Research progress of mitogen-activated protein kinase interacting kinases inhibitors in tumor immunotherapy / 中国药科大学学报

@#With the rise of tumor immunotherapy, small molecule modulators targeting the immune system have become a research hotspot. As well-developed and mature targets, immunity protein kinases have attracted more and more attention. Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are located at the meeting-point of ERK and p38 MAPK signaling pathways, which can phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at the conserved serine 209 exclusively and modulate the translation of mRNA. Herein we review the structural characteristics, mechanism, signaling transduction pathways and close relationship with tumors of MNKs.Meanwhile, the development process and clinical research progress of the MNKs inhibitors reported by different research institutions are introduced in detail.

Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR

Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft

Disturbed Yin-Yang balance: stress increases the susceptibility to primary and recurrent infections of herpes simplex virus type 1

Herpes simplex virus type 1 (HSV-1), a neurotropic herpes virus, is able to establish a lifelong latent infection in the human host. Following primary replication in mucosal epithelial cells, the virus can enter sensory neurons innervating peripheral tissues nerve termini. The viral genome is then transported to the nucleus where it can be maintained without producing infectious progeny, and thus latency is established in the cell. Yin-Yang balance is an essential concept in traditional Chinese medicine (TCM) theory. Yin represents stable and inhibitory factors, and Yang represents the active and aggressive factors. When the organism is exposed to stress, especially psychological stress caused by emotional stimulation, the Yin-Yang balance is disturbed and the virus can re-engage in productive replication, resulting in recurrent diseases. Therefore, a better understanding of the stress-induced susceptibility to HSV-1 primary infection and reactivation is needed and will provide helpful insights into the effective control and treatment of HSV-1. Here we reviewed the recent advances in the studies of HSV-1 susceptibility, latency and reactivation. We included mechanisms involved in primary infection and the regulation of latency and described how stress-induced changes increase the susceptibility to primary and recurrent infections.

Down-regulation of miRNA-99b expression in mTOR/4E-BP1 signal pathway and invasion in glioma U251 cells / 中华神经医学杂志

Objective To detect the down-regulation ofmiRNA-99b expression in cell invasion and its mechanism in human glioma cell line U251.Methods Glioma cell line U251 were routinely cultured in vitro.(1) U251 cells were divided into blank control group,negative control group and miRNA-99b inhibitor group;cells in the latter two groups were transfected with negative control sequences and miRNA-99b inhibitors,respectively;and cells in the blank control group did not give any treatment;mRNA expressions of miRNA-99b and mammalian target of rapamycin (mTOR) in U251 cells were measured by reverse transcription (RT)-PCR;the changes of mTOR,eIF4E-binding protein 1 (4E-BP1) andphosphorylated (p)-4E-BPl protein expressions in U251 cells were detected by Westem blotting;cell invasion was evaluated by Transwell assay.(2) U251 cells were divided into negative control group Ⅰ and mTOR siRNA group,and cells in the two groups were transfected with negative control sequences and mTOR siRNA,respectively;the miRNA-99b and mTOR mRNA expressions in U251 cells were measured by RT-PCR;the mTOR and p-4E-BP1 protein expressions in U251 cells were measured by Western blotting.(3) U251 cells were divided into miRNA-99b inhibitor+negative control group and miRNA-99b inhibitor+mTOR siRNA group,and cells in the two groups were transfected with miRNA-99b inhibitor+negative control sequences and miRNA-99b inhibitor+mTOR siRNA,respectively;the p-4E-BP1 protein expression in U251 cells was measured by Western blotting;cell invasion was evaluated by Transwell assay.Results (1) As compared with those in the blank control group and negative control group,the miRNA-99b rnRNA expression was significantly decreased,the mTOR mRNA and protein expressions and p-4E-BP1 protein expression were significantly increased,and the number of transmembrane cells was significantly larger in U251 cells of miRNA-99b inhibitor group (P＜0.05);there were no significant differences in 4E-BP1 protein expression among the three groups (P＞0.05).(2) As compared with those in the negative control group Ⅰ,the mTOR mRNA and protein expressions and p-4E-BP1 protein expression were significantly decreased in U251 cells of mTOR siRNA group (P＜0.05);there was no significant difference in miRNA-99b mRNA expression between the two groups (P＞0.05).(3) As compared with those in the miRNA-99b inhibitor+negative control group,the p-4E-BP1 protein expression and number of transmembrane cells were significantly decreased/smaller in U251 cells ofmiRNA-99b inhibitor+mTOR siRNA group (P＜0.05).Conclusions Down-regulation ofmiRNA-99b expression promotes glioma cell invasion,and its mechanism is related to the regulation of mTOR/4E-BP1 signaling pathway.

