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Activated epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target for a variety of solid tumors, particularly malignant gliomas. A recently discovered transmembrane glycoprotein, LRIG1, antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases and acts as a negative feedback loop of EGFR and proposed tumor suppressors. The aim of this study was to investigate the impact of LRIG1 on the biological features of glioma cells and the possible mechanisms of enhanced apoptosis induced by upregulation of LRIG1. We observed that the expression of LRIG1 was decreased, while the expression of EGFR was increased in the majority of astrocytomas, and the ratio of EGFR/LRIG1 was increased by sixfold in tumors versus corresponding non-neoplastic tissue. Upregulation of LRIG1, followed by a decrease of EGFR on the cytomembrane of the cells, induced cell apoptosis and cell growth inhibition, and further reversed invasion in glioma cell lines and primary glioma cells. Our study now clearly indicates that LRIG1 indeed affects cell fate and biology behaviors of the cells in vitro by inhibiting phosphorylation of downstream MAPK and AKT signaling pathway, and the elevated release level of caspase-8 might contribute to the enhanced apoptosis in LRIG1 transfected glioma cells. Taken together, these findings provide us with an insight into LRIG1 function, and we conclude that LRIG1 evolved in gliomas as a rare feedback negative attenuator of EGFR and could offer a novel therapeutic target to treat patients with malignant gliomas.

The leucine-rich and immunoglobulin-like domains (LRIG) gene family contains LRIG1, 2 and 3. LRIG1 is a negative regulator of EGFR, but little is known about the function of LRIG2. To determine the role of LRIG2 in the progression of glioma, we performed RNA interference-mediated knockdown of LRIG2 in a human glioma cell line (GL15). Downregulation of LRIG2 expression resulted in: rapid EGF-mediated loss of EGFR; decreased proliferation; G(0)/G(1) arrest; increased spontaneous apoptosis; enhanced cell adhesion and increased invasion capability of GL15 cells in vitro. These findings indicate that LRIG2 possesses distinct functions compared with LRIG1 and validate the attractiveness of LRIG2 as a target in glioma therapy.

Peroxisome proliferators activate nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) and enhance the transcription of several genes in liver. We report here that synthetic PPARalpha ligands Wy-14,643, ciprofibrate, clofibrate, and others induce the nuclear translocation of constitutive androstane receptor (CAR) in mouse liver cells in vivo. Adenoviral-enhanced green fluorescent protein-CAR expression demonstrated that PPARalpha synthetic ligands drive CAR into the hepatocyte nucleus in a PPARalpha- and PPARbeta-independent manner. This translocation is dependent on the transcription coactivator PPAR-binding protein but independent of coactivators PRIP and SRC-1. PPARalpha ligand-induced nuclear translocation of CAR is not associated with induction of Cyp2b10 mRNA in mouse liver. PPARalpha ligands interfered with coactivator recruitment to the CAR ligand binding domain and reduced the constitutive transactivation of CAR. Both Wy-14,643 and ciprofibrate occupied the ligand binding pocket of CAR and adapted a binding mode similar to that of the CAR inverse agonist androstenol. These observations, therefore, provide information for the first time to indicate that PPARalpha ligands not only serve as PPARalpha agonists but possibly act as CAR antagonists.

Disruption of the genes encoding for the transcription coactivators, peroxisome proliferator-activated receptor (PPAR)-interacting protein (PRIP/ASC-2/RAP250/TRBP/NRC) and PPAR-binding protein (PBP/TRAP220/DRIP205/MED1), results in embryonic lethality by affecting placental and multiorgan development. Targeted deletion of coactivator PBP gene in liver parenchymal cells (PBP(LIV-/-)) results in the near abrogation of the induction of PPARalpha and CAR (constitutive androstane receptor)-regulated genes in liver. Here, we show that targeted deletion of coactivator PRIP gene in liver (PRIP(LIV-/-)) does not affect the induction of PPARalpha-regulated pleiotropic responses, including hepatomegaly, hepatic peroxisome proliferation, and induction of mRNAs of genes involved in fatty acid oxidation system, indicating that PRIP is not essential for PPARalpha-mediated transcriptional activity. We also provide additional data to show that liver-specific deletion of PRIP gene does not interfere with the induction of genes regulated by nuclear receptor CAR. Furthermore, disruption of PRIP gene in liver did not alter zoxazolamine-induced paralysis, and acetaminophen-induced hepatotoxicity. Studies with adenovirally driven EGFP-CAR expression in liver demonstrated that, unlike PBP, the absence of PRIP does not prevent phenobarbital-mediated nuclear translocation/retention of the receptor CAR in liver in vivo and cultured hepatocytes in vitro. These results show that PRIP deficiency in liver does not interfere with the function of nuclear receptors PPARalpha and CAR. The dependence of PPARalpha- and CAR-regulated gene transcription on coactivator PBP but not on PRIP attests to the existence of coactivator selectivity in nuclear receptor function.

