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A new pathway controlling cancer-related inflammation


Project Description

We have discovered that inactivation of the MAPK ERK5 in epidermal keratinocytes prevented inflammation-driven tumourigenesis in a skin cancer mouse model. Furthermore, suppressing cancer-related inflammation via anti-ERK5 therapy regressed existing tumours and this effect was potentiated by the concurrent administration of sub-therapeutic doses of the chemotherapeutic agent, doxorubicin. These findings have led us to propose that ERK5 is part of a core signal transduction pathway required for inflammation-driven tumourigenesis. Based on this hypothesis, the overall objective of this project is to fully delineate the role of ERK5 signalling in cancer-related inflammation, thereby revealing new avenues for therapeutic cancer research. More specifically, this study will have two aims: first, to identify the molecular basis underlying the inflammatory function of ERK5 in keratinocytes; second, to determine whether constitutive activation of ERK5 in the skin is sufficient to trigger an inflammatory reaction, and as such, constitutes a risk factor for cancer. Overall, this study is highly relevant to human cancer considering that an inflammatory environment is an essential component of all tumours and elevated MEK5/ERK5 expression in human tumours correlates with unfavourable prognosis, shorter disease-free intervals, increased risk of metastasis, and resistance to chemotherapy.

Funding Notes

This project has a Band 3 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. 2012 Semin Cancer Biol. 22:33-40.
Hayashi M, Fearns C, Eliceiri B, Yang Y, Lee JD. Big mitogen-activated protein kinase 1/extracellular signal-regulated kinase 5 signaling pathway is essential for tumor-associated angiogenesis. 2005 Cancer Res. 2005 65:7699-706.
Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. 2012 Physiol. Rev. 92:689-737.
Nithianandarajah-Jones GN, Wilm B, Goldring CE, Müller J, Cross MJ. ERK5: structure, regulation and function. 2012 Cell Signal. 24:2187-96.
Yang Q, Lee JD. Targeting the BMK1 MAP kinase pathway in cancer therapy. 2011 Clin Cancer Res. 17:3527-32.

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