Advertisement

Journal of Biosciences

, Volume 42, Issue 3, pp 491–499 | Cite as

Hypoxia stimulates invasion and migration of human cervical cancer cell lines HeLa/SiHa through the Rab11 trafficking of integrin αvβ3/FAK/PI3K pathway-mediated Rac1 activation

  • Hao Xu
  • Yuan Yuan
  • Wenqian Wu
  • Min Zhou
  • Qian Jiang
  • Linjun Niu
  • Jiayin Ji
  • Nianli Liu
  • Longzhen Zhang
  • Xia WangEmail author
Article

Abstract

Hypoxia plays a key role in tumour cell survival, invasion, and metastasis. An increasing number of studies have attempted to characterize the tumour response to hypoxia and to identify predictive markers of disease. Here we show that hypoxia increases tumour cell invasion and migration by the modulation of Rab11, an important molecule for vesicular trafficking. In our study, we found that Rab11, together with the activation of Rac1, could stimulate invasion and migration of cervical cancer cell lines HeLa/SiHa in hypoxia. Activation of Rac1 activity by hypoxia seems to be central to carcinoma invasion. We also found that these effects could be related to the integrin αvβ3. In addition, we studied the molecular pathway for this process. Our results showed that in cervical cancer cell lines HeLa/SiHa, Rac1 activation in hypoxia could stimulate invasion and migration, and this process was mediated by integrin αvβ3-mediated FAK and PI3K phosphorylation. Furthermore, hypoxia induced a dramatic increase in αvβ3 integrin surface expression, and this increase is dependent on Rab11. In conclusion, our study might provide a new mechanism for the effect of hypoxia on stimulating cervical carcinoma invasion.

