 23261525 PMC3821043 · DOI
  41. [41]Hospital MA Green AS Lacombe C Mayeux P Bouscary D Tamburini J The FLT3 and Pim kinases inhibitor SGI-1776 preferentially target FLT3-ITD AML cells Blood 2012 119 7 1791 2 10.1182/blood-2011-11-393066 22343664 · DOI
  42. [42]Zemskova MY Song JH Cen B Cerda-Infante J Montecinos VP Kraft AS Regulation of prostate stromal fibroblasts by the PIM1 protein kinase Cell Signal 2015 27 1 135 46 10.1016/j.cellsig.2014.10.010 25451079 PMC4314374 · DOI
  43. [43]Santio NM Eerola SK Paatero I Yli-Kauhaluoma J Anizon F Moreau P Tuomela J Harkonen P Koskinen PJ Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts PLoS One 2015 10 6 10.1371/journal.pone.0130340 26075720 PMC4467846 · DOI
  44. [44]Peng YH Li JJ Xie FW Chen JF Yu YH Ouyang XN Liang HJ Expression of pim-1 in tumors, tumor stroma and tumor-adjacent mucosa co-determines the prognosis of colon cancer patients PLoS One 2013 8 10 10.1371/journal.pone.0076693 24116137 PMC3792018 · DOI
  45. [45]Liu HT Wang N Wang X Li SL Overexpression of Pim-1 is associated with poor prognosis in patients with esophageal squamous cell carcinoma J Surg Oncol 2010 102 6 683 8 10.1002/jso.21627 20544717 · DOI

Authors
Xu, J., Xiong, G., Cao, Z., Huang, H., Wang, T., You, L., Zhou, L., Zheng, L., Hu, Y., Zhang, T., & Zhao, Y.
Affiliations
  • Shandong University (CN)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Peking University Cancer Hospital (CN)
Corresponding author
  • Zhang, Taiping
  • Zhao, Yupei
ORCID
Venue
Journal of Experimental & Clinical Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2016-09-05
Volume
35
Issue
1
Pages
133-133
ISSN
  • 0392-9078 (ISSN-L)
  • 1756-9966
DOI
10.1186/s13046-016-0406-z
PMC
PMC5011911
OpenAlex
W2515382091
Cited by
53
References
46
Citations by year
2026: 2 · 2025: 4 · 2024: 2 · 2023: 10 · 2022: 8 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 1
FWCI
2.88
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Ministry of Science and Technology of the People's Republic of China (2014BAI09B11)
  • National Natural Science Foundation of China (No.81272484)
  • Natural Science Foundation of Beijing Municipality (No. 7132179)
  • National Program on Key Basic Research Project(973 Program) (No. 2014CB542300)
  • Research Special Fund for Public Welfare Industry of Health: the translational research of early diagnosis and comprehensive treatment in pancreatic cancer (No.201202007)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
PIM-1, pancreatic cancer, prognostic factors, diagnostic biomarkers, EGFR signaling, ABCG2, EZH2, gemcitabine resistance, erlotinib resistance, cell proliferation, apoptosis, cell cycle arrest, tumor malignancy
MeSH terms
Erlotinib Hydrochloride, ATP Binding Cassette Transporter, Subfamily G, Member 2, Enhancer of Zeste Homolog 2 Protein, Gemcitabine, Deoxycytidine, Female, Humans, Male, Neoplasm Proteins, Pancreatic Neoplasms, Prognosis, Signal Transduction, Survival Analysis, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-pim-1, Gene Knockdown Techniques, Cell Cycle Checkpoints

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review