Prognostic value of ZFP36 and SOCS3 expressions in human prostate cancer

Purpose: ZFP36 ring finger protein (ZFP36) and the suppressor of cytokine signaling 3 (SOCS3) have been reported to, respectively, regulate NF-jB and STAT3 signaling pathways. To better understand the correlation of NF-jB and STAT3 negative regulates pathway, we have investigated the involvement of ZFP36 and SOCS3 expressions in human prostate cancer (PCa). Methods: In the present study, paired patient tissue microarrays were analyzed by immunohistochemistry, and the ZFP36 protein expression was quantitated as immunoreactive scores in patients with PCa. Associations between ZFP36/SOCS3 expression and various clinicopathological features and prognosis of PCa patients were statistically analyzed based on the Taylor database. Then, the functions of ZFP36 and SOCS3 in cancerous inflammation were determined using qPCR and immunohistochemistry in vitro and in vivo. Results: ZFP36 protein expression in PCa tissues was significantly lower than those in non-cancerous prostate tissues (P < 0.05). In mRNA level, ZFP36 and SOCS3 had a close correlation with each other (P < 0.01, Pearson r = 0.848), and its upregulation was both significantly associated with low Gleason score (P < 0.001 and P < 0.001, respectively), negative metastasis (P < 0.001 and P < 0.001, respectively), favorable overall survival (P < 0.001 and P < 0.05, respectively), and negative biochemical recurrence (P < 0.001 and P < 0.001, respectively). Functionally, LPS treatment could lead to the overexpression of ZFP36 and SOCS3 in vitro and vivo. Conclusions: Our data offer the convincing evidence for the first time that the aberrant expressions of ZFP36 and SOCS3 may be involved into the progression and patients’ prognosis of PCa, implying their potentials as candidate markers of this cancer

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Prognostic value of ZFP36 and SOCS3 expressions in human prostate cancer.

PURPOSE: ZFP36 ring finger protein (ZFP36) and the suppressor of cytokine signaling 3 (SOCS3) have been reported to, respectively, regulate NF-κB and STAT3 signaling pathways. To better understand the correlation of NF-κB and STAT3 negative regulates pathway, we have investigated the involvement of ZFP36 and SOCS3 expressions in human prostate cancer (PCa). METHODS: In the present study, paired patient tissue microarrays were analyzed by immunohistochemistry, and the ZFP36 protein expression was quantitated as immunoreactive scores in patients with PCa. Associations between ZFP36/SOCS3 expression and various clinicopathological features and prognosis of PCa patients were statistically analyzed based on the Taylor database. Then, the functions of ZFP36 and SOCS3 in cancerous inflammation were determined using qPCR and immunohistochemistry in vitro and in vivo. RESULTS: ZFP36 protein expression in PCa tissues was significantly lower than those in non-cancerous prostate tissues (P < 0.05). In mRNA level, ZFP36 and SOCS3 had a close correlation with each other (P < 0.01, Pearson r = 0.848), and its upregulation was both significantly associated with low Gleason score (P < 0.001 and P < 0.001, respectively), negative metastasis (P < 0.001 and P < 0.001, respectively), favorable overall survival (P < 0.001 and P < 0.05, respectively), and negative biochemical recurrence (P < 0.001 and P < 0.001, respectively). Functionally, LPS treatment could lead to the overexpression of ZFP36 and SOCS3 in vitro and vivo. CONCLUSIONS: Our data offer the convincing evidence for the first time that the aberrant expressions of ZFP36 and SOCS3 may be involved into the progression and patients' prognosis of PCa, implying their potentials as candidate markers of this cancer.

Tristetraprolin downregulates the expression of both VEGF and COX-2 in human colon cancer.

