Skip to main content

Advertisement

SpringerLink
Log in

Her3 is associated with poor survival of gastric adenocarcinoma: Her3 promotes proliferation, survival and migration of human gastric cancer mediated by PI3K/AKT signaling pathway

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

ErbB3 (Her3) is a membrane-bound protein which can form heterodimers with other EGF receptor family members with kinase activity. Previous reports identified Her3 as a significant predictor of poor survival in human gastric cancer (GC), but its mechanism has remained unclear. We sought to investigate the mechanism of Her3 in GC and its association with clinical characteristics. Her3 was detected by both real-time PCR and immunohistochemistry (IHC) in 161 GC patients, and its related downstream signaling PI3K/AKT activity and clinical characteristics were accessed by statistical analysis. Her3 siRNA was used in both in vitro and in vivo assay to investigate the mechanism. Her3 expression was significantly increased in human GC compared with adjacent normal gastric tissues as observed by both real-time PCR and IHC. Her3 expression was associated with downstream AKT activation and increased tumor size, metastasis and poor survival in GC patients. Knockdown of Her3 in human GC cell line can inhibit cell proliferation and tumor growth both in vitro and in vivo by inactivation of AKT. Her3 knockdown had no observed impact on Her2 expression or activity. G2/M arrest was investigated due to decreased CyclinB1 and p27kip1 at T157. Increased apoptosis occurred in Her3 silenced GC cell treated with cisplatin due to decreased BAD at S112. Moreover, Her3 silence can inhibit cell migration in vitro and metastasis in vivo by down-regulating MMPs via PI3K/AKT signaling. Her3 is a new prognostic factor associated with tumor growth and metastasis via PI3K/AKT signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kelley JR, Duggan JM. Gastric cancer epidemiology and risk factors. J Clin Epidemiol. 2003;56:1–9.

    Article  PubMed  Google Scholar 

  2. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK. ToGA trial investigators: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.

    Article  PubMed  CAS  Google Scholar 

  3. Cervantes A, Roda D, Tarazona N, Roselló S, Pérez-Fidalgo JA. Current status of targeted therapies in advanced gastric cancer. Expert Opin Ther Targets. 2012;16:S29–34.

    Article  CAS  Google Scholar 

  4. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159–67.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Schlessinger J. Common and distinct elements in cellular signaling via EGF and FGF receptors. Science. 2004;306:1506–7.

    Article  PubMed  CAS  Google Scholar 

  6. Han W, Lo HW. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett. 2012;318:124–34.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Petrelli F, Barni S. Role of HER2-neu as a prognostic factor for survival and relapse in pT1a-bN0M0 breast cancer: a systematic review of the literature with a pooled-analysis. Med Oncol. 2012;29:2586–93.

    Article  PubMed  CAS  Google Scholar 

  8. Allgayer H, Babic R, Gruetzner KU, Tarabichi A, Schildberg FW, Heiss MM. c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems. J Clin Oncol. 2000;18:2201–9.

    PubMed  CAS  Google Scholar 

  9. Freeman MR. HER2/HER3 heterodimers in prostate cancer: whither HER1/EGFR? Cancer Cell. 2004;6:427–8.

    Article  PubMed  CAS  Google Scholar 

  10. Smirnova T, Zhou ZN, Flinn RJ, Wyckoff J, Boimel PJ, Pozzuto M, Coniglio SJ, Backer JM, Bresnick AR, Condeelis JS, Hynes NE, Segall JE. Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis. Oncogene. 2012;31:706–15.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. Begnami MD, Fukuda E, Fregnani JH, Nonogaki S, Montagnini AL, da Costa WL, Soares FA Jr. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol. 2011;29:3030–6.

    Article  PubMed  CAS  Google Scholar 

  12. Hayashi M, Inokuchi M, Takagi Y, Yamada H, Kojima K, Kumagai J, Kawano T, Sugihara K. High expression of HER3 is associated with a decreased survival in gastric cancer. Clin Cancer Res. 2008;14:7843–9.

    Article  PubMed  CAS  Google Scholar 

  13. Jiang R, Xia Y, Li J, Deng L, Zhao L, Shi J, Wang X, Sun B. High expression levels of IKKalpha and IKKbeta are necessary for the malignant properties of liver cancer. Int J Cancer. 2010;126:1263–74.

    PubMed  CAS  Google Scholar 

  14. Zhang XL, Yang YS, Xu DP, Qu JH, Guo MZ, Gong Y, Huang J. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J Surg. 2009;33:2112–8.

    Article  PubMed  Google Scholar 

  15. Tozawa K, Oshima T, Kobayashi T, Yamamoto N, Hayashi C, Matsumoto T, Miwa H. Oxaliplatin in treatment of the cisplatin-resistant MKN45 cell line of gastric cancer. Anticancer Res. 2008;28:2087–92.

    PubMed  CAS  Google Scholar 

  16. Dhomen NS, Mariadason J, Tebbutt N, Scott AM. Therapeutic targeting of the epidermal growth factor receptor in human cancer. Crit Rev Oncog. 2012;17:31–50.

