The epithelial-mesenchymal transition (EMT) induced by chemotherapeutic agents promotes malignant tumor progression; however, the mechanism underlying the drug-induced EMT remains unclear. In this study, we reported that miR-448 is the most downregulated microRNA following chemotherapy. Suppression of miR-448 correlated with EMT induction in breast cancer in vitro and in vivo. With the use of chromatin immunoprecipitation-seq analysis, we demonstrated that miR-448 suppression induces EMT by directly targeting special AT-rich sequence-binding protein-1 (SATB1) mRNA, leading to elevated levels of amphiregulin and thereby, increasing epidermal growth factor receptor (EGFR)-mediated Twist1 expression, as well as nuclear factor jB (NF-jB) activation. On the other hand, we also found that the adriamycin-activated NF-jB directly binds the promoter of miR-448 suppressing its transcription, suggesting a positive feedback loop between NF-jB and miR-448. Furthermore, all patients who received cyclophosphamide (CP), epirubicin plus taxotere/CP, epirubicin plus 5-fluorouracil chemotherapy showed miR-448 suppression, an increased SATB1, Twist1 expression and acquisition of mesenchymal phenotypes. These findings reveal an underlying regulatory pathway, in which the autoregulation between NF-jB and miR-448 is important for restrain miR-448 suppression upon chemotherapy and may have a role in the regulation of chemotherapy-induced EMT. Disruption of the NF-jB-miR-448 feedback loop during clinical treatment may improve the chemotherapy response of human breast cancers in which EMT is a critical component. Chemotherapy is a systemic treatment that destroys reproducing cells, but it cannot differentiate between normal and cancerous cells. Side effects occur when normal cells become damaged. Apart from the side effects of cancer chemotherapy, unexpected 'opposite effects' of chemotherapy, which enhance the critical steps in malignancy rather than inhibiting them, 1-3 have attracted progressively more attention, suggesting that novel strategies should be developed to reverse these opposite effects and render chemotherapy more effective.Tumor cells progress from non-invasive to malignant phenotypes via a series of critical steps that involve morphological changes referred to as the epithelial-mesenchymal transition (EMT). 4 EMT is a process originally observed during the embryonic development, in which cells lose epithelial characteristics. [5][6][7][8][9][10] With respect to the chemotherapy, recent studies have demonstrated a close link between EMT and insensitivity to chemotherapeutic agents. Hiscox et al. 11 showed increased b-catenin expression and elevated levels of transcription of b-catenin target genes known to be involved in tumor progression and EMT in the tamoxifen (TAM)-resistant MCF7 cells. Kajiyama et al. 12 identified an association between chronic paclitaxel resistance and induction of EMT in epithelial ovarian carcinomas. In addition, we previously showed that transient adriamycin treatmentinduced EMT and apoptosi...

Metastasis is the chief cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. We used a proteomics approach to screen for metastasis-associated proteins and found that collapsin response mediator protein-4 (CRMP4) expression was inversely associated with the lymph node metastasis of prostate cancer (PCa). Subsequent in vitro and in vivo studies revealed that overexpression of CRMP4 not only suppressed the invasion ability of PCa cells, but also strongly inhibited tumor metastasis in an animal model. Furthermore, methylation of a CpG island within the promoter region of the CRMP4 gene is responsible for downregulation of CRMP4 expression. Thus, in this study, we show new function of CRMP4 as a metastasissuppressor in PCa. The findings provide new mechanistic insights into metastasis and therapeutic potential for this most common male cancer.

Ecdysone 20-monooxygenase (E20MO), a cytochrome P450 monooxygenase (CYP314A1), catalyses the conversion of ecdysone (E) to 20hydroxyecdysone (20E). We report here the cloning and characterization of the Halloween gene Shade (Shd) encoding E20MO in the Colorado potato beetle, Leptinotarsa decemlineata. LdSHD has five conserved motifs typical of insect P450s, ie the Helix-C, Helix-I, Helix-K, PxxFxPE/DRF (PERF) and heme-binding motifs. LdShd was expressed in developing eggs, the first to fourth instars, wandering larvae, pupae and adults, with statistically significant fluctuations. Its mRNA was ubiquitously distributed in the head, thorax and abdomen. The recombinant LdSHD protein expressed in Spodoptera frugiperda 9 (Sf9) cells catalysed the conversion of E to 20E. Dietary introduction of double-stranded RNA (dsRNA) of LdShd into the second instar larvae successfully knocked down the LdShd expression level, decreased the mRNA level of the ecdysone receptor (LdEcR) gene, caused larval lethality, delayed development and affected pupation. Moreover, ingestion of LdShd-dsRNA by the fourth instars also down-regulated LdShd and LdEcR expression, reduced the 20E titre, and negatively influenced pupation. Introduction of 20E and a nonsteroidal ecdysteroid agonist halofenozide into the LdShd-dsRNA-ingested second instars, and of halofenozide into the LdShd-dsRNA-ingested fourth instars almost completely relieved the negative effects on larval performance. Thus, LdSHD functions to regulate metamorphotic processes by converting E to 20E in a coleopteran insect species Le. decemlineata.

Our findings provide the first evidence for an age- and region-dependent reduction and intracellular translocation of EphB2 in Tg2576 mice, and the foremost decrement of EphB2 in the olfactory bulb may represent an early sign of AD.

Diffuse palmoplantar keratoderma (DPPK) is an autosomal dominant genodermatosis characterized by uniform hyperkeratosis of the palm and sole epidermis. This disorder can be caused by mutations in the genes keratin 1, keratin 9, keratin 16, desmoglein 1 and plakoglobin. Here we present a DPPK Chinese pedigree and identify the aetiology as a novel missense mutation, L437P, located in a highly conserved helix motif in domain 2B of KRT1. Functional analysis shows that overexpression of the L437P mutant in cultured cells leads to abnormal intermediate filament networks and filament aggregation. This gain-of-function mutation highlights the role of domain 2B in mediating filament assembly.