Key words ether à go  go; potassium channel; tumor; markers; target molecules

 In recent years, the study found that the number of ion channels, such as potassium, calcium, chlorine, sodium channel associated with tumors, in particular potassium channel with tumor most closely. Potassium channels in the cell membrane types, the most complex class of ion channels, it exists in a variety of cell membrane potential control factors.

    ether à go  go (EAG) potassium channels are a family of voltage-gated potassium channels, some of the family members, such as Eag1 and Erg channels, especially Eag1 channel, specifically in primary tumor cells and expression in tumor cell lines and malignant transformation of cells, tumor cell proliferation and metastasis. But due to the lack of specificity of the channel blockers and most studies only in cell lines but not in the primary tumor cells and other factors limit EAG potassium channels in tumorigenesis is unclear role in the development process. Carry out the study will help to elucidate the pathogenesis of the tumor;, but also provide a new strategy for the early diagnosis and treatment of clinical tumor.

    1 ether à go  go potassium channel

    The 1.1 ether à go  go potassium channel structural features

    Kaplan et al in 1969 [1] in the study of Drosophila variability found a male fruit flies under ether anesthesia, can exhibit slow rhythmic leg swing activities, and found that the variation independent loci, named ether à go  go (eag) (eag, erg and elk lowercase letters in this article indicates that the gene, EAG ether à go  go potassium channel family). 1983 Ganetzky, etc. [2], this variant This variant motor neurone with an increase in a high frequency of spontaneous action potential and release of neurotransmitters, and the cloned gene sequence results show the variation with similar to the voltage-gated potassium channels, the eag expression in frog eggs confirmed the gene encodes a voltage-gated potassium channels [3].

    The mammalian homologous gene screening found another the two the eag closely related genes, elk (eag  like gene) and erg (eag  related gene). Therefore, EAG channel family comprises the three subgenomic family Eag (to include Eag1 and Eag2 the first letter capitalized said EAG potassium channel subfamily), Elk (including two members) and Erg (including three members) [4 ]. People eag1 gene chromosomes located in 1q32.1  2 [5] eag2 gene is located at 14q24.3 [6]. This article mainly on the relationship between the tumor EAG potassium channel family Eag1 and Erg channels and the tumor were reviewed.

    EAG potassium channel by functional tetramer, the basic structure of each subunit in addition to the six transmembrane pore area, there are several highly conserved regions, N  end most of the structure and Per  Arnt  Sim The zone is similar to the area and probing redox reactions related C  end including a conserved cyclic nucleotide binding domain, the district may channel proteins shuttle about [7], a calmodulin-binding sites, a bi-nuclear targeting signal and a channel subunit interaction region [8]. Eag1 channel (may also include Eag2) is also carried on the amino acid residues in the extracellular glycosylation area, the N406 amino acid residue, a necessary condition to maintain the normal structure and function is the channel protein glycosylation, deglycosylation will caused by the sharp decline of the channel current amplitude, and slows down the channel activator, [9].

    From the complexity of the point of view of the EAG channel family structure, the channel is not just a by-mediated regulation of membrane potential pore potassium ion transmembrane flow at the same time it can also feel the changes in the environment outside the cell membrane (such as hypoxia, calmodulin prime signal, etc.), so that the channel open, or inhibit, to adjust the electrical physiological environment of the cells and thus affect the functional activity of the cells, as well as growth and proliferation.

    The 1.2 ether à go  go potassium channel distribution

    Physiological state, Eag1 channel is mainly distributed in the brain (hypothalamus excluded) cell populations before myoblast fusion transient probe, Northern blot assay showed little expression in the placenta, while in others The organization does not find its expression [10]. But a new study shows that, although not detected by real-time RT  PCR method other organizations outside of the above organizations Eag1 channel mRNA expression, but in some biopsies using immunohistochemical methods found a small amount of the channel protein expression, including the principal cells of the gastric glands, pancreatic acini cells, spermatogenic cells of the male reproductive system and the female reproductive system, endometrial and endocervical, especially the number of active secretion glands, are presented immunohistochemical positive reaction, suggesting that the above organization Eag1 channel [11]. Since the Eag1 channel was restricted expression in normal tissues, but showed ectopic expression in the tumor tissue, suggesting that it may be a potential tumor marker. , Eag2 relatively abundant in the brain and bones, heart, lung and other tissue expression [6]. Erg channel distribution is wider, has heart, brain, kidney, liver, testis, uterus, prostate and other organizations found that the transcription factors [12] of the channel.

