Prostate cancer is the most common malignancy in North American men. However, the genetic events associated with the malignant transformation of prostatic cells are largely unknown. Identification of new prostate specific genes could provide new markers and could be instrumental for development of new treatment modalities. Cten (C-terminal tensin-like) is a new focal adhesion molecule, whose expression is relatively restricted at the normal prostate gland. We have reported that cten is absent or down-regulated in prostate cancers, is a target of caspase 3 and an effector during apoptosis, regulates cell migration, recruits a tumor suppressor, DLC1 (deleted in liver cancer 1), to focal adhesions and this interaction is critical for DLC1's tumor suppression activity. Interestingly, cten localizes not only to focal adhesions but also in the nucleus, suggesting that cten may be a transducer molecule, possibly involved in nuclear events in addition to events at the cell surface. Human cten gene is located on chromosome 17q21, a region often deleted in prostate cancer. These studies suggest that cten is a prostate-specific tumor suppressor whose disruption has repercussions in prostate cancer. However, our recent studies have shown that although not normally expressed in other tissues, cten is overexpressed in a large number of colon cancer patients, indicating that cten may possess an oncogenic activity in the colon. Therefore, cten may have dual functions that are tissue type specific. In this renewal proposal we will continually investigate the role of cten in the prostate and offer a molecular mechanism for the seemingly contradictory function of cten in colon cancer. We hypothesize that cten is a prostate-specific tumor suppressor that plays important roles at the focal adhesions and in the nucleus; and that alteration of cten expression/ function disrupts its normal actions and increases the risk for prostate cancer.
Three specific aims are proposed to test our hypothesis.
Aim 1. To determine the role of cten in regulating the tumor suppression activity of DLC1 Aim 2. To establish the mechanism of cten nuclear translocation and its role in tumorigenesis Aim 3. To demonstrate the function of cten in prostate tumorigenesis using in vivo systems The gene to be studied is a very unique molecule, a focal adhesion-nucleus protein that may regulate the DLC1 tumor suppressor at focal adhesions and mediate a crosstalk between Wnt and androgen signaling in the nucleus. Verification of our hypothesis would indicate a possible role for cten as a novel therapeutic target for prostate cancer and maybe other cancer types as well. Our animal studies will reveal cten's in vivo function and provide better mouse prostate cancer models for studying prostate tumorigenesis and drug screening.
Prostate cancer is the most common malignancy in North American men. However, the genetic events associated with the malignant transformation of prostatic cells are largely unknown. Cten is a very unique focal adhesion-nucleus protein that may regulate the DLC1 tumor suppressor at focal adhesions and mediate a crosstalk between Wnt and androgen signaling and gene expression in the nucleus. Our proposed studies may offer a possible role for cten as a novel therapeutic target for prostate cancer and other cancer types as well. Our animal studies may provide better mouse prostate cancer models for studying prostate tumorigenesis and drug screening.
|Yang, Kuan; Wu, Wei-Ming; Chen, Ya-Chi et al. (2016) ?Np63? Transcriptionally Regulates the Expression of CTEN That Is Associated with Prostate Cell Adhesion. PLoS One 11:e0147542|
|Hong, Shiao-Ya; Shih, Yi-Ping; Sun, Peng et al. (2016) Down-regulation of tensin2 enhances tumorigenicity and is associated with a variety of cancers. Oncotarget 7:38143-38153|
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|Hung, Shih-Ya; Shih, Yi-Ping; Chen, Michelle et al. (2014) Up-regulated cten by FGF2 contributes to FGF2-mediated cell migration. Mol Carcinog 53:787-92|
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|Hong, Shiao-Ya; Shih, Yi-Ping; Li, Tianhong et al. (2013) CTEN prolongs signaling by EGFR through reducing its ligand-induced degradation. Cancer Res 73:5266-76|
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|Shih, Yi-Ping; Takada, Yoshikazu; Lo, Su Hao (2012) Silencing of DLC1 upregulates PAI-1 expression and reduces migration in normal prostate cells. Mol Cancer Res 10:34-9|
|Lin, Y; Chen, N-T; Shih, Y-P et al. (2010) DLC2 modulates angiogenic responses in vascular endothelial cells by regulating cell attachment and migration. Oncogene 29:3010-6|
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