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WNT6 is a novel target gene of caveolin-1 promoting chemoresistance to epirubicin in human gastric cancer cells

Oncogene volume 32, pages 375–387 (2013)Cite this article

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Abstract

Resistance to chemotherapy is a major obstacle for curative treatment of human gastric cancer (GC). However, the underlying molecular mechanisms are largely unknown. Wingless-type MMTV integration site family members (WNTs) are secreted glycoproteins involved in embryogenesis and, on inappropriate expression in the adult, in cancer. Here, we show expression of WNT6 in GC patient specimens, human GC cell lines and in a mouse model of GC. In human GC cells, WNT6 expression was enhanced by caveolin-1 (Cav1), a scaffold protein of plasma membrane caveolae. WNT6 knock-down and overexpression experiments demonstrated that WNT6 increased the resistance to apoptotic cell death induced by the anthracycline chemotherapeutics epirubicin (Epi) and doxorubicin (Dox). Epi increased the activity of the human WNT6 promoter through Cav1-dependent binding of β-catenin to the proximal WNT6 promoter. Epi increased both WNT6/Wnt6 and Cav1 expression in human GC cells and within the tumor area of a murine model of GC (CEA424-SV40 TAg). In GC patients, WNT6 expression was positively associated with the tumor stage and the nodal status, and inversely correlated with the response to ECF (Epi, cisplatin, 5-fluorouracil) chemotherapy. These results showed that WNT6 and Cav1 are upregulated by chemotherapeutics and enhance the resistance of GC cells to anthracycline drugs. Understanding the molecular mechanisms driving WNT6/Cav1-induced drug resistance will provide benefits in developing new therapies for GC.

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Abbreviations

WNT:

wingless-type MMTV integration site family member

GC:

gastric cancer

Cav1:

caveolin-1

TCF:

transcription factor 4

Dox:

doxorubicin

Epi:

epirubicin

5-FU:

5-fluorouracil

ECF:

epirubicin/cisplatin/5-fluorouracil.

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Acknowledgements

We are grateful to Minhu Chen, Xiao Chen, Jie Chen for support on collaborations. M Ebert is supported by grants from the Deutsche Krebshilfe (107885, 108096), the DFG (SFB 824, TP B1), the Else Kröner Stiftung (Nr P14/07//A104/06), the BMBF (Mobimed 01EZ0802 and KMU-innovativ Initiative of the BMBF No 0315116B). E Burgermeister receives funds from the Deutsche Krebshilfe (108287) and DFG (BU-2285).

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Authors and Affiliations

  1. Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany

    G Yuan, I Regel, T Friedrich & R M Schmid

  2. Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China

    G Yuan & F Lian

  3. Department of Medicine II, Universitätsklinikum Mannheim, Universität Heidelberg, Baden-W, ü, rttemberg, Germany

    I Hitkova, M P A Ebert & E Burgermeister

  4. Department of Medicine III, Universitätsklinikum Mannheim, Universität Heidelberg, Baden-W, ü, rttemberg, Germany

    R D Hofheinz

  5. Institute of Pathology, Universitätsklinikum Mannheim, Universität Heidelberg, Baden-W, ü, rttemberg, Germany

    P Ströbel

  6. Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, München, Germany

    R Langer & G Keller

  7. Institute of Pathology, Christian-Albrechts Universität Kiel, Kiel, Germany

    C Röcken

  8. Tumor Immunology Laboratory, LIFE Center, Universität München, München, Germany

    W Zimmermann

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Yuan, G., Regel, I., Lian, F. et al. WNT6 is a novel target gene of caveolin-1 promoting chemoresistance to epirubicin in human gastric cancer cells. Oncogene 32, 375–387 (2013). https://doi.org/10.1038/onc.2012.40

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