Studies in liver and breast have indicated that extracellular matrix plays a critical role in limiting the growth and promoting the differentiation of epithelial cells. However, the signaling mechanism that leads to inhibition of over-growth of epithelial cells is not well understood. Recently, we performed a mutational analysis on ITGA7 gene (ITGA7). We found mutations on ITGA7 in prostate cancer, hepatocellular carcinoma, leiomyosarcoma and glioblastoma multiforms with frequencies ranging from 25% to 83%. Many of these mutations caused truncation, micro-deletion or frameshift of the protein. Interestingly, patients with ITGA7 mutations had higher rate of clinical relapse in both prostate cancer and hepatocellular carcinoma. Mouse model of PC3 and Du145 xenografted prostate tumors showed a dramatic reduction in tumor volume, rate of metastasis and rate of mortality when expression of ITGA7 was restored in these cell lines. ITGA7 induced the expression of cyclin dependent kinase inhibitor 3 (CDKN3) and RACGAP1. siRNA knocking down of CDKN3 and RACGAP1 completely reversed the growth inhibition effect of IGGA7, while only partially reversed the migration inhibition activity. Recently, Annexin V staining and TUNEL assays indicated that over-expression of ITGA7 induced apoptosis in PC3 cells. Through a Yeast two-hybrid system, we identified that the C-terminus of ITGA7 interacted with HtrA2, a cell death protein. A 30 amino acid motif located in the C-terminus of ITGA7 was identified as critical for its interaction with HtrA2. Expression of ITGA7 induced protease activity of HtrA2. siRNA knocking down of HtrA2 abolished the cell death induction by ITGA7. Separately, expression of ITGA7 induced the kinase activity of integrin link kinease (ILK). Interestingly, we also found that ILK, a serine/threonine kinase and structural protein associated with integrins and the cytoskeleton, bound and phosphorlyated a tumor suppressor gene called myopodin, which regulates cell growth and cell motility. Based on these preliminary data, we hypothesize that ITGA7 activates HtrA2 and ILK signaling pathways to achieve induction of apoptosis, cell growth inhibition and migration deceleration. In this study, we propose: 1) To elucidate the role of ITGA7/HtrA2 interaction in mediating cell death and inhibition of cancer invasion by analyzing the mutant ITGA7 molecule defective of binding with HtrA2 in PC3 and DU145 cells;2) To investigate the role of ILK/myopodin interaction in ITGA7 regulated cell motility, cell growth and inhibition of invasiveness by analyzing myopodin defective cell system;3) To study the impact of ITGA7 knock-out on the carciongenesis of TRAMP mice, and to investigate the biological role of ITGA7 in prostate gland tissue development, cell differentiation and tumorigenesis in pure ITGA7 knockout mice.
The project is to investigate how integrin ?7 dictates cell growth, migration, cell death and invasiveness in prostate cancer, what role integrin ?7 plays in prostate gland organogenesis and prostate cancer development, and whether restoration of integrin ?7 expression has a role in suppressing metastasis for prostate cancer.
|Zuo, Ze-Hua; Yu, Yan P; Martin, Amantha et al. (2017) Cellular stress response 1 down-regulates the expression of epidermal growth factor receptor and platelet-derived growth factor receptor through inactivation of splicing factor 3A3. Mol Carcinog 56:315-324|
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|Chen, Zhang-Hui; Yu, Yan P; Tao, Junyan et al. (2017) MAN2A1-FER Fusion Gene Is Expressed by Human Liver and Other Tumor Types and Has Oncogenic Activity in Mice. Gastroenterology 153:1120-1132.e15|
|Chen, Zhang-Hui; Yu, Yan P; Zuo, Ze-Hua et al. (2017) Targeting genomic rearrangements in tumor cells through Cas9-mediated insertion of a suicide gene. Nat Biotechnol 35:543-550|
|Chen, Zhang-Hui; Yu, Yan P; Michalopoulos, George et al. (2015) The DNA replication licensing factor miniature chromosome maintenance 7 is essential for RNA splicing of epidermal growth factor receptor, c-Met, and platelet-derived growth factor receptor. J Biol Chem 290:1404-11|
|Luo, Jian-Hua; Liu, Silvia; Zuo, Ze-Hua et al. (2015) Discovery and Classification of Fusion Transcripts in Prostate Cancer and Normal Prostate Tissue. Am J Pathol 185:1834-45|
|Yu, Yan P; Liu, Silvia; Huo, Zhiguang et al. (2015) Genomic Copy Number Variations in the Genomes of Leukocytes Predict Prostate Cancer Clinical Outcomes. PLoS One 10:e0135982|
|Zuo, Ze-Hua; Yu, Yan P; Ding, Ying et al. (2015) Oncogenic Activity of miR-650 in Prostate Cancer Is Mediated by Suppression of CSR1 Expression. Am J Pathol 185:1991-9|
|Yu, Yan P; Michalopoulos, Amantha; Ding, Ying et al. (2014) High fidelity copy number analysis of formalin-fixed and paraffin-embedded tissues using Affymetrix Cytoscan HD chip. PLoS One 9:e92820|
|Yu, Yan P; Ding, Ying; Chen, Zhanghui et al. (2014) Novel fusion transcripts associate with progressive prostate cancer. Am J Pathol 184:2840-9|
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