MicroRNAs recruit eIF4E2 to repress translation of target mRNAs

MicroRNAs (miRNAs) recruit the RNA-induced silencing complex (RISC) to repress the translation of target mRNAs. While the 5' 7-methylguanosine cap of target mRNAs has been well known to be important for miRNA repression, the underlying mechanism is not clear. Here we show that TNRC6A interacts with eIF4E2, a homologue of eIF4E that can bind to the cap but cannot interact with eIF4G to initiate translation, to inhibit the translation of target mRNAs. Downregulation of eIF4E2 relieved miRNA repression of reporter expression. Moreover, eIF4E2 downregulation increased the protein levels of endogenous IMP1, PTEN and PDCD4, whose expression are repressed by endogenous miRNAs. We further provide evidence showing that miRNA enhances eIF4E2 association with the target mRNA. We propose that miRNAs recruit eIF4E2 to compete with eIF4E to repress mRNA translation.

Clinical significance of expression of eIF-4E and p-4EBP-1 protein in the gastric carcinoma / 临床与实验病理学杂志

Purpose To study the expression of eIF-4E and p-4EBP-1 and its clinical significance in the gastric carcinoma.Methods Expression of eIF-4E and p-4EBP-1 was detected in tissue array including 168 cases of gastric carcinoma and 52 cases of peri-cancer tissues by immunohistochemical SP method.Results The positive expression of eIF-4E and p-4EBP-1 in the gastric carcinoma was significantly higher than that of peri-cancer tissues (P =0.001,P =0.000).There was significantly higher expression of eIF-4E and p-4EBP-1 with lymph node metastases than without lymph node metastases in the gastric carcinoma (P =0.025,P =0.001).Also,there was significantly higher expression of eIF-4E and p-4EBP-1 with clinical stages Ⅲ + Ⅳ than that of stages Ⅰ + Ⅱ (P =0.001,P=0.049).In addition,there was a significantly positive correlation between the expression of eIF-4E and p-4EBP-1 in the gastric carcinoma (r =0.432,P ＜ 0.01).The overall survival rates for patients with negative expression of eIF-4E protein was higher than that with positive expression (P =0.012).Conclusion The abnormal co-expression of eIF-4E and p-4EBP-1 may be related to the tumorgenesis,development,metastasis and invasion of gastric carcinoma,and eIF-4E and p-4EBP-1 may act as the new molecular targets for the therapy and diagnosis of gastric carcinoma.

HIF-1α pathway: role, regulation and intervention for cancer therapy

Hypoxia-inducible factor-1 (HIF-1) has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels) is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1α pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1α pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1α in cancer, and recent therapeutic approaches targeting this important pathway.

Expression of eIF4E in acute myeloid leukemia / 白血病·淋巴瘤

Objectives To analysis the expression difference of eIF4E in bone marrow between the acute myeloid leukemia (AML) and the non-tumor patient,before and after induction therapy,and the different subtypes of AML,and to explore the relation between eIF4E and other molecular biology abnormalities in AML.Methods The bone marrow specimens of newly diagnosed AML and non-tumor control patients were collected.The expression level of eIF4E was detected by RT-PCR.Results The positive rate of eIF4E was 65.2 ％ (101/155) in AML.eIF4E turned to negative in 12 patients (17.6 ％) who got complete remission after induction therapy.eIF4E was negatively expressed in bone marrow of the nontumor control patients.The positive rates of eIF4E were 75.0 ％ (15/20) and 80.8 ％ (21/26) in M4 and M5 type AML,respectively,and was 59.6 ％ (65/109) in other subtype AML (P ＞ 0.05).FLT3/ITD gene mutation was found in 26 cases of newly diagnosed AML.The eIF4E expression and FLT3-ITD gene mutation were independent each other (P ＞ 0.05).Conclusions eIF4E is positive in most of the newly diagnosed AML and turns to negative in part of AML achieving complete remission.The expression of eIF4E is no difference among different subtype of AMLs.eIF4E and FLT3-ITD gene mutation are independent each other.

