EGFR is a well-studied cell surface receptor that stimulates cell growth by transmitting growth factor signals acting outside the cell. EGFR is often present at abnormally elevated levels in human cancer cells. Increased EGFR activity has been linked to metastasis and treatment resistance for aggressive human tumors and, as a result, the EGFR has been identified as an attractive target for cancer therapeutics. However, the precise role of EGFR in cancer cell biology has remained elusive.
Recent studies have shown that in response to growth factor stimulation, a fraction of EGFR molecules move from the cell membrane into the nucleus, where the genetic material of the cell is located. These research studies suggest that EGFR itself probably does not directly regulate gene expression, but may interact with other as yet unidentified molecules in the nucleus. A better understanding of the role of the EGFR signaling pathway in the progression of cancer will be useful for development of new anticancer therapeutics.
In the current study, Dr. Mien-Chie Hung and colleagues from the Department of Molecular and Cellular Oncology at the University of Texas M.D. Anderson Cancer Center found that EGFR interacts with STAT3 in the cell nucleus. STAT3 is a molecule that is known to bind to DNA and directly regulate gene expression. STAT3 has also been shown to have a major role in oncogenesis. Importantly, interaction with STAT3 provides a mechanism for EGFR-driven regulation of gene transcription. The researchers also discovered that the EGFR/STAT3 interaction leads increased expression of inducible nitric oxide synthase (iNOS). Although elevated iNOS is also a key characteristic of many human malignanc ies, there has previously been no direct connection made between EGFR and the iNOS/NO pathway.
The researchers conclude that the complex formed by EGFR and STAT3 can directly regulate gene expression and provides a new transcriptional mechanism that may play a significant role in human cancers, transducing cell signals from outside the cell into the nucleus. According to Dr. Hung, "As in OS serves as a direct target of the identified EGFR/STAT3 transcriptional complex, the deregulated iNOS/NO pathway may, in part, contribute to the malignant biology of tumor cells with high levels of nuclear EGFR and STAT3." This research may open new avenues for designing anticancer therapies against EGFR, STAT3, and iNOS/NO.