Correlation between SHP-1 and carotid plaque vulnerability in humans.

BACKGROUND: Advanced atherosclerotic plaques tend to indicate an increased risk of cerebral ischemic events. SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a class I classical nonreceptor protein tyrosine phosphatase associated with plaque stability, as shown by analysis of a Gene Expression Omnibus (GEO) dataset showing differences in mRNA levels. However, the correlation between SHP-1 and human carotid plaque stability at the protein level remains unclear. METHODS AND RESULTS: Thirty-nine carotid plaque tissue samples were acquired from 39 carotid artery stenosis patients after carotid endarterectomy. Hematoxylin and eosin, Masson trichrome, and CD68 staining was performed for pathological characterization, and immunohistochemical staining for SHP-1 was carried out. Within stable and unstable plaques, SHP-1 mainly accumulated in the necrotic area, plaque shoulder, and fibrous cap, similar to the distribution of CD68. A quantitative analysis of SHP-1 was carried out. The relative SHP-1-positive cell area was higher in the vulnerable group than in the stable group (P < .001). The number of symptomatic patients in the vulnerable group was no greater than that in the stable group (P = .098). Moreover, the integrated optical density (IOD)/area of SHP-1 was significantly higher in the vulnerable group than in the stable group (P < .001). Besides, SHP-1 colocalized with CD68 and vascular cell adhesion protein 1(VCAM-1). CONCLUSIONS: We demonstrate that SHP-1 expression increases during carotid atherosclerotic plaque progression. The protein expression of SHP-1 was related to an increase in plaque instability in not only symptomatic but also asymptomatic patients with carotid artery stenosis. SHP-1 may play a role in atherosclerosis progression by macrophage polarization-mediated efferocytosis. Furthermore, SHP-1 may become a promising biomarker for plaque vulnerability in the future.

Immunohistochemical detection of tyrosine phosphatase SHP-1 predicts outcome after radical prostatectomy for localized prostate cancer.

The protein tyrosine kinase (PTK) receptors and cytosolic signaling proteins as well as the protein tyrosine phosphatases (PTPs) have important roles in regulation of growth of the benign and malignant prostate gland. Here, we studied expression of the protein tyrosine phosphatase SHP-1 in prostate cancer cell lines and in human prostatic tissues. SHP-1 is expressed at a high level in LNCaP prostate cancer cells compared with PC3 cells. Silencing of SHP-1 expression with siRNA in LNCaP cells led to an increased rate of proliferation, whereas overexpression of SHP-1 by means of transient and stable transfection in PC3 cells led to a decrease in proliferation. Corresponding changes were observed in cyclin D1 expression. We further demonstrate that LNCaP and PC3 cells respond differently to IL-6 stimulation. SHP-1 overexpression in PC3 cells reversed IL-6 stimulation of proliferation, whereas in SHP-1-silenced LNCaP cells, IL-6 inhibition of proliferation was not affected. In addition, IL-6 treatment led to higher levels of phosphorylated STAT3 in SHP-1-silenced LNCaP cells than in control cells. Next, SHP-1 expression in human prostate cancer was analyzed by immunohistochemical staining of tissue microarrays comprising tumor specimens from 100 prostate cancer patients. We found an inverse correlation between the tumor level of SHP-1 expression and time to biochemical recurrence and clinical progression among prostate cancer patients. In conclusion, our results suggest that a decreased level of SHP-1 expression in prostate cancer cells is associated with a high proliferation rate and an increased risk of recurrence or clinical progression after radical prostatectomy for localized prostate cancer.

Expression of PTEN and SHP1, investigated from tissue microarrays in pediatric acute lymphoblastic, leukemia.

PTEN and SHP1 are tumor suppressor genes involved in the regulation of cell cycle control and apoptosis. The authors investigated the protein expression of PTEN and SHP1, by immunohistochemistry in tissue microarrays from bone marrow samples in children, diagnosed with acute lymphoblastic leukaemia and nonmalignant controls. PTEN was overexpressed in diagnostic ALL samples, while SHP1 showed a low expression. Both proteins showed a significant difference in expression compared to nonmalignant controls. The roles of PTEN and SHP1 are not well investigated in pediatric leukemia and could in the future play a role as prognostic factors.

Elevated expression of the tyrosine phosphatase SHP-1 defines a subset of high-grade breast tumors.

OBJECTIVES: Protein tyrosine phosphatases are key regulators of intracellular signaling that contribute to determining cancer cell growth, which thus makes them attractive targets for therapeutic and diagnostic agents. SHP-1 phosphotyrosine phosphatase is rarely expressed in epithelial tumor cells, but expression has been found in several breast cancer cell lines and tumors. To determine the potential significance of SHP-1 as a prognostic marker in the clinical setting, we examined SHP-1 protein expression in breast tumors. METHODS: We analyzed SHP-1 expression by immunohistochemistry in a breast tissue microarray composed of 2,081 cores, either alone or in combination with known prognostic markers. RESULTS: Our data showed that SHP-1 expression was confined to a well-defined subset of high-grade tumors characterized by unique biological parameters. SHP-1 expression correlated directly with expression of the tyrosine kinase receptor HER-2 and inversely with expression of the estrogen receptor, while it was weakly associated with Bcl-2 expression. CONCLUSIONS: Levels of SHP-1 were correlated with conventional pathologic parameters of tumor aggressiveness and were associated with reduced patient survival, suggesting that elevated expression of SHP-1 is a common molecular abnormality in a defined subset of breast tumors and might be used in routine diagnosis to identify patients with high-risk tumors.

TIMP1 induces CD44 expression and the activation and nuclear translocation of SHP1 during the late centrocyte/post-germinal center B cell differentiation.

Tissue inhibitor of metalloproteinase-1 (TIMP1) is a survival factor of germinal center (GC) B cells, and its over-expression is correlated with aggressive B cell lymphomas and classical Hodgkin lymphomas. We previously demonstrated that TIMP1 down-regulates B-cell receptor and BCL6, and activates interleukins-6,-10 (ILs)/signal transducer and activator of transcription-3 (STAT3) signaling in GC B cells. The activation of ILs/STAT3 signaling can amplify CD44 function, and vice versa, and induce protein-tyrosine phosphatase SHP1 activity by a negative feedback mechanism. Here, we show that TIMP1 up-regulates cell surface CD44 (standard and variants 3 and 7-10) and induces the activity and nuclear localization of SHP1 in an Epstein Barr virus (EBV)-negative Burkitt lymphoma cell line, the neoplastic counterpart of GC centroblasts. These results suggest that TIMP1 functions as a differentiating and survival factor of GC B cells by modulating CD44 and SHP1 in the late centrocyte/post-GC stage, regardless of EBV infection.