Tumor Biology

, Volume 37, Issue 4, pp 4849–4855 | Cite as

Predictive significance of combined LAPTM4B and VEGF expression in patients with cervical cancer

  • Fanling Meng
  • Shu Tan
  • Tianbo Liu
  • Hongtao Song
  • Ge Lou
Original Article


Lysosome-associated protein transmembrane 4ß-35 (LAPTM4B-35) is overexpressed in several solid malignancies. This study determines the expression level of LAPTM4B-35 in the cervical cancer during tumor development and progression. The present study investigated the clinicopathological significance of the coexpression of LAPTM4B-35 and VEGF in patients with cervical cancer. Immunohistochemistry was used to evaluate the expression of LAPTM4B-35 and VEGF in 62 cervical intraepithelial neoplasia (CIN) and 226 cervical carcinoma in comparison with 45 normal cervical specimens. The correlation of combined LAPTM4B-35 and VEGF with clinicopathologic characteristics was analyzed using a chi-squared test. Patient survival was determined using Kaplan–Meier method and log-rank test. A Cox regression analysis was performed to determine the prognostic significance of the factors. Combined LAPTM4B-35 and VEGF expression was significantly associated with FIGO stage (P = 0.014), tumor histologic grade (P = 0.033), lymph node metastasis (P = 0.045), and recurrence (P = 0.010). Kaplan–Meier survival analysis showed that patients with cervical cancer expressing both LAPTM4B-35 and VEGF exhibited both poor overall survival (OS) and disease-free survival (DFS) (P = 0.015 and P = 0.016, respectively). Cox analysis demonstrated that combined LAPTM4B-35 and VEGF expression was an independent factor for both OS and DFS (P = 0.015 and P = 0.016, respectively). Overexpression of LAPTM4B-35combined with positive VEGF expression may serve as a new biological marker to predict the prognosis of cervical carcinoma patients.


Lysosomal protein transmembrane 4 beta Vascular endothelial growth factor Immunohistochemistry Cervical carcinoma Prognosis 



We express our thanks to Dr. H-T Song for the evaluation procedures.

Compliance with ethical standards

Conflicts of interest


Grant support

This work was supported by grants of the National Natural Science Foundation of China (81201613), the Specialized Research Fund for the Doctoral Program of Higher Education (20122307120027), the Postdoctoral Foundation of Heilongjiang Province of China (LBH-Z11067), the scientific research project of Health Department of Heilongjiang Province (663), and the Haiyan Foundation of the Affiliated Tumor Hospital of Harbin Medical University/the Foundation of the Affiliated Tumor Hospital of Harbin Medical University (JJZ2011-04). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