To estimate the bioconcentration factor (BCF) of benzene derivatives in fish by gas chromatography retention time (t(R)), this paper measured the BCF of chlorobenzene, o-chloro-toluene, p-dichlorobenzene, m-dichlorobenzene, 1,2-dichlorobenzene, nitrobenzene, p-chloro-aniline, p-chloro-nitrobenzene, and 4-chlorodiphenyl in grass crap, and the t(R) of test derivatives on the stationary phases of six kinds polarity. The monodic regression equation (Type I Eq.) of BCF and t(R) and the binary regression equation (Type II Eq.) of BCF, t(R) and 1X(V) were established, and the statistical test showed that there was a significant correlation between BCF and t(R), and the average correlation coefficients on stationary phases of six kinds polarity were 0.952 and 0.965, respectively. The regression equations could be used to estimate the BCF of the benzene derivatives in grass crap, and the results were not affected by the polarity of stationary phases.

We have previously characterized three human leucine-rich repeats and immunoglobulin-like domains (LRIG) genes and proteins, named LRIG1-3 and proposed that they may act as suppressors of tumor growth. The LRIG1 transmembrane protein antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases. In this study, we evaluated the mRNA expression level of LRIG1-3 in human glioma cell lines and control-matched glioma tissues, characterized the sub-cellular localization of an LRIG3-GFP fusion protein, and analyzed the relationship between sub-cellular localization of LRIG1-3 and clinical parameters in 404 astrocytic tumors by immunohistochemistry. LRIG1-3 mRNA was detected in all human glioma cell lines and matched glioma samples, with large differences in the expression levels. Ectopically expressed LRIG3-GFP localized to perinuclear and cytoplasmic compartments, and to the cell surface of transfected glioma cells. Perinuclear staining of LRIG1-3 was associated with low WHO grade and better survival of the patients. Perinuclear staining of LRIG3 was associated with a lower proliferation index and was in addition to tumor grade, an independent prognostic factor. Furthermore, within the groups of grade III and grade IV tumors, perinuclear staining of LRIG3 significantly correlated with better survival. These results indicate that expression and sub-cellular localization of LRIG1-3 might be of importance in the pathogenesis and prognosis of astrocytic tumors.

The expression of epidermal growth factor receptor (EGFR) and leucine-rich repeats and immunoglobulin-like domain 1 (LRIG-1) in human trigeminal neurinoma was investigated and their effect on the origination and development of trigeminal neurinoma, and the relationship between them was studied. By using immunohistochemistry with tissue chip, the expression of EGFR and LRIG-1 was detected in 23 cases of trigeminal neurinoma. It was found that in the 23 cases, the expression rate of EGFR was 21.74%, while that of the LRIG-1 was 78.26%. There was a negative correlation between them. It was suggested that LRIG-1 might inhibit the malignant differentiation and proliferation of the trigeminal neurinoma possibly by the negative feedback loop of EGFR.

From May, 2000 to June, 2001, 27 patients with Parkinson disease (PD), including 10 cases of rigidity, 13 cases of tremor, 4 cases of rigidity and tremor, were treated by microelectrode-guided technique. Among them, phlebotomy was carried out in 17 cases and thalamotomy in 10 cases. All the targets of lesion were anatomically located by using MR and neurophysiological signals on microelectrode. Our results showed that the efficiency of microelectrode-guided technique for treatment of PD was 98%. The postoperative unified parkinson disease rating scale were 12.3 +/- 9.1 and 13.2 +/- 8.9 respectively, which significantly improved as compared with those before operation. It was concluded that by recognizing special electrical signals in neurons microelectrode-guided neuropsychological techniques can locate target at cellular level, which overcomes the individual difference in anatomy and function, and allow more accuracy, safety and efficiency of operation. This is especially true of PD patients who fail to respond to medical treatment.