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Vacuolar protein sorting 4B, an ATPase protein positively regulates the progression of NSCLC via promoting cell division

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Abstract

Vacuolar protein sorting 4B (VPS4B), a member of ATPase family proteins, plays a crucial role in lysosome-dependent degradation. Recently, it was found that VPS4B could negatively regulate breast cancer progression through promoting lysosomal-dependent degradation for EGFR. Nevertheless, other studies found that VPS4B was also essential for cell division and mitosis through insuring the maintenance of centrosome and spindle assembly. Thus, the role of VPS4B in cancer biology remains under debate. In this study, we analyzed the clinical significance of VPS4B in NSCLC. The expression of VPS4B was evaluated by Western blot in 8 paired fresh NSCLC tissues and immunohistochemistry on 105 paraffin-embedded slices. VPS4B was highly expressed in NSCLC and significantly associated with NSCLCs tumor size, histological differentiation, clinical stage and Ki-67. Besides, high VPS4B expression was an independent prognostic factor for NSCLC patients’ poor survival. To determine whether VPS4B could regulate the proliferation of NSCLC cells, we knocked down the expression of VPS4B and analyzed the proliferation of A549 NSCLC cells using Western blot, CCK8 and flow cytometry assays, which together indicated that loss of VPS4B could inhibit cell cycle progress. These data suggest that VPS4B may promote the progression of NSCLC and be a biotarget for NSCLCs therapy.

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References

  1. Ji XD, Li G, Feng YX, Zhao JS, Li JJ, Sun ZJ, Shi S, Deng YZ, Xu JF, Zhu YQ et al (2011) EphB3 is overexpressed in non-small-cell lung cancer and promotes tumor metastasis by enhancing cell survival and migration. Cancer Res 71(3):1156–1166

    Article  PubMed  CAS  Google Scholar 

  2. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300

    Article  PubMed  Google Scholar 

  3. Rom WN, Hay JG, Lee TC, Jiang Y, Tchou-Wong KM (2000) Molecular and genetic aspects of lung cancer. Am J Respir Crit Care Med 161(4 Pt 1):1355–1367

    Article  PubMed  CAS  Google Scholar 

  4. Geradts J, Fong KM, Zimmerman PV, Maynard R, Minna JD (1999) Correlation of abnormal RB, p16ink4a, and p53 expression with 3p loss of heterozygosity, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers. Clin Cancer Res 5(4):791–800

    PubMed  CAS  Google Scholar 

  5. Ohsaki Y, Sugimoto Y, Suzuki M, Hosokawa H, Yoshimori T, Davies JP, Ioannou YA, Vanier MT, Ohno K, Ninomiya H (2006) Cholesterol depletion facilitates ubiquitylation of NPC1 and its association with SKD1/Vps4. J Cell Sci 119(Pt 13):2643–2653

    Article  PubMed  CAS  Google Scholar 

  6. Liao Z, Thomas SN, Wan Y, Lin HH, Ann DK, Yang AJ (2013) An internal standard-assisted synthesis and degradation proteomic approach reveals the potential linkage between vps4b depletion and activation of fatty acid beta-oxidation in breast cancer cells. Int J Proteomics 2013:291415

    PubMed  Google Scholar 

  7. Gan X, Gould SJ (2011) Identification of an inhibitory budding signal that blocks the release of HIV particles and exosome/microvesicle proteins. Mol Biol Cell 22(6):817–830

    Article  PubMed  CAS  Google Scholar 

  8. Watanabe R, Lamb RA (2010) Influenza virus budding does not require a functional AAA+ATPase, VPS4. Virus Res 153(1):58–63

    Article  PubMed  CAS  Google Scholar 

  9. Bishop N, Woodman P (2000) ATPase-defective mammalian VPS4 localizes to aberrant endosomes and impairs cholesterol trafficking. Mol Biol Cell 11(1):227–239

    Article  PubMed  CAS  Google Scholar 

  10. Bishop N, Horman A, Woodman P (2002) Mammalian class E vps proteins recognize ubiquitin and act in the removal of endosomal protein-ubiquitin conjugates. J Cell Biol 157(1):91–101

    Article  PubMed  CAS  Google Scholar 

  11. Zhang B, Chang A, Kjeldsen TB, Arvan P (2001) Intracellular retention of newly synthesized insulin in yeast is caused by endoproteolytic processing in the Golgi complex. J Cell Biol 153(6):1187–1198

    Article  PubMed  CAS  Google Scholar 

  12. Lin HH, Li X, Chen JL, Sun X, Cooper FN, Chen YR, Zhang W, Chung Y, Li A, Cheng CT et al (2012) Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia. Mol Cell Biol 32(6):1124–1138

    Article  PubMed  CAS  Google Scholar 

  13. Watanabe T, Sorensen EM, Naito A, Schott M, Kim S, Ahlquist P (2007) Involvement of host cellular multivesicular body functions in hepatitis B virus budding. Proc Natl Acad Sci USA 104(24):10205–10210