  1. 1.
    de Sanjose S, Serrano B, Castellsague X, Brotons M, Munoz J, Bruni L, et al. Human papillomavirus (HPV) and related cancers in the global alliance for vaccines and immunization (GAVI) countries. A WHO/ICO HPV information centre report. Vaccine. 2012;30 Suppl 4:D1–D83. vi.PubMedGoogle Scholar
  2. 2.
    Hwang SJ, Shroyer KR. Biomarkers of cervical dysplasia and carcinoma. J Oncol. 2012;2012:507286.CrossRefPubMedGoogle Scholar
  3. 3.
    Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. Lancet. 2013;382(9895):889–99.CrossRefPubMedGoogle Scholar
  4. 4.
    Romanowski B. Long term protection against cervical infection with the human papillomavirus: review of currently available vaccines. Human vaccies. 2011;7(2):161–9.CrossRefGoogle Scholar
  5. 5.
    Shao GZ, Zhou RL, Zhang QY, Zhang Y, Liu JJ, Rui JA, et al. Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma. Oncogene. 2003;22(32):5060–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Yang H, Xiong F, Wei X, Yang Y, McNutt MA, Zhou R. Overexpression of LAPTM4B-35 promotes growth and metastasis of hepatocellular carcinoma in vitro and in vivo. Cancer Lett. 2010;294(2):236–44.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhou L, He XD, Yu JC, Zhou RL, Yang H, Qu Q, et al. Overexpression of LAPTM4B promotes growth of gallbladder carcinoma cells in vitro. Am J Surg. 2010;199(4):515–21.CrossRefPubMedGoogle Scholar
  8. 8.
    Liu X, Xiong F, Wei X, Yang H, Zhou R. LAPTM4B-35, a novel tetratransmembrane protein and its PPRP motif play critical roles in proliferation and metastatic potential of hepatocellular carcinoma cells. Cancer Sci. 2009;100(12):2335–40.CrossRefPubMedGoogle Scholar
  9. 9.
    Yang H, Xiong F, Qi R, Liu Z, Lin M, Rui J, et al. LAPTM4B-35 is a novel prognostic factor of hepatocellular carcinoma. J Surg Oncol. 2010;101(5):363–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhang H, Tian B, Yu H, Yao H, Gao Z. LAPTM4B-35 protein as a potential therapeutic target in gastric cancer. Tumour Biol. 2014;35(12):12737–42.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhou L, He XD, Yu JC, Zhou RL, Shan Y, Rui JA. Overexpression of LAPTM4B-35 attenuates epirubucin-induced apoptosis of gallbladder carcinoma GBC-SD cells. Surgery. 2011;150(1):25–31.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhou L, He XD, Cui QC, Zhou WX, Qu Q, Zhou RL, et al. Expression of LAPTM4B-35: a novel marker of progression, invasiveness and poor prognosis of extrahepatic cholangiocarcinoma. Cancer Lett. 2008;264(2):209–17.CrossRefPubMedGoogle Scholar
  13. 13.
    Kang Y, Yin M, Jiang W, Zhang H, Xia B, Xue Y, et al. Overexpression of LAPTM4B-35 is associated with poor prognosis in colorectal carcinoma. Am J Surg. 2012;204(5):677–83.CrossRefGoogle Scholar
  14. 14.
    Meng F, Luo C, Hu Y, Yin M, Lin M, Lou G, et al. Overexpression of LAPTM4B-35 in cervical carcinoma: a clinicopathologic study. Int J Gynecol Pathol. 2010;29(6):587–93.CrossRefPubMedGoogle Scholar
  15. 15.
    Meng F, Chen X, Song H, Lou G. LAPTM4B down regulation inhibits the proliferation, invasion and angiogenesis of HeLa cells in vitro. Cell Physiol Biochem. 2015;37(3):890–900.CrossRefPubMedGoogle Scholar
  16. 16.
    Folkman J, Kalluri R. Cancer without disease. Nature. 2004;427(6977):787.CrossRefPubMedGoogle Scholar
  17. 17.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang Y, Huang L, Wu S, Jia Y, Yang Y, Luo L, et al. Bioinformatics analyses of the role of vascular endothelial growth factor in patients with non-small cell lung cancer. PLoS One. 2015;10(9):e0139285.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Eswarappa SM, Fox PL. Antiangiogenic VEGF-Ax: a new participant in tumor angiogenesis. Cancer Res. 2015;75(14):2765–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Abdel-Rahman O. Targeting vascular endothelial growth factor (VEGF) pathway in iodine-refractory differentiated thyroid carcinoma (DTC): from bench to bedside. Crit Rev Oncol Hematol. 2015;94(1):45–54.CrossRefPubMedGoogle Scholar