Dendritic eIF4E-binding Protein 1 (eIF4E-BP1) mRNA Is Upregulated by Neuronal Activation

Long-term synaptic plasticity requires addition of new proteins at the synaptic site. The local protein synthesis at subsynaptic sites confers advantageous mechanisms that would regulate the protein composition in local domains on a moment-by-moment basis. However, our information on the identities of 'dendritic' mRNAs is very limited. In this study we investigated the expression of the protein and mRNA for eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) in cultured rat hippocampal neurons. Immunocytochemistry (ICC) showed that 4EBP1 protein is highly localized to the nucleus. In dendrites most 4EBP1 punctae were not colocalized with those of eIF4E. In situ hybridization (ISH) and Fluorescence ISH (FISH) revealed that 4EBP1 mRNA was present in dendrites. The FISH signals formed clusters along dendrites that colocalized with ICC signals for Staufen, a marker for RNA granules. The neuronal activation by KCl (60 mM, 10 min) significantly increased the density of 4EBP1 FISH signals in the nucleus after 2 hr, and both in the nucleus and dendrites after 6 hr. Our results indicate that 4EBP1 and its mRNA are present in dendrites, and the mRNA is upregulated and transported to dendritic domains in RNA granules upon neuronal activation.

Effect of eIF4E expression in the formation of pathological scar / 中华医学美学美容杂志

Objective To study the expression of eukaryotic translation initiation factor 4E(eIF4E)in the pathological scars and its probable role in the pathogenesis of pathological scars.Methods Immunohistochemiscal technique was performed to detect the expression and distribution of eIF4E protein in hypertrophic scars(14 cases),keloids(25 cases),mature scars(20 cases)and normal skins(20 cases).Reverse transcription polymerase chain reaction(RT-PCR)was used to detect the eIF4E mRNA level in hypertrophic scars(7 cases),keloids(8 cases),mature scars(8 cases)and normal skins(8 cases).Results Thepositive rate of eIF4E protein expression was remarkably significant difference between normal scars and pathological scars(P＜0.05).The level of eIF4E mRNA in pathological scars 1.73±0.31was higher than that in control group 0.99±0.28.There was significant difference between two groups (P＜O.05).Conclusions The expression of eIF4E is increased in pathological scar.eIF4 E expression is closely associated with the development of pathological scar.Therefore,eIF4E overexpression may play an important role in the proliferation of fibroblasts and in the pathogenesis of pathological scar.

Advances of eIF4E in breast cancer research / 国际肿瘤学杂志

Eukaiyotic translation initiation factor 4E(eIF4E) is a key factor initiate eukaryotic transla-tion. eIF4E has significant correlation with the carcinogenesis, cancer development and invasion, etc. Recent studies in breast cancer show that eIF4E is an important prognostic factor and associated with sensitivity of breast cancer cells to radiotherapy. eIF4E expression has a potential contribution to therapeutic strategy mak-ing, meanwhile, it is a promising effective target of breast cancer treatment.

Associated Expression of PTEN,eIF4E and CyclinDl in Gastric Carcinoma and Their Clinical Significance / 医学研究杂志

