Suppressor of cytokine signaling-2 (SOCS2) and epidermal growth factor (EGF) modulate insulin-like growth factor-I receptor (IGF-IR) signaling in intestinal cancer Public Deposited
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- Last Modified
- March 21, 2019
Newton, Victoria Ann
- Affiliation: School of Medicine, Department of Cell Biology and Physiology
- The insulin-like growth factor (IGF-I) pathway is associated with increased risk and progression of colorectal cancer. Understanding mechanisms that inhibit or promote this key pathway would be useful in developing better therapies and strategies for the treatment of colorectal cancer. Suppressor of cytokine signaling-2 (SOCS2) limits the trophic effects of IGF-I in the intestine and therefore, may negatively regulate intestinal tumorigenesis. We crossed SOCS2-/- mice with ApcMin/+ mice, a widely used model of spontaneous intestinal tumorigenesis, to test whether loss of SOCS2 promotes increased intestinal tumorigenesis and to identify possible mechanisms. Epidermal growth factor (EGF) is also associated with establishment and progression of colorectal cancer. Studies suggest that EGF impacts on IGF-IR signaling to synergistically increase growth in non-transformed intestinal epithelial cells and that combined inhibition of EGF and IGF-I would be more effective in reducing growth and survival of intestinal tumors than inhibition of either pathway alone. Whether EGF and IGF-I synergistically promote activation of tumor-promoting pathways in normal intestinal epithelial cells is unknown. In addition, combined inhibition of IGF-I and EGF pathways in a model of sporadic intestinal tumorigenesis has not been tested. To test synergistic effects of EGF and IGF-I, we used IEC-6 cells, a non-transformed intestinal epithelial cell line, to assess mechanisms of additive or synergistic activation of the IGF-IR and a key tumor promoting pathway in colorectal cancer, the beta-catenin pathway. Combined inhibition of IGF-IR and EGFR signaling on intestinal tumor development was assessed using ApcMin/+ mice lacking one allele of IRS-1, a downstream signaling molecule that mediates trophic effects of IGF signaling, and given a specific EGFR inhibitor. Loss of SOCS2 promoted significant increases in tumor number, size, and load in the small intestine and colon of ApcMin/+ mice. This was associated with increases local IGF-I, serine-phosphorylation of STAT3, a downstream mediator of IGF-I action and a target of SOCS2, and enhanced AP-1 DNA binding. In IEC-6 cells, EGF treatment increases IGF-IR, activation and combined treatment of EGF and IGF-I additively increases nuclear beta-catenin and its transcriptional activation. Combined heterozygous deletion of IRS-1 and inhibition of the EGFR dramatically reduced tumor number, size, and load, as well as tumor incidence, in the colon of ApcMin/+ mice. Surprisingly, this effect was confined to female mice and was not observed in male mice. Together, these studies identified novel mechanisms that regulate IGF-IR signaling. Our studies indicate that SOCS2 may be a useful biomarker of colorectal cancer. The interactions between IGF-I and EGF suggest that combined inhibition of these pathways will be more effective in treating colorectal cancer, than use of either treatment alone. Future studies using microarrays will identify molecular pathways that are activated tumors and normal tissue in response to complete loss of SOCS2 in ApcMin/+ mice or in response to combined activation or inhibition of EGF and IGF-I signaling.
- Date of publication
- August 2010
- Resource type
- Rights statement
- In Copyright
- "... in the partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell and Molecular Physiology-School of Medicine."
- Lund, Pauline Kay
- Degree granting institution
- University of North Carolina at Chapel Hill
- Place of publication
- Chapel Hill, NC
- Open access
This work has no parents.
|Suppressor of cytokine signaling-2 (SOCS2) and epidermal growth factor (EGF) modulate insulin-like growth factor-I receptor (IGF-IR) signaling in intestinal cancer||2019-04-10||Public||