  21. 21.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: a Cancer J Clin. 2015;65(1):5–29.Google Scholar
  22. 22.
    Gadducci A, Lanfredini N, Sergiampietri C. Antiangiogenic agents in gynecological cancer: State of art and perspectives of clinical research. Crit Rev Oncol Hematol. 2015;96(1):113–28.CrossRefPubMedGoogle Scholar
  23. 23.
    Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2(10):727–39.CrossRefPubMedGoogle Scholar
  24. 24.
    Rigiracciolo DC, Scarpelli A, Lappano R, Pisano A, Santolla MF, De Marco P, Cirillo F, Cappello AR, Dolce V, Belfiore A et al.: Copper activates HIF-1alpha/GPER/VEGF signalling in cancer cells. Oncotarget 2015Google Scholar
  25. 25.
    Scartozzi M, Loretelli C, Galizia E, Mandolesi A, Pistelli M, Bittoni A, et al. Role of vascular endothelial growth factor (VEGF) and VEGF-R genotyping in guiding the metastatic process in pT4a resected gastric cancer patients. PLoS One. 2012;7(7):e38192.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gremonprez F, Descamps B, Izmer A, Vanhove C, Vanhaecke F, Wever O, Ceelen W: Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model. Oncotarget 2015Google Scholar
  27. 27.
    Zhang Y, Yu LK, Lu GJ, Xia N, Xie HY, Hu W, et al. Prognostic values of VEGF and endostatin with malignant pleural effusions in patients with lung cancer. Asian Pac J Cancer Prev. 2014;15(19):8435–40.CrossRefPubMedGoogle Scholar
  28. 28.
    Koutras A, Kotoula V, Fountzilas G. Prognostic and predictive role of vascular endothelial growth factor polymorphisms in breast cancer. Pharmacogenomics. 2015;16(1):79–94.CrossRefPubMedGoogle Scholar
  29. 29.
    Huang S, He P, Peng X, Li J, Xu D, Tang Y. Pristimerin inhibits prostate cancer bone metastasis by targeting PC-3 stem cell characteristics and VEGF-induced vasculogenesis of BM-EPCs. Cell Physiol Biochem. 2015;37(1):253–68.CrossRefPubMedGoogle Scholar
  30. 30.
    Saijo Y, Furumoto H, Yoshida K, Nishimura M, Irahara M. Clinical significance of vascular endothelial growth factor expression and microvessel density in invasive cervical cancer. J Med Invest. 2015;62(3–4):154–60.CrossRefPubMedGoogle Scholar
  31. 31.
    Dong J, Cheng M, Sun H. Function of inducible nitric oxide synthase in the regulation of cervical cancer cell proliferation and the expression of vascular endothelial growth factor. Mol Med Rep. 2014;9(2):583–9.PubMedGoogle Scholar
  32. 32.
    Chen L, Wu YY, Liu P, Wang J, Wang G, Qin J, et al. Down-regulation of HPV18 E6, E7, or VEGF expression attenuates malignant biological behavior of human cervical cancer cells. Med Oncol. 2011;28 Suppl 1:S528–39.PubMedGoogle Scholar
  33. 33.
    Huygens C, Lienart S, Dedobbeleer O, Stockis J, Gauthy E, Coulie PG, et al. Lysosomal-associated transmembrane protein 4B (LAPTM4B) decreases transforming growth factor beta1 (TGF-beta1) production in human regulatory T cells. J Biol Chem. 2015;290(33):20105–16.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Milkereit R, Persaud A, Vanoaica L, Guetg A, Verrey F, Rotin D. LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nat Commun. 2015;6:7250.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Tang H, Tian H, Yue W, Li L, Li S, Gao C, et al. Overexpression of LAPTM4B is correlated with tumor angiogenesis and poor prognosis in non-small cell lung cancer. Med Oncol. 2014;31(6):974.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Fanling Meng
    • 1
  • Shu Tan
    • 1
  • Tianbo Liu
    • 1
  • Hongtao Song
    • 2
  • Ge Lou
    • 1
  1. 1.Department of Gynecology, The Affiliated Tumor HospitalHarbin Medical UniversityHarbinChina
  2. 2.Department of Pathology, The Affiliated Tumor HospitalHarbin Medical UniversityHarbinChina

Personalised recommendations