CoChat
Sign Up
Cited by 49Mechanisms of cancer metastasisLung Cancer Research StudiesHeat shock proteins research

Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer

Open access
Xiong, Yuanping, He, Leilei, Shay, Chloe, Lang, Liwei, Loveless, Jenni, Yu, Jieqing, Chemmalakuzhy, Ron, Jiang, Hongqun +2 more·2019·Journal of Experimental & Clinical Cancer Research
DOI 10.1186/s13046-019-1124-0PMC PMC6417146
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized. METHODS: Genetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis. RESULTS: Nck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells. CONCLUSIONS: Our insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.

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/s13046-019-1124-0

Cites

3 of 3 references verified0 citation errors · 0 not checkable

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 HEM2-containing WRC is associated with tumor progression and metastasis in melanoma, non-small cell lung cancer, and breast cancer.

    “the HEM2-containing WRC has been broadly implicated in non-immunological diseases and is especially associated with tumor progression and metastasis in melanoma, non-small cell lung cancer, and breast cancer [46–48].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [47]

Self-check

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

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

Cites

Flagged first, then by citations

Research works printed but not linked: 29

  1. [1]Siegel RL Miller KD Jemal A Cancer statistics, 2016 CA Cancer J Clin 2016 66 1 7 30 26742998
  2. [2]Yu JL Simmons C Victor JC Han D Hogeveen S Leighl N Verma S Impact of new chemotherapeutic and targeted agents on survival in stage IV non-small cell lung cancer Oncologist. 2011 16 9 1307 1315 21835896 PMC3228167
  3. [3]Popper HH Progression and metastasis of lung cancer Cancer Metastasis Rev 2016 35 1 75 91 27018053 PMC4821869
  4. [4]Nakao S Platek A Hirano S Takeichi M Contact-dependent promotion of cell migration by the OL-protocadherin-Nap1 interaction J Cell Biol 2008 182 2 395 410 18644894 PMC2483522
  5. [5]Teng Y Qin HY Bahassan A Bendzunas NG Kennedy EJ Cowell JK The WASF3-NCKAP1-CYFIP1 Complex Is Essential for Breast Cancer Metastasis Cancer Res 2016 76 17 5133 5142 27432794 PMC5010469
  6. [6]Teng Y Bahassan A Dong DY Hanold LE Ren XO Kennedy EJ Cowell JK Targeting the WASF3-CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion Cancer Res 2016 76 4 965 973 26676744 PMC4828974
  7. [7]Frank M Egile C Dyachok J Djakovic S Nolasco M Li R Smith LG Activation of Arp2/3 complex-dependent actin polymerization by plant proteins distantly related to Scar/WAVE Proc Natl Acad Sci U S A 2004 101 46 16379 16384 15534215 PMC528980
  8. [8]Beli P Mascheroni D Xu DL Innocenti M WAVE and Arp2/3 jointly inhibit filopodium formation by entering into a complex with mDia2 Nat Cell Biol 2008 10 7 849 857 18516090
  9. [9]Steffen A Rottner K Ehinger J Innocenti M Scita G Wehland J Stradal TEB Sra-1 and Nap1 link Rac to actin assembly driving lamellipodia formation EMBO J 2004 23 4 749 759 14765121 PMC380996
  10. [10]Watanabe T Sato T Amano T Kawamura Y Kawamura N Kawaguchi H Yamashita N Kurihara H Nakaoka T Dnm3os, a Non-Coding RNA, Is Required for Normal Growth and Skeletal Development in Mice Dev Dyn 2008 237 12 3738 3748 18985749
  11. [11]Lomakina ME Lallemand F Vacher S Molinie N Dang I Cacheux W Chipysheva TA Ermilova VD de Koning L Dubois T Arpin downregulation in breast cancer is associated with poor prognosis Br J Cancer 2016 114 5 545 553 26867158 PMC4782208
  12. [12]Teng Y Zhao H Gao L Zhang W Shull AY Shay C FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4–GSK3β–Nrf2 Signaling Cancer Res 2017 77 22 6215 6225 28951455
  13. [13]Lang LW, Shay C, Zhao XD, Teng Y. Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics. J Exp Clin Cancer Res. 2017;36. PMC5568197 28830537
  14. [14]Teng Y, Cai YF, Pi WH, Gao LX, Shay C. Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity. J Hematol Oncol. 2017;10. PMC5469135 28606127
  15. [16]Iniesta P Moran A De Juan C Gomez A Hernando F Garcia-Aranda C Frias C Diaz-Lopez A Rodriguez-Jimenez FJ Balibrea JL Biological and clinical significance of MMP-2, MMP-9, TIMP-1 and TIMP-2 in non-small cell lung cancer Oncol Rep 2007 17 1 217 223 17143501
  16. [17]Tsutsumi S Beebe K Neckers L Impact of heat-shock protein 90 on cancer metastasis Future Oncol 2009 5 5 679 688 19519207 PMC2714685
  17. [18]Teng Y Ngoka L Mei Y Lesoon L Cowell JK HSP90 and HSP70 Proteins Are Essential for Stabilization and Activation of WASF3 Metastasis-promoting Protein J Biol Chem 2012 287 13 10051 10059 22315230 PMC3323057
  18. [19]Anazi S Maddirevula S Salpietro V Asi YT Alsahli S Alhashem A Shamseldin HE AlZahrani F Patel N Ibrahim N Expanding the genetic heterogeneity of intellectual disability Hum Genet 2017 136 11–12 1419 1429 28940097
  19. [20]Xiao CZ Wei W Guo ZX Zhang MY Zhang YF Wang JH Shi M Wang HY Guo RP MicroRNA-34c-3p promotes cell proliferation and invasion in hepatocellular carcinoma by regulation of NCKAP1 expression J Cancer Res Clin Oncol 2017 143 2 263 273 27704267 PMC11819091
  20. [21]Koga F Xu WP Karpova TS McNally JG Baron R Neckers L Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation Proc Natl Acad Sci U S A 2006 103 30 11318 11322 16844778 PMC1544084
  21. [22]Neckers L Workman P Hsp90 molecular chaperone inhibitors: Are we there yet? Clin Cancer Res 2012 18 1 64 76 22215907 PMC3252205
  22. [24]Sreedhar AS Kalmár E Csermely P Shen YF Hsp90 isoforms: functions, expression and clinical importance FEBS Lett 2004 562 1–3 11 15 15069952
  23. [26]Biaoxue R Xiling J Shuanying Y Wei Z Xiguang C Jinsui W Min Z Upregulation of Hsp90-beta and annexin A1 correlates with poor survival and lymphatic metastasis in lung cancer patients J Exp Clin Cancer Res 2012 31 70 22929401 PMC3444906
  24. [27]Barrott JJ Haystead TA Hsp90, an unlikely ally in the war on cancer FEBS J 2013 280 6 1381 1396 23356585 PMC3815692
  25. [28]Cedrés S Felip E Cruz C Martinez de Castro A Pardo N Navarro A Martinez-Marti A Remon J Zeron-Medina J Balmaña J Llop-Guevara A Activity of HSP90 Inhibiton in a Metastatic Lung Cancer Patient With a Germline BRCA1 Mutation J Natl Cancer Inst 2018 110 8 914 917 29529211 PMC6093313
  26. [29]Lee JH Kang KW Kim JE Hwang SW Park JH Kim SH Ji JH Kim TG Nam HY Roh MS Differential expression of heat shock protein 90 isoforms in small cell lung cancer Int J Clin Exp Pathol 2015 8 8 9487 9493 26464709 PMC4583941
  27. [30]Kurisu S Takenawa T WASP and WAVE family proteins: Friends or foes in cancer invasion? Cancer Sci 2010 101 10 2093 2104 20707804 PMC11158077
  28. [31]Teng Y Ren X Li H Shull A Kim J Cowell JK Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein Oncogene. 2016 35 3 333 343 25823022 PMC4828935
  29. [32]Teng Y Liu MY Cowell JK Functional interrelationship between the WASF3 and KISS1 metastasis-associated genes in breast cancer cells Int J Cancer 2011 129 12 2825 2835 21544801 PMC3154992