Objective To explore the relationship between the associated expression of PTEN, eIF4E and CyclinDl and clinical pathological features in gastric carcinoma. Methods The expression of PTEN,eIF4E and CyclinD1 was detected in tissues of 56 gastric carcinomas and 10 normal gastric mucosa by immunohistochemical method. Results ①The positive rate of PTEN protein expression was 51.8% (29/56) in gastric carcinoma,which was lower than that in normal gastric mucosa tissues 100% (10/10,P = 0.012). The positive rates of eIF4E and CyclinD1 protein expression were 76.8% (43/56) and 51.8% (29/56) respectively in gastric carcinoma,which were higher than those in normal gastric mucosa tissues 0% (0/10,P =0.000) and 0% (0/10,P =0.007). ②The expression of PTEN was positively correlated to the degree of differentiation(P = 0.029) , but negative correlated to the depth of invasion (P = 0.033) , lymph node metastasis (P =0.003). The expression level of eIF4E was negative correlated to the degree of differentiation (P =0.010) , but the expression of eIF4E was unrelated to infiltrative depthand and lymph node metastasis. The expression level of CyclinDl was correlated to the degree of differentiation (P =0.004) ,the depth of invasion (P =0.032) , lymph node metastasis (P =0.013). ③The expression was found being negative correlated between PTEN and eIF4E or CyclinDl (P = 0.006 ,P =0.007) , while a positive correlation could also be found between eIF4E and CyclinD1 (P =0.041). Conclusion PTEN ,eIF4E and CyclinD1 may play certain roles in the oncogenesis and progression of gastric carcinoma. Combined evaluation of PTEN, eIF4E and CyclinD1 may be helpful to assess the malignant degree, treatment and prognosis of gastric carcinoma.

Construction of eIF-4E Adenovirus and Its Effect on Metastasis Ability of Human Breast Cancer Cell Line MCF-7 / 中国生物工程杂志

Objective: To reconstruct adenovirus vector of breast eukaryotic initiation factor 4E and to observe its effect on the metastasis ability of breast cancer cell line MCF-7. Methods: eIF-4E gene was constructed into adenovirus vector pAD-X by gene recombination technique, which was transformed into 293 packaged cell for high titer adenovirus. Real-time PCR was applied to detect eIF-4E gene expression. eIF-4E siRNA was applied and then transwell cabin assay was used to observe changes of invasion and motor ability of MCF-7 cells transfected with reconstruction adenovirus. Result:The finding of digestion was coincided with expected. eIF-4E gene over-expression was detected in transfected MCF-7 cells with real-time PCR. And the invasion and motor abilities of transfected MCF-7 cells were more significantly inhibited in transwell cabin assay (respectively p

Contribution of eIF-4E inhibition to heparanase expression at both mRNA and protein levels in human colon adenocarcinoma cell line LS-174T / 中国病理生理杂志

AIM: To determine whether the eukaryotic initiation factor-4E (eIF-4E) inhibition facilitates the degradation of heparanase mRNA and alters heparanase protein expression in human colon adenocarcinoma cell line, LS-174T. METHODS: A 20-mer antisense s-oligodeoxynucleotide (asODN) targeted against the translation start site of eIF-4E mRNA were introduced into LS-174T cells by lipid-mediated DNA-transfection. eIF-4E protein and mRNA levels were detected by Western blot and RT-PCR, respectively. The mRNA levels of heparanase were determined by Northern blot. The alterations of heparanase expression were confirmed by Western blot analysis. RESULTS: The 20-mer asODN against eIF-4E specifically and significantly inhibited eIF-4E protein expression. Following eIF-4E inhibition, a significant reduction of heparanase mRNA was observed on Northern blot, and at the same time, heparanase protein expression significantly decreased as well. CONCLUSIONS: The results indicate that the inhibition of eIF-4E strongly reduces the stability of heparanase mRNA in colon adenocarcinoma cell line, LS-174T and resultes in an apparent reduction in the expression of heparanase protein. [

Expression and correlation of eIF4E and c-myc in laryngeal carcinoma / 中国免疫学杂志

Objective:To observe the expression and correlation of eIF4E and c-myc in laryngeal squamous cell carcinoma.Methods:Western blot was applied to examine the expression of eIF4E and c-myc on tumor core,transition core and tumor-free core from 36 laryngeal carcinoma patients.The results were statistically analyzed.Results:The overexpression of eIF4E and c-myc protein levels suggests an increasing tendency from tumor-free core,transition core and tumor core;and shows an significant correlation of eIF4E and c-myc expression.Conclusion:The overexpression of eIF4E and c-myc cause the laryngeal carcinoma cell malignant transformation;the correlation of eIF4E and c-myc may provide a basis for gene therapy of laryngeal carcinoma.