Article

Integrin alpha 7 interacts with high temperature requirement A2 (HtrA2) to induce prostate cancer cell death.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
American Journal Of Pathology (Impact Factor: 4.6). 09/2010; 177(3):1176-86. DOI: 10.2353/ajpath.2010.091026
Source: PubMed

ABSTRACT Integrins are a family of receptors for extracellular matrix proteins that have critical roles in human tissue development. Previous studies identified down-regulation and/or mutations of integrin alpha7 (ITGA7) in prostate cancer, liver cancer, soft tissue leiomyosarcoma, and glioblastoma multiforme. Here we report that expression of ITGA7 induced apoptosis in the human prostate cancer cell lines PC3 and DU145. Yeast two-hybrid analysis revealed that the C-terminus of ITGA7 interacts with high temperature requirement A2 (HtrA2), a serine protease with a critical role in apoptosis. Expression of ITGA7 increases the protease activity of HtrA2 both in vitro and in vivo. Deletion of the HtrA2 interaction domain abrogates the cell death activity of ITGA7, whereas down-regulation of HtrA2 dramatically reduced cell death mediated by ITGA7. In addition, site-directed protease-null mutant HtrA2S306A expression blocked apoptosis induced by ITGA7. Interestingly, interaction between ITGA7 and its ligand laminin 2 appears to protect against cell death, since depleting laminin beta2 with a small-interfering RNA significantly exacerbated apoptosis induced by ITGA7 expression. This report provides a novel insight into the mechanism by which ITGA7 acts as a tumor suppressor.

Download full-text

Full-text

Available from: Zehua Zhu, Feb 18, 2014
0 Followers
 · 
137 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is the leading cause of cancer deaths among women worldwide, including Thailand. In the present study, the differential mRNA expression of SVEP1, LPHN3, KLB, ITGA7, SEMA3G, TNS1 and MMP13 genes was examined in breast cancer using quantitative real-time reverse transcription polymerase chain reaction (QRT-PCR). Among these genes, increased LPHN3 and MMP13 mRNA expression levels correlated with axillary-node metastasis (P=0.02). Multiple logistic regression analysis revealed that LPHN3 and MMP13 mRNA expression is significantly associated with axillary node status in breast cancer (P=0.04).
    Asian Pacific journal of cancer prevention: APJCP 11/2012; 13(11):5879-82. DOI:10.7314/APJCP.2012.13.11.5879 · 1.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Miniature chromosome maintenance 7 (MCM7) is an essential component of DNA replication licensing complex. Recent studies indicate that MCM7 is amplified and over-expressed in a variety of human malignancies. In this report, we showed that MCM7 binds SF3B3. The binding motif is located in the N-terminus (aa221-248) of MCM7. Knocked-down of MCM7 or SF3B3 significantly increased unspliced RNA of epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and c-met. Dramatic drop of reporter gene expression of oxytocin exon1-intron-exon2-EGFP construct was also identified in SF3B3 and MCM7 knocked-down PC3 and DU145 cells. The MCM7 or SF3B3 depleted cell extract failed to splice reporter RNA in in vitro RNA splicing analyses. Knock-down of SF3B3 and MCM7 leads to increase of cell death of both PC3 and DU145 cells. Such cell death induction is partially rescued by expressing spliced c-met. To our knowledge, this is the first report suggesting that MCM7 is a critical RNA splicing factor, and thus give significant new insight into the oncogenic activity of this protein. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 11/2014; 290(3). DOI:10.1074/jbc.M114.622761 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumor metastasis is one of the causes for the high mortality rate of prostate cancer (PCa) patients, yet the molecular mechanisms of PCa metastasis are not fully understood. In our previous studies, we found that PSMA suppresses the metastasis of PCa, yet the underlying mechanism remains unknown. To identify the genes related to tumor metastasis possibly regulated by PSMA, we performed tumor metastasis PCR array assay to analyze the differentially expressed tumor metastasis-related genes. Eighty-four tumor metastasis related genes were screened in si-PSMA LNCap cells (PSMA silenced by siRNA)/LNCap cells and in PC-3/LNcap cells, respectively. Expression levels of possible related genes were verified by real-time PCR in 4 prostate cancer cell lines (LNCap, 22RV1, PC-3 and DU145) and in 85 clinical samples (12 normal, 26 benign prostatic hypertrophy and 47 prostate cancer tissues). The results showed that 10 genes (including CDH6 and CXCL12) were upregulated and 4 genes (CCL7, ITGB3, MDM2 and MMP2) were downregulated in the si-PSMA LNCap cells. There were 41 genes significantly upregulated and 15 genes downregulated in PC-3 cells when compared with LNCap cells. Eight common genes were found in both the si-PSMA and PSMA(-) groups. CDH6, MMP3, MTSS1 were further identified as PSMA-related genes in the prostate cancer cell lines and clinical samples, and their expression showed a negative correlation with the stage of prostate cancer (P<0.0001) and PSMA level (P<0.05) in clinical samples, indicating their possible involvement in PSMA-related PCa metastasis regulation. These findings may provide insights into the mechanism involved in the suppression of PCa metastasis by PSMA and its possible interacting proteins, and may provide clues for further exploration of the molecular mechanism of PCa metastasis.
    Oncology Reports 08/2013; 30(4). DOI:10.3892/or.2013.2656 · 2.19 Impact Factor