Cited by

Sorted by citations

Authors
Xiong, Y., He, L., Shay, C., Lang, L., Loveless, J., Yu, J., Chemmalakuzhy, R., Jiang, H., Liu, M., & Teng, Y.
Affiliations
  • Augusta University (US)
  • Emory University (US)
  • First Affiliated Hospital of Nanchang University (CN)
  • Chongqing Medical University (CN)
Corresponding author
Teng, Yong
ORCID
Venue
Journal of Experimental & Clinical Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2019-03-11
Volume
38
Issue
1
Pages
122-122
ISSN
  • 0392-9078 (ISSN-L)
  • 1756-9966
DOI
10.1186/s13046-019-1124-0
PMC
PMC6417146
OpenAlex
W2939668854
Cited by
49
References
3
Citations by year
2026: 2 · 2025: 3 · 2024: 8 · 2023: 11 · 2022: 10 · 2021: 7 · 2020: 5 · 2019: 3
FWCI
2.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Augusta University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
NCKAP1, HSP90, non-small cell lung cancer, metastasis, tumor invasion, MMP-9, MMP-2, epithelial-mesenchymal transition, protein-protein interaction, protein stabilization, molecular chaperones, therapeutic target
MeSH terms
Animals, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Neoplasm Metastasis, HSP90 Heat-Shock Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Mice, Gene Knockdown Techniques

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