    Article  PubMed  CAS  Google Scholar 

  14. Urata S, Yokosawa H, Yasuda J (2007) Regulation of HTLV-1 Gag budding by Vps4A, Vps4B, and AIP1/Alix. Virol J 4:66

    Article  PubMed  Google Scholar 

  15. Morita E, Colf LA, Karren MA, Sandrin V, Rodesch CK, Sundquist WI (2010) Human ESCRT-III and VPS4 proteins are required for centrosome and spindle maintenance. Proc Natl Acad Sci USA 107(29):12889–12894

    Article  PubMed  CAS  Google Scholar 

  16. Lafaurie-Janvore J, Maiuri P, Wang I, Pinot M, Manneville JB, Betz T, Balland M, Piel M (2013) ESCRT-III assembly and cytokinetic abscission are induced by tension release in the intercellular bridge. Science 339(6127):1625–1629

    Article  PubMed  CAS  Google Scholar 

  17. Carlton JG, Caballe A, Agromayor M, Kloc M, Martin-Serrano J (2012) ESCRT-III governs the Aurora B-mediated abscission checkpoint through CHMP4C. Science 336(6078):220–225

    Article  PubMed  CAS  Google Scholar 

  18. Hang Q, Fei M, Hou S, Ni Q, Lu C, Zhang G, Gong P, Guan C, Huang X, He S (2012) Expression of Spy1 protein in human non-Hodgkin’s lymphomas is correlated with phosphorylation of p27 Kip1 on Thr187 and cell proliferation. Med Oncol 29(5):3504–3514

    Article  PubMed  CAS  Google Scholar 

  19. Wang F, Wang Y, Yu X, Yang D, Wang Z, Lu C, Yuan Z, Xiao M, Shen A (2009) Significance of Jab1 expression in human esophageal squamous cell carcinoma. J Clin Gastroenterol 43(6):520–526

    Article  PubMed  CAS  Google Scholar 

  20. Yao H, Zhang Z, Xiao Z, Chen Y, Li C, Zhang P, Li M, Liu Y, Guan Y, Yu Y et al (2009) Identification of metastasis associated proteins in human lung squamous carcinoma using two-dimensional difference gel electrophoresis and laser capture microdissection. Lung Cancer 65(1):41–48

    Article  PubMed  Google Scholar 

  21. Zu YF, Wang XC, Chen Y, Wang JY, Liu X, Li X, Li CW, Xie YC, Luo Y, Shang XQ et al (2012) Thyroid transcription factor 1 represses the expression of Ki-67 and induces apoptosis in non-small cell lung cancer. Oncol Rep 28(5):1544–1550

    PubMed  CAS  Google Scholar 

  22. Takeda H, Takigawa N, Ohashi K, Minami D, Kataoka I, Ichihara E, Ochi N, Tanimoto M, Kiura K (2013) Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. Exp Cell Res 319(4):417–423

    Article  PubMed  CAS  Google Scholar 

  23. Kumar MS, Hancock DC, Molina-Arcas M, Steckel M, East P, Diefenbacher M, Armenteros-Monterroso E, Lassailly F, Matthews N, Nye E et al (2012) The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 149(3):642–655

    Article  PubMed  CAS  Google Scholar 

  24. Fujita H, Yamanaka M, Imamura K, Tanaka Y, Nara A, Yoshimori T, Yokota S, Himeno M (2003) A dominant negative form of the AAA ATPase SKD1/VPS4 impairs membrane trafficking out of endosomal/lysosomal compartments: class E vps phenotype in mammalian cells. J Cell Sci 116(Pt 2):401–414

    Article  PubMed  CAS  Google Scholar 

  25. Yoshimori T, Yamagata F, Yamamoto A, Mizushima N, Kabeya Y, Nara A, Miwako I, Ohashi M, Ohsumi M, Ohsumi Y (2000) The mouse SKD1, a homologue of yeast Vps4p, is required for normal endosomal trafficking and morphology in mammalian cells. Mol Biol Cell 11(2):747–763

    Article  PubMed  CAS  Google Scholar 

  26. Mizuno E, Iura T, Mukai A, Yoshimori T, Kitamura N, Komada M (2005) Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes. Mol Biol Cell 16(11):5163–5174

    Article  PubMed  CAS  Google Scholar 

  27. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137

    Article  PubMed  CAS  Google Scholar 

  28. Saksena S, Sun J, Chu T, Emr SD (2007) ESCRTing proteins in the endocytic pathway. Trends Biochem Sci 32(12):561–573

    Article  PubMed  CAS  Google Scholar 

  29. Carlton JG, Martin-Serrano J (2007) Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science 316(5833):1908–1912

    Article  PubMed  CAS  Google Scholar 

  30. Srsen V, Merdes A (2006) The centrosome and cell proliferation. Cell Div 1:26

    Article  PubMed  Google Scholar 

  31. Vermeulen K, Van Bockstaele DR, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36(3):131–149

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Natural Science Foundation of China (No. 81272708).

Conflict of interest

We declare no conflict of interest.

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Correspondence to Runzhou Ni or Guoxin Mao.

Additional information

Yifei Liu and Liting Lv contributed equally to this study.

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Liu, Y., Lv, L., Xue, Q. et al. Vacuolar protein sorting 4B, an ATPase protein positively regulates the progression of NSCLC via promoting cell division. Mol Cell Biochem 381, 163–171 (2013). https://doi.org/10.1007/s11010-013-1699-2

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  • DOI: https://doi.org/10.1007/s11010-013-1699-2

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