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  • As for the molecular mechanism Ferguson BD suggested that Ep


    As for the molecular mechanism, Ferguson BD suggested that EphB4/EphrinB2 stimulation induced topoisomerase I activity in small cell lung cancer cell lines. Treatment of ursolic acid with EphrinB2/Fc induced topoisomerase activity as assessed by DNA relaxation in cells with high EphB4 expression levels, but not in those with no EphB4 expression (Ferguson et al., 2013). Hu F reported that EphB4 interacted with the adaptor protein RACK1 and that RACK1 decreased EphB4 phosphorylation levels (Liu et al., 2013). It was also suggested that the decrease and/or loss of EphBs expression in colorectal carcinomas was due to promoter hypermethylation (Davalos et al., 2006). However, an opposite view indicated that the promoters of EphB2, EphB3, and EphB4 were unmethylated in a vast majority of colon and ovarian cancer samples according to methylation-specific polymerase chain reaction and direct bisulphite sequencing. They concluded that promoter hypermethylation of EphB2, EphB3, and EphB4 is not a common event in colon and ovarian cancers and therefore plays no major role in these tumours (Wu et al., 2007). In our study, we suggested that EphB4 may modulate the growth behaviour, metastatic pattern, and tumour angiogenesis of CRC cells by weakening cell–cell connections. Because increased evidence indicates that EphB4 consistently acts as a tumour promoter and may be a potential therapeutic target, more work has been focus on its study. EphB4 inhibitor halted the growth of established tumours in mouse xenograft models when used as part of a single-target strategy, and caused nearly complete regression of established tumours when used in combination with paclitaxel. These data suggested an important role for EphB4 as a potential novel therapeutic target in lung cancer (Ferguson et al., 2013). Targeting EphB4 in fibrosarcoma, synovial sarcoma, liposarcoma, and MFH sarcoma cell lines by siRNA or by inhibition of autophosphorylation using the specific EphB4 kinase inhibitor (NVP-BHG712) led to both decreased proliferation rates and metastasis of synovial and fibrosarcoma cells (Becerikli et al., 2015).
    Conflicts of interest
    Acknowledgements This work was supported by the National Natural Science Foundation of China (81171391).
    Introduction The EphB4 receptor tyrosine kinase is a member of the largest family of receptor tyrosine kinases and is an important regulator of fundamental physiological and pathophysiological processes such as tissue patterning during development, angiogenesis and tumour progression [1]. EphB4 is commonly over-expressed in epithelial cancers—for example, in prostate (66% of cases studied) [2], [3], colon (63%) [4], [5], [6], breast (58–94%) [7], [8], [9], [10], ovarian (80–100%) [11], [12], [13], endometrial (100%) [14], [15] and cervical cancers (95%) [16]. Receptor tyrosine kinase-mediated signalling from the plasma membrane is a well-established mode of communication, however, certain receptor tyrosine kinases, including members of the EGFR family, the FGFRs and IGF-1R possess the ability to translocate to the nucleus and engage in regulation of gene expression [17], [18], [19]. In particular, the EGFR has been shown to act as a co-activator of transcription for several cancer-promoting genes such as Cox-2 [20], c-Myc [21] and cyclin-D1 [22]. Transport of proteins into the nucleus through the nuclear pore complex can be facilitated by the dedicated nuclear transport receptors of the β-karyopherin family, which includes the importins [23]. Proteins able to translocate by use of importins contain one or more nuclear localisation signals (NLS), a short stretch of amino acids that facilitate the binding of importin to the cargo protein [24]. An importin-α adaptor protein binds to a lysine-rich NLS in the cargo protein. An importin-β protein then binds to this importin-α/cargo complex through an NLS in the importin-α protein itself and guides the complex through the nuclear pore. Importin-β proteins can also bind non-classical NLS motifs to transport proteins without requiring importin-α interaction [25].