BACKGROUND/AIMS: Although both VEGF and COX-2 are important factors influencing angiogenesis (and thus, carcinogenesis), the regulation of these factors in carcinogenesis remains poorly understood. The aim is to investigate the effects of tristetraprolin, an AU-rich element-binding protein on the expression of VEGF and COX-2 in human colon cancer cells. METHODOLOGY: Expression of TTP, VEGF and COX-2 in the resected colorectal cancer surgical specimens were analyzed by immunohistochemistry. Colon cancer cells were transfected with luciferase reporter linked to 3'UTR of VEGF or COX-2. The effects of TTP overexpression on the expression of VEGF, COX-2 and luciferase were determined by semiquantitative RT-PCR or luciferase assay. RESULTS: Immunohistochemical staining of resected colorectal cancer surgical specimens revealed that TTP expression was low in cancer cells but high in non-malignant mucosa. In contrast, the expression of both COX-2 and VEGF was high in cancer cells and very low in non-malignant mucosa. TTP overexpression markedly decreased the expression of both COX-2 and VEGF in colon cancer cells. In addition, TTP inhibited the expression of luciferase linked to 3'UTR of COX-2 or VEGF mRNA. CONCLUSIONS: TTP inhibits the expression of both VEGF and COX-2 and reduced expression of TTP may be responsible for the increased expression of COX-2 and VEGF in human colorectal cancer.

Cinnamon polyphenol extract affects immune responses by regulating anti- and proinflammatory and glucose transporter gene expression in mouse macrophages.

Tristetraprolin (TTP/zinc finger protein 36) family proteins have antiinflammatory effects by destabilizing proinflammatory mRNA. TTP expression is reduced in fats of obese people with metabolic syndrome and brains of suicide victims and is induced by insulin and cinnamon polyphenol extract (CPE) in adipocytes, by lipopolysaccharide (LPS) in macrophages, and by green tea polyphenol extract in rats. CPE was reported to improve immune function against microorganisms, but the mechanism is unknown. This study tested the hypothesis that CPE regulates immune function involving genes encoding TTP, proinflammatory cytokines, and glucose transporter (GLUT) families and compared the effects of CPE to those of insulin and LPS in mouse RAW264.7 macrophages. CPE increased TTP mRNA and protein levels, but its effects were less than LPS. CPE (100 mg/L, 0.5-4 h) increased TTP and tumor necrosis factor (TNF) mRNA levels by up to 2- and 6-fold that of the control, respectively, and the base level of TTP was 6-fold that of TNF. LPS (0.1 mg/L, 4 h) increased TTP, TNF, granulocyte-macrophage colony-stimulating factor, cyclooxgenase-2, and interleukin 6 mRNA levels by 39-1868 fold. CPE and LPS increased GLUT1 expression (the major GLUT form in macrophages) to 3- and 2-fold that of the control, respectively. Insulin (100 nmol/L, 0.5-4 h) did not exhibit major effects on the expression of these genes. CPE increased TTP expression more rapidly than those of proinflammatory cytokines and the net increases of TTP mRNA levels were larger than those of proinflammatory cytokines. These results suggest that CPE can affect immune responses by regulating anti- and proinflammatory and GLUT gene expression.

The U(L)41 protein of herpes simplex virus 1 degrades RNA by endonucleolytic cleavage in absence of other cellular or viral proteins.

The herpes simplex virus 1 ORF U(L)41 encodes a protein (virion host shutoff or vhs) associated with selective degradation of mRNA early in infection. Some mRNAs, exemplified by GAPDH or beta-actin mRNAs, are degraded rapidly. Others, for example IEX-1 mRNA, are degraded in two stages: whereas the 3' domain disappears rapidly, a large 5' domain fragment of the mRNA lingers for several hours. Still a third, exemplified by tristetraprolin mRNA, is not degraded, allowing its protein product to accumulate in infected cells. Here we report the following: (i) a GST-vhs protein produced in Escherichia coli, solubilized and purified to homogeneity acts as bona fide endoribonuclease when tested on in vitro transcribed IEX-1 probes. A GST-vhs protein in which three key vhs amino acids were replaced with alanines, solubilized and purified by the same protocol, had no enzymatic activity. (ii) The number of fragments generated by cleavage of a truncated IEX-1 RNA by vhs appears to be small; the cleavage sites are centered at or near the AU-rich elements located at the 3' untranslated region of the mRNA. A truncated RNA containing only the IEX-1 coding domain was cleaved numerous times. (iii) In cells infected at high multiplicity and exposed to a large number of particles per cell, the vhs protein accumulated within 3 h after infection, in small uniform cytoplasmic granules raising the possibility that vhs colocalizes with tristerapolin, a protein induced after infection, in structures involved in degradation of RNA.