Interactions between growth factors secreted by the stroma cells, extracellular matrix, and their receptors on carcinoma cells resulting in signal transduction are key to understanding the mechanisms underlying carcinoma cell migration and invasion. Such understanding requires identification of the genes induced by these interactions and the convergence of signaling pathways. Scatter factor, also known as Hepatocyte growth factor, (SF) and its tyrosine kinase protooncogene, Met, are upregulated in most metastatic cancers and is associated with a poor prognosis. SF causes migration of cancer cells, a process that requires de novo gene transcription. However, the early genes expressed by this new transcription are not known. Our long range goal is to determine carcinoma cell specific targets to inhibit metastasis. We have isolated a novel cDNA we call Mig-7 that is induced by SF in the human endometrial carcinoma cell lines, RL-95 [and HECIA, as well as the pancreatic carcinoma cell line FG] before migration occurs. Homology searches show that Mig-7 cDNA sequence possesses 99% homology with two human ESTs. However, no full length cDNA, gene or protein homologies were found. Expression of this gene is lacking in normal tissue as determined by reverse transcription and polymerase chain reaction. In contrast, it is detected in various metastatic human tumors such as ovary, colon, endometrial and squamous cell. Furthermore, the Mig-7 induction by SF is also regulated by ?v?5 integrin ligation. The focus of this proposal is to understand the role of Mig-7 in expression in carcinoma cell migration. Our hypothesis is that Mig-7 expression plays a role in migration of cancer cells. To test this hypothesis and accomplish the objective of this application we will pursue the following two specific aims:
Aim 1 is to determine if the degree of cell migration is dependent upon the level of Mig-7 expression in carcinoma cells to test our hypothesis that Mig-7 expression leads to migration of carcinoma cells. [We base our hypothesis on our preliminary results showing that we can inhibit carcinoma cell migration by 83.50% +/- 2.77% (p<0.05) in vitro using antisense oligonucleotides specific to Mig-7 as compared to irrelevant oligonucleotide.] We will overexpress Mig-7 in carcinoma cell lines and measure migration and invasion capabilities as compared to controls using migration [and invasion] assays.
Aim 2 is to determine the signaling mechanism underlying the cross talk between the Met and alphavbeta5 integrln signal transduction pathways because our studies indicate that both Met and alphavbeta5 integrin signaling pathways are required to induce Mig-7 expression. [Met activation has been shown to activate focal adhesion kinase (FAK). Further, tyrosine kinase receptor induction of FG carcinoma cell migration requires alphavbeta5 integrin binding. However, gene expression resulting from this cross-talk signaling has not been determined.] Mig-7 is a novel gene expressed in this signaling system. We expect that these studies will lead to a significant advance in the knowledge of how carcinoma cells migrate and could lead to a target for new anti-metastatic therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA093925-01A1
Application #
6681190
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Mohla, Suresh
Project Start
2003-09-01
Project End
2004-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$111,000
Indirect Cost
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
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Prante, Brianna C; Garman, Kiera L; Sims, Brandon N et al. (2008) Matrix-coated transwell-cultured TM4 sertoli cell testosterone-regulated gene expression mimics in vivo expression. In Vitro Cell Dev Biol Anim 44:434-43
Petty, Aaron P; Dick, Charles L; Lindsey, J Suzanne (2008) Translation of an atypical human cDNA requires fidelity of apurine-pyrimidine repeat region and recoding. Gene 414:49-59
Petty, Aaron P; Garman, Kiera L; Winn, Virginia D et al. (2007) Overexpression of carcinoma and embryonic cytotrophoblast cell-specific Mig-7 induces invasion and vessel-like structure formation. Am J Pathol 170:1763-80
Gaasch, Julie A; Bolwahnn, Alanna B; Lindsey, J Suzanne (2006) Hepatocyte growth factor-regulated genes in differentiated RAW 264.7 osteoclast and undifferentiated cells. Gene 369:142-52
Phillips, Troy M; Lindsey, J Suzanne (2005) Carcinoma cell-specific Mig-7: a new potential marker for circulating and migrating cancer cells. Oncol Rep 13:37-44