Keywords

Cervical cancer hypoxia Rab11 Rac1 αvβ3/FAK/PI3K 

Notes

References

  1. Avraham H, Park SY, Schinkmann K and Avraham S 2000 RAFTK/Pyk2-mediated cellular signalling. Cell. Signal. 12 123–133CrossRefPubMedGoogle Scholar
  2. Bae KM, Dai Y, Vieweg J and Siemann DW 2015 Hypoxia regulates SOX2 expression to promote prostate cancer cell invasion and sphere formation. Am. J. Cancer Res. 6 1078–1088Google Scholar
  3. Bhuin T and Roy JK 2015 Rab11 in disease progression. Int. J. Mol. Cell. Med. 4 1–8PubMedPubMedCentralGoogle Scholar
  4. Binker MG, Gaisano HY, Cosen RHD and Binker LIC 2010 Hypoxia-reoxygenation increase invasiveness of PANC-1 cells through Rac1/MMP-2. Biochem. Biophys. Res. Commun. 393 371–376CrossRefPubMedGoogle Scholar
  5. Brown JM 1999 The hypoxic cell: a target for selective cancer therapy-eighteenth Bruce F. Cain Memorial Award lecture. Cancer Res. 59 5863–5870PubMedGoogle Scholar
  6. Carnero A and Lleonart M 2016 The hypoxic microenvironment: a determinant of cancer stem cell evolution. BioEssays 38 Suppl 1 96–105Google Scholar
  7. Caswell PT, Chan M, Lindsay AJ, McCaffrey MW, Boettiger D and Norman JC 2008 Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J. Cell Biol. 183 143–155CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, Huang HY, Tsai KK, et al. 2012 The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 149 1098–1111CrossRefPubMedPubMedCentralGoogle Scholar
  9. Choi YA, Lim HK, Kim JR, Lee CH, Kim YJ, Kang SS and Baek SH 2004 Group IB secretory phospholipase A2 promotes matrix metalloproteinase-2-mediated cell migration via the phosphatidylinositol 3-kinase and Akt pathway. J. Biol. Chem. 279 36579–36585CrossRefPubMedGoogle Scholar
  10. Dang D, Bamburg JR and Ramos DM 2006 αvβ3 integrin and cofilin modulate K1735 melanoma cell invasion. Exp. Cell Res. 312 468–477CrossRefPubMedGoogle Scholar
  11. Deneka M and van der Sluijs P 2002 ‘Rab’ing up endosomal membrane transport. Nat. Cell Biol. 4 E33–E35CrossRefPubMedGoogle Scholar
  12. Emery G and Ramel D 2013 Cell coordination of collective migration by Rab11 and Moesin. Commun. Integr. Biol. 6 e24587CrossRefPubMedPubMedCentralGoogle Scholar
  13. Hutagalung AH and Novick PJ 2011 Role of Rab GTPases in membrane traffic and cell physiology. Physiol. Rev. 91 119–149CrossRefPubMedPubMedCentralGoogle Scholar
  14. Jayachandran G, Sazaki J, Xu K, Girard L, Minna J, Roth J and Ji L 2007 Fragile histidine triad-mediated tumor suppression of lung cancer by targeting multiple components of the Ras/Rho GTPase molecular switch. Cancer Res. 67 10379–10388CrossRefPubMedGoogle Scholar
  15. Li G 2011 Rab GTPases, membrane trafficking and diseases. Curr. Drug. Targets 12 1188–1193CrossRefPubMedPubMedCentralGoogle Scholar
  16. Lin Y, Rao J, Zha XL and Xu H 2013 Angiopoietin-like 3 induces podocyte F-actin rearrangement through integrin alpha (V)beta (3)/FAK/PI3K pathway-mediated Rac1 activation. Biomed. Res. Int. 2013 135608PubMedPubMedCentralGoogle Scholar
  17. Liu SS, Chen XM, Zheng HX, Shi SL and Li Y 2011 Knockdown of Rab5a expression decreases cancer cell motility and invasion through integrin-mediated signaling pathway. J. Biomed. Sci. 18 1–9CrossRefGoogle Scholar
  18. Liu Z, Wang F and Chen X 2008 Integrin αvβ3‐targeted cancer therapy. Drug. Dev. Res. 69 329–339CrossRefPubMedPubMedCentralGoogle Scholar
  19. Knowles LM, Gurski LA, Engel C, Gnarra JR, Maranchie JK and Pilch J 2013 Integrin αvβ3 and fibronectin upregulate Slug in cancer cells to promote clot invasion and metastasis. Cancer Res. 73 6175–6184CrossRefPubMedGoogle Scholar
  20. Maxfield FR and Mcgraw TE 2004 Endocytic recycling. Nat. Rev. Mol. Cell Biol. 5 121–132CrossRefPubMedGoogle Scholar
  21. Mosesson Y, Mills GB and Yarden Y 2008 Derailed endocytosis: an emerging feature of cancer. Nat. Rev. Cancer 8 835–850CrossRefPubMedGoogle Scholar
  22. Pulgar TGD, Bandrés E, Espina C, Valdés-Mora F, Pérez-Palacios R, García-Amigot F, García-Foncillas J and Lacal JC 2007 Differential expression of Rac1 identifies its target genes and its contribution to progression of colorectal cancer. Int. J. Biochem. Cell Biol. 39 2289–2302CrossRefGoogle Scholar
  23. Reiske HR, Kao SC, Cary LA, Guan JL, Lai JF and Chen HC 1999 Requirement of phosphatidylinositol 3-kinase in focal adhesion kinase-promoted cell migration. J. Biol. Chem. 274 12361–12366CrossRefGoogle Scholar
  24. Shi Z, Wu D, Tang R, Li X, Chen R, Xue S, Zhang C and Sun X 2016 Silencing of HMGA2 promotes apoptosis and inhibits migration and invasion of prostate cancer cells. J. Biosci. 41 1–8CrossRefGoogle Scholar
  25. Whaley-Connell AT, Morris EM, Rehmer N, Yaghoubian JC, Wei Y, Hayden MR, Habibi J, Stump CS, et al. 2007 Albumin activation of NAD (P)H oxidase activity is mediated via Rac1 in proximal tubule cells. Am. J. Nephrol. 27 15–23CrossRefPubMedGoogle Scholar
  26. Xu CL, Wang JZ, Xia XP, Pan CW, Shao XX, Xia SL, Yang SX and Zheng B 2016 Rab11-FIP2 promotes colorectal cancer migration and invasion by regulating PI3K/AKT/MMP7 signaling pathway. Biochem. Biophys. Res. Commun. 470 397–404CrossRefPubMedGoogle Scholar
  27. Xu CS, Wang ZF, Huang XD, Dai LM, Cao CJ and Li ZQ 2015 Involvement of ROS-alpha v beta 3 integrin-FAK/Pyk2 in the inhibitory effect of melatonin on U251 glioma cell migration and invasion under hypoxia. J. Transl. Med. 13 1–11CrossRefGoogle Scholar
  28. Yang L, Zheng J, Xu R, Zhang Y, Luo G, Dong J, Zhu Y, Zhou R, et al. 2014 Melatonin suppresses hypoxia-induced migration of HUVECs via inhibition of ERK/Rac1 activation. Int. J. Mol. Sci. 15 14102–14121CrossRefPubMedCentralGoogle Scholar
  29. Yoon SO, Shin S and Mercurio AM 2005 Hypoxia stimulates carcinoma invasion by stabilizing microtubules and promoting the Rab11 trafficking of the alpha6beta4 integrin. Cancer Res. 65 2761–2769CrossRefPubMedGoogle Scholar

Copyright information

© Indian Academy of Sciences 2017

Authors and Affiliations

  • Hao Xu
    • 1
  • Yuan Yuan
    • 2
  • Wenqian Wu
    • 3
  • Min Zhou
    • 4
  • Qian Jiang
    • 1
  • Linjun Niu
    • 5
  • Jiayin Ji
    • 1
  • Nianli Liu
    • 6
  • Longzhen Zhang
    • 1
  • Xia Wang
    • 1
    Email author
  1. 1.Department of RadiotherapyThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouChina
  2. 2.Department of OncologyThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouChina
  3. 3.Department of ImmunologyThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouChina
  4. 4.Intensive Care UnitThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouChina
  5. 5.Department of Interventional RadiologyThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouChina
  6. 6.Tumor Biological Therapy InstituteXuzhou Medical UniversityXuzhouChina

Personalised recommendations