Presentation Title:
"HMGA1 drives expansion of the intestinal stem cell compartment in transgenic mice and tumor progression in colon cancer cells".
Presentation Time: Sunday, Apr 03, 2011, 3:35 PM - 3:50 PM
Location: Room W209, Orange County Convention Center
Amy M. Belton 1, Christine Iacobuzio-Donahue 2, Evan J. Colletti 2, Graca D. Almeida-Porada 2, David L. Huso 1, and Linda Resar 1.
1 Johns Hopkins Univ. School of Medicine, Baltimore, MD;
2 University of Nevada, Reno, NV
Abstract Body:
The molecular mechanisms that enable colon cancer cells to evade therapy and metastasize are poorly understood and have not been effectively targeted by current therapies. Recent evidence suggests that tumor cells with stem-like properties (poor differentiation, long-term self-renewal, and a relatively quiescent state) are responsible for metastatic progression and resistance to therapy. Our laboratory is investigating molecular pathways that give rise to metastatic progression and “stemness” in refractory colon cancer with the long-term goal of identifying novel therapeutic targets. Our focus is the HMGA1 gene, which encodes the HMGA1a and HMGA1b chromatin remodeling proteins. HMGA1 is highly expressed during embryogenesis, but not in differentiated, adult tissues. Strikingly, HMGA1 is overexpressed in virtually all high-grade (poorly differentiated) cancers studied to date.
To study the role of HMGA1 in tumor progression and the stem cell state, we engineered HMGA1a transgenic mice. As previously reported, these mice succumb to aggressive lymphoid malignancies. Here, we report that the HMGA1 transgenics also develop hyperproliferative changes in the intestines with hamartomatous polyps. In addition, we found that the HMGA1 mice develop an expansion in the intestinal stem cell compartment, suggesting that HMGA1 promotes the maintenance or survival of intestinal stem cells.
To assess the role of HMGA1 in tumor progression and the stem cell phenotype in colon cancer, we inhibited HMGA1 expression in the poorly differentiated, HCT116 colon cancer cell line. We found that knock-down of HMGA1 blocks anchorage-independent cell growth, migration, and invasion in vitro. We also demonstrate that knock-down of HMGA1 blocks tumorigenesis and metastatic progression in vivo. Moreover, three-dimensional colonosphere formation is decreased in the knock-down cells, indicating that HMGA1 is required for this stem cell phenotype.
To further assess the role of HMGA1 in colon cancer stem cells, we performed limiting dilution tumorigenesis experiments. Inhibiting HMGA1 expression blocks tumorigenesis at limiting dilutions, consistent with depletion of tumor-initiator cells in the HMGA1 knock-down cells. In HCT116 cells, we also found that HMGA1 induces expression of Vimentin and Twist1, two genes involved in embryogenesis, EMT, and tumor progression.
Analysis of prior gene expression profile analyses show that HMGA1 is among the most enriched genes in colon cancer compared to normal mucosa and we confirmed this by quantitative, RT-PCR in a subset of primary, high-grade tumors. Taken together, these findings suggest that HMGA1 drives tumor progression by inducing a stem-like state. Although further studies are needed, our results also suggest that HMGA1 or downstream pathways could be rational therapeutic targets in poorly differentiated colon cancer.
1. Resar LMS,
"The High
Mobility Group A1 Gene: Transforming Inflammatory Signals into Cancer?"
2. Hovsepian JH,
"Embryoma Gene Networks".
1. Each cell retains all of its embryonic genes for a lifetime.
2. Controls for embryonic genes are often absent in adults.
3. Uncontrolled embryonic genes can replicate wildly.
4. Replicating genes participate in intra-cellular competition.
5. The basis for gene competition is selective transcription.
6. MicroRNAs can reprogram embryomic transcription.
7. Gene reprogramming can produce normal phenotypes.
8. Normal phenotypes can by-pass chromosomal lesions.
9. MicroRNA therapy may need to be permanent.
10. Transplantation of microRNAs could be preferred.
1. Pathways within cell genomes involve a flow of information.
2. Information can flow by direct contact or by third parties.
3. Direct contact within whole genomes is difficult to regulate.
4. DNA-DNA direct contects are influenced by agents.
5. Nuclear agents include hydrophilic ionic and hydrophobic conforming ligands.
6. Third parties within genomes involve RNAs and proteins.
7. RNAs and proteins are easy to regulate or reverse.
8. Information can be shared, lost, or transformed.
9. System information can be hidden during system isolation.
10. Local information can be permanently lost during system entropy.
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