Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival

Abstract

Emerging evidences suggest the existence of a new mode of epidermal growth factor receptor (EGFR) signalling pathway in which activated EGFR undergoes nuclear translocalization and subsequently regulates gene expression and potentially mediates other cellular processes. This signalling route is distinct from the better-characterized, traditional EGFR pathway that involves transduction of mitogenic signals through activation of multiple signalling cascades. Transcriptional activity of nuclear EGFR appears to depend on its C-terminal transactivation domain and its physical and functional interaction with other transcription factors that contain DNA-binding activity. Likely via its ability to upregulate gene expression, nuclear EGFR pathway is associated with major characteristics of more aggressive tumours: increased proliferative potential, nitric oxide synthesis, and accelerated G1/S cell cycle progression. A role of nuclear EGFR in prognostic prediction is further suggested in patients with breast carcinomas and oropharyngeal squamous cell carcinomas. It is noted that significant advances were made towards the knowledge of the nuclear EGFR pathway; however, many aspects of this new pathway remain unresolved and will be discussed in this review. As a number of other receptor tyrosine kinases (RTKs) and cytokine receptors also undergo similar nuclear translocalization, a better understanding of the physiological and malignant nature of the nuclear EGFR pathway will likely shed light into the biology of cancer with nuclear RTKs.

Figure 1

Cytoplasmic/traditional and nuclear modes of the EGFR signalling pathway. The EGFR signalling pathway exerts its biological effects via two major modes of actions, namely, cytoplasmic/traditional (A) and nuclear (B) modes. (A) The cytoplasmic EGFR pathway is consisted of four major modules: PLC-γ-CaMK/PKC, Ras-Raf-MAPK, PI-3K-Akt-GSK and STATs. Activation of these signalling modules often leads to tumorigenesis, tumour proliferation, metastasis, chemoresistance and radioresistance. (B) The nuclear EGFR pathway can be initiated by ligand binding and exposure to vitamin D, radiation, cisplatin, heat and H₂O_2. Following nuclear translocalization, nuclear EGFR interacts with DNA-binding transcription factors, E2F1 and STAT3, and activates expression of B-Myb and iNOS, respectively. Nuclear EGFR also upregulates cyclin D1 gene expression. Increased expression of cyclin D1 and B-Myb contributes to accelerated G1/S cell cycle progression and, on the other hand, elevated iNOS is associated with tumour proliferation and metastasis. Upon DNA damage and oxidative/heat stress, EGFR enters the cell nucleus and interacts with DNA-PK, leading to DNA repair and radioresistance.