Shambhavi Singh and Mary Durston ACF Abstract FY13

Identifying a regulatory role for the tumor metastasis suppressor gene KAI1/CD82 in metastatic prostate cancer cell lines

2012 American Society of Cell Biology (ASCB) Annual Meeting

KAI1/CD82, a metastasis prostate tumor suppressor gene expression is lost when the cancer progresses from a primary to a metastatic stage. CD82 has also been shown to be down-regulated in cancers of the gastrointestinal tract, colon, cervix, breast, lung, pancreas, skin, thyroid and liver etc. As a member of the tetraspanin family of proteins, CD82 interacts with proteins and may act as a master regulator of membrane organization at the cell surface. Even though some of the interacting proteins have been identified, the significance of these associations and its role in metastasis prevention is unclear. By reintroducing CD82 into highly metastatic prostate cells (PC3), we have shown CD82 to regulate c-Met (phosphorylation) and activation. Currently we are focused on studying the exact mechanism by which CD82 regulates c-Met. CD82 does not seem to associate with c-Met nor does it seem to down-regulate c-Met. Preliminary indications are that as a tetraspanin and thus as a molecular organizer it may be redistributing c-Met on the cell surface. It is also highly possible that it may bring a c-Met specific phosphatase (such as DEP-1) to the surface to dephosphorylate and deactivate c-Met. We are currently exploring both possibilities. Even though we have identified c-Met protein to be regulated by CD82, we have reason to believe that there may be more proteins regulated by CD82. Microarray studies done on CD82 (+/-), on both tumor and normal prostate cells suggests that CD82 may be regulating genes involved in cell cycle, growth, and metastatic suppression. To validate the results, we have utilized Q-PCR assays, investigating genes specifically involved in metastasis suppression and growth. These genes include: CXCR4, CXCR7, RUNX3, TFF-3, and MMP10. CXCR4 and CXCR7 are chemokine receptors, RUNX3, a tumor suppressor gene, and MMP10, which encodes the matrix metalloproteinase 10 needed for invasion and continuation of metastasis. Two of the genes involved in metastasis (TFF-3, RUNX-3) have been quantified and the data correlates with the microarray data. MMP10, CXCR4, and CXCR7 are currently being validated. Identifying the proteins regulated by CD82 and deciphering the downstream signaling mechanisms involved in this regulation is the focus of our future studies.   

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