Integrin ß6 can be translationally regulated by eukaryotic initiation factor 4E: Contributing to colonic tumor malignancy.

It is well known that both eukaryotic initiation factor 4E (eIF4E) and integrin αvß6 can contribute to malignant behavior of colon cancer. We have found that integrin αvß6 and eIF4E were co-expressed and positively correlated in colon cancer tissues. Recently, deregulation of the protein synthesis apparatus has begun to gain attention as a major participant in cancer development and progression. However, the regulation of integrin ß6 expression at translational level has never been investigated before. In present study, gene-silencing technique for eIF4E by small interfering RNA (siRNA) was used in all the subsequent experiments, in order to investigate whether eIF4E could translationally regulate expression of integrin ß6 in colon cancer SW480 and HT-29 cell lines. Additionally, the subsequent effects of eIF4E knockdown on cellular malignant behavior were observed. siRNA in SW480 and HT-29 transfectants. Subsequently, protein expression of ß6 was markedly suppressed, while mRNA expression of ß6 showed no significant variation before and after eIF4E RNA interfering. Therefore, it could be seen that eIF4E could upregulate the expression of ß6, without effect on ß6 mRNA expression. More importantly, after treated with eIF4E siRNA, cellular migratory capacity on fibronectin of HT-29 and ß6-transfected SW480 as well as their survival to 5-FU was decreased distinctly. Expression of integrin ß6 could be translationally regulated by eIF4E, which subsequently contributed to tumor malignancy through enhancing cellular migration, survival, anti-apoptosis, and chemoresistance of colon cancer in vitro. Thus, targeting eIF4E in integrin αvß6 expressing tumors can be a potential therapeutic strategy for patients with colon cancer.

The clinical significance and underlying correlation of pStat-3 and integrin αvß6 expression in gallbladder cancer.

BACKGROUND: Both phosphorylated signal transducer and activator of transcription 3(pStat-3) and integrin αvß6 can play vital role in the development and progression of cancer. However, little is known about their expression correlation and clinical significance in gallbladder cancer(GBC). OBJECTIVE: The aim of our present study was to investigate the expression of pStat-3 and integrin αvß6, two proteins' correlation and their clinical significance in GBC tissues. RESULTS: The expression of pStat-3 and integrin αvß6 were both significantly associated with T stage, lymph node metastasis status, TNM stage (P=0.008, P=0.000, P=0.000 and P=0.036, P=0.001,P=0.000,respectively). IHC and Western blot showed their expressions in GBC tissues were higher than that in paraneoplastic tissues. Moderate positive correlation existed between the two proteins (r =0.349, P <0.001). The survival analysis by Kaplan-Meier and Cox regression model showed that GBC patients with pStat-3 or integrin αvß6 positive expression had a significantly poorer 2-year survival rate (P = 0.002 and 0.000, the log-rank test, respectively), and either marker could act as unfavorable independent prognostic factors(RR=1.907, P=0.021 and RR=2.046, P=0.038). MATERIALS AND METHODS: The expression levels of pStat-3 and integrin αvß6 were analyzed in GBC cancerous and paraneoplastic tissues of 97 cases via immunohistochemistry(IHC) and further validated by western blot method. Besides, SPSS software was used to observe their clinical significance as well as the two proteins' correlation. CONCLUSION: pStat-3 and integrin αvß6 were indicators of tumor's progression and poor prognosis of patients with GBC. And the further study involving them may provide a helpful therapeutic target in prevention and treatment of GBC patients.

Changes of mGluR4 and the effects of its specific agonist L-AP4 in a rodent model of diffuse brain injury.

OBJECTIVE: Excessive release of glutamate from nerve terminals following diffuse brain injury (DBI) is thought to contribute to neuronal calcium overload leading to calcium-mediated cell damage. Metabotropic glutamate receptor subtype 4 (mGluR4) is regarded as one of the neuroprotective receptors in mammalian brains. Therefore, the mGluR4 specific agonists might exert neuroprotective effects after DBI. The focus of this study is to examine the changes of expression of mGluR4 after DBI and the role of its specific agonist L-AP4 in vivo. METHODS: One hundred and sixty-one male SD rats were randomized into two groups. Group A included normal control, sham-operated control and DBI group. DBI was produced by Marmarou's diffuse head injury model. The mRNA expression of mGluR4 was detected by hybridization in situ. Group B included DBI alone, DBI treated with normal saline and DBI treated with L-AP4. All DBI rats were trained in a series of performance tests, following which they were subjected to DBI. At 1 and 12 h, animals were injected intracerebroventricularly with L-AP4 (100 mM, 10 microl) or normal saline, respectively. The rats were tested for motor and cognitive performance at 1, 3, 7, 14 days post-injury and the damaged neurons were detected. RESULTS: There was no significant difference between the normal control group and sham-operated group in the expression of mGluR4 (P>0.05). The animals exposed to DBI showed a significant increased expression of mRNA of mGluR4 compared with that of the sham-operated animals 1 h after injuries (P<0.05). At 6 h, the evolution of neuronal expression of mGluR4 in the trauma alone group was relatively static. Compared with saline-treated control animals, rats treated with L-AP4 showed decreased number of damaged neurons and a better motor and cognitive performance. CONCLUSIONS: The increased expression of mGluR4 is an important process in the pathophysiological of DBI and its specific agonist L-AP4 can provide a remarkable neuroprotection against DBI not only at the histopathological level but also in the motor and cognitive performance.