    Article  PubMed  Google Scholar 

  17. Howe LR, Brown PH. Targeting the HER/EGFR/ErbB family to prevent breast cancer. Cancer Prev Res (Phila). 2011;4:1149–57.

    Article  CAS  Google Scholar 

  18. Jathal MK, Chen L, Mudryj M, Ghosh PM. Targeting ErbB3: the new RTK(id) on the prostate cancer block. Immunol Endocr Metab Agents Med Chem. 2011;11:131–49.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. 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;21:951–60.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Jin Q, Esteva FJ. Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:485–98.

    Article  PubMed  Google Scholar 

  21. Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci USA. 2012;109:2718–23.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sánchez V, Chakrabarty A, Dave B, Cook RS, Pao W, McKinely E, Manning HC, Chang J, Arteaga CL. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci USA. 2011;108:5021–6.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004;9:667–76.

    Article  PubMed  CAS  Google Scholar 

  24. Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011;1813:1978–86.

    Article  PubMed  CAS  Google Scholar 

  25. Carnero A, Hannon GJ. The INK4 family of CDK inhibitors. Curr Top Microbiol Immunol. 1998;227:43–55.

    PubMed  CAS  Google Scholar 

  26. Choi YH, Zhang L, Lee WH, Park KY. Genistein-induced G2/M arrest is associated with the inhibition of cyclin B1 and the induction of p21 in human breast carcinoma cells. Int J Oncol. 1998;13:391–6.

    PubMed  CAS  Google Scholar 

  27. Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E, Slingerland JM. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002;8:1153–60.

    Article  PubMed  CAS  Google Scholar 

  28. Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med. 2002;8:1145–52.

    Article  PubMed  CAS  Google Scholar 

  29. Viglietto G, Motti ML, Bruni P, Melillo RM, D’Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med. 2002;8:1136–44.

    Article  PubMed  CAS  Google Scholar 

  30. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–41.

    Article  PubMed  CAS  Google Scholar 

  31. Chen YY, Liu FC, Chou PY, Chien YC, Chang WS, Huang GJ, Wu CH, Sheu MJ. Ethanol extracts of fruiting bodies of Antrodia cinnamomea suppress CL1-5 human lung adenocarcinoma cells migration by inhibiting matrix metalloproteinase-2/9 through ERK, JNK, p38, and PI3K/Akt signaling pathways. Evid Based Complement Alternat Med. 2012;2012:378415–26.

    PubMed Central  PubMed  Google Scholar 

  32. Ko HS, Lee HJ, Kim SH, Lee EO. Piceatannol suppresses breast cancer cell invasion through the Inhibition of MMP-9: Involvement of PI3K/AKT and NF-kappaB pathways. J Agric Food Chem. 2012;60:4083–9.

    Article  PubMed  CAS  Google Scholar 

  33. Tsubaki M, Satou T, Itoh T, Imano M, Ogaki M, Yanae M, Nishida S. Reduction of metastasis, cell invasion, and adhesion in mouse osteosarcoma by YM529/ONO-5920-induced blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathway. Toxicol Appl Pharmacol. 2012;259:402–10.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to the participation of patients. This work was supported by the National Natural Science Foundation of China (81201797 to LG, 30901750 and 81272322 to CY), the Priority Academic Program Development of Jiangsu Higher Education Institutions to CY, Jiangsu Province “Six adults just” high peak (2009-D-63 to LG), Youth Projects of Jiangsu Provincial Health Department (H201065 to LG), the Natural Science Foundation of Jiangsu Province (BK2010532 to CY and BK2009445 to LG), China Postdoctoral Science Foundation funded project (20090461133 to CY), Jiangsu Planned Projects for Postdoctoral Research Funds (1001028B to CY), Jiangsu Province Laboratory of Pathogen Biology (11BYKF02 to CY).

Conflict of interest

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

  1. Department of Digestive Tumor Surgery, Jiangsu Province Hospital of Traditional Chinese Medicine, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, 210029, China

    Xiaoyu Wu

  2. Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, 210029, China

    Yun Chen

  3. Department of General Surgery, Jiangsu Cancer Hospital, Gastric Tumor Center, The Affiliated Cancer Hospital with Nanjing Medical University, Nanjing, 210009, China

    Gang Li, Rongmin Gu, Xu Wen, Xuezhi Ming & Huanqiu Chen

  4. Department of Pathology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital with Nanjing Medical University, Nanjing, 210009, China

    Lei Xia

Authors
  1. Xiaoyu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lei Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rongmin Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xu Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xuezhi Ming
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huanqiu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gang Li.

Additional information

Xiaoyu Wu and Yun Chen contributed equally to this work and should be considered co-first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, X., Chen, Y., Li, G. et al. Her3 is associated with poor survival of gastric adenocarcinoma: Her3 promotes proliferation, survival and migration of human gastric cancer mediated by PI3K/AKT signaling pathway. Med Oncol 31, 903 (2014). https://doi.org/10.1007/s12032-014-0903-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0903-x

Keywords

Search

Navigation