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Growth factors regulate heterogeneous nuclear ribonucleoprotein K expression and function
M Mandal1, R Vadlamudi, D Nguyen
1Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center-108, Houston 77030, USA.
Abstract:
Epidermal growth factor (EGF) family of growth factors and their receptors regulate normal and cancerous epithelial cell proliferation, a process that can be suppressed by antireceptor blocking antibodies. To identify genes whose expression may be modulated by antireceptor blocking antibodies, we performed a differential display screen with cells grown in the presence or absence of antireceptor blocking antibodies; isolates from one cDNA clone were 100% identical to human heterogeneous nuclear ribonucleoprotein K (hnRNP K), a protein with a conserved KH motif and RGG boxes, has been implicated in such functions as sequence-specific DNA binding, transcription, RNA binding, and nucleocytoplasmic shuttling. Both EGF and heregulin-beta1 induced expression of hnRNP K mRNA and protein in human breast cancer cells. This growth factor-mediated hnRNP K expression was effectively blocked by pretreatment of cultures with humanized anti-EGF receptor (EGFR) antibody C225, or anti-human epidermal growth factor receptor-2 (HER2) antibody. Anti-EGFR monoclonal antibody also caused regression of human tumor xenografts and reduction in hnRNP K levels in athymic mice. Samples from grade III human breast cancer contained more hnRNP K protein than samples from grade II cancer. Finally, overexpression of hnRNP K in breast cancer cells significantly increased target c-myc promoter activity and c-Myc protein, hnRNP K protein levels, and enhanced breast cancer cell proliferation and growth in an anchorage-independent manner. These results suggested that the activity of human EGF receptor family members regulates hnRNP K expression by extracellular growth promoting signals and that therapeutic humanized antibodies against EGFR and HER2 can effectively block this function.
Insights
Epidermal Growth Factor (EGF) receptor signaling drives cancer cell growth by increasing hnRNP K expression. Therapeutic antibodies targeting EGF receptors (EGFR) and HER2 block this pathway, inhibiting tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Epidermal Growth Factor (EGF) family receptors regulate epithelial cell proliferation in normal and cancerous tissues.
- Antireceptor blocking antibodies can suppress these processes.
- Identifying genes modulated by these antibodies is crucial for therapeutic development.
Purpose of the Study:
- To identify genes regulated by antireceptor blocking antibodies.
- To investigate the role of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in EGF receptor signaling and breast cancer.
- To evaluate the therapeutic potential of anti-EGFR and anti-HER2 antibodies.
Main Methods:
- Differential display screening to identify modulated genes.
- Treatment of human breast cancer cells with EGF, heregulin-beta1, and antireceptor antibodies (anti-EGFR C225, anti-HER2).
- Xenograft studies in athymic mice with anti-EGFR monoclonal antibody.
- Analysis of hnRNP K protein levels in breast cancer tissues of varying grades.
- Overexpression studies of hnRNP K in breast cancer cells.
Main Results:
- hnRNP K was identified as a gene modulated by antireceptor antibodies.
- EGF and heregulin-beta1 increased hnRNP K mRNA and protein levels in breast cancer cells.
- Anti-EGFR and anti-HER2 antibodies blocked EGF-mediated hnRNP K expression.
- Anti-EGFR antibody treatment led to tumor xenograft regression and reduced hnRNP K levels in vivo.
- Higher hnRNP K protein levels were observed in grade III vs. grade II breast cancer.
- hnRNP K overexpression enhanced c-myc promoter activity, c-Myc protein levels, and anchorage-independent breast cancer cell growth.
Conclusions:
- EGF receptor family activity regulates hnRNP K expression in response to extracellular growth signals.
- Therapeutic antibodies targeting EGFR and HER2 effectively block EGF-mediated hnRNP K expression and breast cancer cell proliferation.
- hnRNP K is a key mediator in EGF receptor-driven breast cancer growth and represents a potential therapeutic target.