    The 2 ether à go  go potassium channel relationship with tumor

    2.1 ether à go  go potassium channel expression in tumor cells

    In recent years, the study found Erg channels in human endometrial cancer [13], leukemia [14], prolactinoma [15], glioma [16] and colorectal cancer [17], abnormal expression or function . Cherubini et al [13] in the human endometrial cancer cells detected Erg channel, and that the channel is no expression in endometrial hyperplasia, a result of Erg channel is a differential endometrial cancer with simple utero Membrane the proliferative potential tool. Studies related Erg channels with leukemia relations Erg channel is always open in leukemia cells, while in the corresponding normal cells, but it is closed conclusions Step Erg channel activity can be used as new molecules of tumor cells of hematopoietic tissue signs [14].

    There are more and more reports in Eag1 channel overexpression in primary tumor cells or functional activities. Farias found Eag1 channel expression in cervical cancer cells and recorded to the channel current [18]; Hemmerlein et al [11] using immunohistochemistry and real-time PCR method from esophageal cancer, liver cancer, breast cancer, bronchial lung cancer and many other kinds of common tumor tissue detected in all the samples, almost 70% to 80% of the tumor tissue were tested Eag1 signal strong positive reaction, the test results are shown in Table 1; Another study in primary soft tissue sarcomas, including fiber sarcoma and rhabdomyosarcoma [19] and colorectal cancer [20] also found a the Eag1 channel expression. This EAG channel in the diagnosis and treatment of the Journal of Clinical Oncology in a molecular basis.

    2.2 ether à go  go potassium channel possible role in the malignant transformation of cells

    Reported mainly seen Pardo et al [5]. They found that rat eag1 gene transfected into CHO cells and its overexpression, CHO cells exhibit rapid growth, growth in the very low serum concentrations of contact inhibition loss characteristics, and as the control, over-expression The Kv1.4 channel CHO cells does not appear, the above phenomenon. Prompted the overexpression Eag1 channel can induce malignant transformation. They were an interesting in vivo experiments, to the severe immunodeficiency mice were injected with transfection of CHO cells the people Eag1 and Kv1.4 gene, discovery to carry Eag1 channel tumors than turn Table 1 Eag1 channels in different tumor The monitoring results of immunohistochemistry in tissue dye the Kv1.4 channel tumors grow more rapidly and more aggressive.

    While Eag1 Channel itself has carcinogenicity and is conducive to the growth of tumor cells, but the exact role of the gene in the tumorigenesis process is unclear. In vivo malignant transformation of cells caused by the abnormal expression of the Eag1 channel abnormal expression or Eag1 of channel triggered a tumor? Why do not cause tumors to the EAG channel normal expression? Its function when the normal expression is it? In eag1 gene in tumor cells break gene silencing state and ectopic expression? These will be further investigated.

    The possible role of of the 2.3 ether à go  go potassium channels in tumor cell proliferation

    Weber et al [21] in HEK  293 cells Eag1 channel conducted study, using siRNA technology the observed interference Eag1 channel expression affect learned behavior of tumor cell lines in vitro, results showed that the, blocking Eag1 channel in mRNA levels after expression, can significantly reduce the proliferation of tumor cell lines without causing any non-specific reaction can be observed. The reason may go in the early G1 phase of the cell cycle, cell membrane polarization state lower the Eag1 channel in this state can be activated (while the other Kv channel can not), causing the outflow of potassium ions, the intracellular hyperpolarization attract Ca2 + into the cell or the endoplasmic reticulum to release Ca2 +, and eventually caused the G1 to S phase transition [22] in a vigorous state of growth of the tumor cells. During this period, Eag1 channel played a role in the control of specific cell cycle checkpoint (specific check point) [23]. Therefore, it can be seen that there is a huge potential in the clinical treatment of tumors, regulate the expression and function of the EAG channel.

    Further, by the passage of a known non-specific blocking agent cisapride Erg channel blocking the gastric mucosal proliferation of tumor cells can be suppressed, and that this inhibition is dose-dependent, and can lead to cell cycle from G1 to stagnant S phase transition [24].

    3 ether à go  go study the clinical application of the potassium channel

    3.1 a potential marker for early diagnosis of tumor

    As mentioned, the EAG channel differentially expressed in the normal tissue and tumor tissue, for the channel to become tumor cell marker may be provided. According to the the Eag1 channel transmembrane characteristics, will be recognized the Eag1 channel membrane specific antigen of the outer part of the excitation by infrared emitting dyes such as AlexaFluor 680 or Cy5.5-labeled with near-infrared fluorescence imaging techniques, such that the small molecules of the antigen in the living body becomes visualization.

    The laboratory of Stuhmer [25] application of this technique to observe the distribution of human breast cancer cells in immunodeficient mice, found that the fluorescence occurs not only at the tumor site, also appears in the lymph nodes around the tumor palpation did not find transfer . In this study, Stuhmer, etc. and the traditional antibody preparation methods improved, improved antibodies contain only a recombinant single chain antibody Fab region Eag1 antibody can more easily penetrate the dense tumor tissue, and more easy-to-infrared fluorescence The tumor marker Eag1 channel detection applications.

    Therefore, the application of this method can not only be observed in the body tumor growth and metastasis, and provide clues for the early diagnosis and treatment, and also by looking at whether the drug caused tumor regression and study some of the efficacy of new drugs.

    3.2 metastasis and prognosis

    Erg channel expression in situ colorectal higher highest expression in metastatic colorectal cancer, while no expression in normal colorectal mucosa and adenoma cells [17]. Similarly another study also showed that the, the Erg and Eag1 channels of the differentially expressed in tumor cells depends on the degree of malignancy and cell properties, and this expression can be based on the reversible changes in the degree of malignancy in human glioma cells 16]. Prompted Eag1 or Erg channel expression as the impact of certain tumor metastasis or prognosis factor.

    3.3 the potential antineoplastic effect of the target molecule

    Eag1 channel is not only a highly specific tumor marker, or a transmembrane protein as the target molecule of the action of the drug, it is more advantageous than the cells within the tumor marker, in particular the channel also has an induced cell transformation, role in promoting cell proliferation and metastasis, therefore, it is an ideal target molecule of the potential antineoplastic effect. However, research in this area is just beginning. Gomez  Varela et al [26] A recent study reported that they have prepared a specific the identification Eag1 channel E3 region the functional antibody mAb56, the antibodies not only have to identify, can also inhibit expression in HEK  293 cells more than 40% of the neuroblastoma cell lines Eag1 channel current amplitude. In the same time, they detect mAb56 antitumor proliferative capacity nanomolar mAb56 can block breast cancer, melanoma, ovarian cancer cell lines of cell proliferation of 20% to 60% of the amplitude. Show that the in vivo experiments, mAb56 growth inhibition of human breast cancer cells (MDA  MB  435) in severe immunodeficiency mice, the effect is equivalent to the standard control drug cyclophosphamide, and nervous system disorders and weight loss side effects. To this inhibitory effect can also be observed in the transplantation of human pancreatic cell carcinoma (PAXF1657) nude mice.

    Pardo [27] The pioneering work laid the foundation for target molecules to Eag1 channel to carry out tumor treatment. They envision that the inhibition of tumor cell growth and proliferation through the following methods: (1) specific antibodies of the application Eag1 channel and channel binding, activation of the host immune activity, targeted to attack the tumor cells; (2) channel-specific antibodies coupled with cytotoxic or radioactivity, targeting the gathering in the vicinity of the tumor cells to destroy tumor cells or cause Eag1 channel protein in the cell membrane, to remove the conditions conducive to the proliferation of tumor cells. Also, there may through the specific portion of the antibody with the channel (such as channel activating conducting paths or channels within the area, etc.) combined, i.e. by the interaction between the protein  protein, causing conformational changes of the channel molecule, to reduce the activity of the channel or a change and modification of the gating properties of the channel, thereby inhibiting the proliferation of tumor cells.

    4 Conclusion

    Channel expression and function of the study reveals the close ties between the the EAG channel and tumors, the EAG channel target molecule as a tumor marker and drug effects research has also made some progress. However, the EAG channel relationship with tumor studies currently there are many limiting factors, such as carried out in the primary cancer research more difficult, a lot of research is carried out in the tumor cell lines, therefore, difficult to determine EAG channel with tumorigenesis, and The exact relationship of the development; Eag1 lack of specific channel blockers, specific antibodies can partially replace its role, but the antibody molecule biophysical characteristics of the study channel, subject to certain restrictions. A good solution to these problems will help to clarify the exact role of the of EAG channel in tumorigenesis and development, and provide clues for the clinical development of new cancer diagnosis and treatment strategies.