The epithelial-mesenchymal transition (EMT) converts epithelial tumor cells into invasive and metastatic cancer cells, leading to mortality in cancer patients. Although TWIST is a master regulator of EMT and metastasis for breast and other cancers, the mechanisms responsible for TWIST-mediated gene transcription remain unknown. In this study, purification and characterization of the TWIST protein complex revealed that TWIST interacts with several components of the Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) complex, MTA2, RbAp46, Mi2 and HDAC2, and recruits them to the proximal regions of the E-cadherin promoter for transcriptional repression. Depletion of these TWIST complex components from cancer cell lines that depend on TWIST for metastasis efficiently suppresses cell migration and invasion in culture and lung metastasis in mice. These findings not only provide novel mechanistic and functional links between TWIST and the Mi2/NuRD complex but also establish new essential roles for the components of Mi2/NuRD complex in cancer metastasis.

Proprotein convertases (PCs) are a group of Ca2+-dependent serine proteases that have homology to the endoproteases subtilisin (bacteria) and kexin (yeast). This group is comprised of less than a dozen members, known as furin/PACE, PC1/PC3, PC2, PC4, PACE4, PC5/PC6, PC7/PC8/LPC, SKI/S1P, and NARC-1/PCSK9. Four PCs (Furin, PACE4, PC5, and PC7) have been localized to several different tissues and epithelial or nervous system tumors. PCs activate their cognate substrates by limited proteolysis at the consensus sequence RXR/KR downward arrow. Many PC substrates are well known cancer-associated proteins such as growth factors, growth factor receptors, integrins, and matrix metalloproteases (MMPs). For example, IGF-1 and its receptor, TGF-beta, VEGF-C, and MT-MMPs have direct roles in tumor progression and metastasis. Furin, a well-studied member of the PC family, has been associated with enhanced invasion and proliferation in head and neck, breast, and lung cancer. Conversely, inhibition of PC activity by PDX or several PC pro-segments, resulted in reduced processing of these key cancer-related substrates in human squamous cell carcinomas (SCC), colon adenocarcinoma, and astrocytoma cell lines. In parallel to these changes in cell proliferation and invasiveness as well as metastatic ability were markedly impaired. By controlling the maturation/activation of key cancer-associated proteins, PCs act as "master switches" at different levels during tumor development and progression. The manifold effects of PCs, influencing tumor cell proliferation, motility, adhesiveness, and invasiveness, should be exploited by further developing competitive/inhibitory therapeutic strategies that would be able to neutralize simultaneously the most salient cancer cell properties.

The epithelial to mesenchymal transition (EMT) is an important step for the developmental process. Recent evidences support that EMT allows the tumor cells to acquire invasive properties and to develop metastatic growth characteristics. Some of the transcription factors, which are actively involved in EMT process, have a significant role in the EMT-metastasis linkage. A number of studies have reported that EMT-inducing transcription factors (EMT-TFs), such as Twist, Snail, Slug, and Zeb, are directly or indirectly involved in cancer cell metastasis through a different signaling cascades, including the Akt, signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK) and Wnt pathways, with the ultimate consequence of the downregulation of E-cadherin and upregulation of metastatic proteins, such as N-cadherin, vimentin, matrix metalloproteinase (MMP)-2, etc. This review summarizes the update information on the association of EMT-TFs with cancer metastasis and the possible cancer therapeutics via targeting the EMT-TFs.

Twist, the basic helix-loop-helix transcription factor, is involved in the process of epithelial to mesenchymal transitions (EMTs), which play an essential role in cancer metastasis. Overexpression of Twist or its promoter methylation is a common scenario in metastatic carcinomas. Twist is activated by a variety of signal transduction pathways, including Akt, signal transducer and activator of transcription 3, mitogen-activated protein kinase, Ras, and Wnt signaling. Activated Twist upregulates N-cadherin and downregulates E-cadherin, which are the hallmarks of EMT. Moreover, Twist plays an important role in some physiological processes involved in metastasis, like angiogenesis, invadopodia, extravasation, and chromosomal instability. Twist also protects cancer cells from apoptotic cell death. In addition, Twist is responsible for the stemness of cancer cells and the generation of drug resistance. Recently, targeting Twist has gained significant interests in cancer therapeutics. The inactivation of Twist by small RNA technology or chemotherapeutic approach has been proved successful. Moreover, several inhibitors which are antagonistic to the upstream or downstream molecules of Twist signaling pathways have also been identified. Development of potential treatment strategies by targeting Twist has a great promise in cancer therapeutics.

Background:Growing evidence suggests that miR-29a has an important role in regulating tumourigenesis and development of various types of cancer. However, the role and the underlying mechanism of miR-29a in colorectal cancer (CRC) remain largely unknown.Methods:MiR-29a targeted gene was identified by the luciferase assay and western blot. MiR-29a function was analysed by invasion assays and the orthotopic transplantation mouse model. The miR-29a pathway was assayed by real-time PCR, western blot and chip analysis.Results:KLF4 was identified as a direct target gene of miR-29a. MiR-29a promoted CRC cell invasion, which was blocked by re-expression of KLF4. In addition, MMP2 was identified as a novel direct target of KLF4. Both miR-29a overexpression and KLF4 knockdown promoted MMP2 expression but inhibited E-cadherin expression. Furthermore, clinical data indicated that both miR-29a high expression and KLF4 mRNA low expression were associated with metastasis and poor prognosis in CRC patients, and KLF4 protein expression was inversely correlated with MMP2 but positively correlated with E-cad protein expression.Conclusion:Increased expression of miR-29a promoted CRC metastasis by regulating MMP2/E-cad through direct targeting KLF4, which highlights the potential of the miR-29a inhibitor as a novel agent against CRC metastasis.

In traditional medicine, Lonicera japonica (Thunb.) has a notable place, and it has been used for thousands of years in China, Japan, Korea and other East-Asian countries for treating cancer, inflammation, hepatic complications, influenza and wounds. However, the molecular or genetic characteristic of this plant is not well defined. In this study, improved random amplified polymorphic DNA (RAPD) has been employed for the genetic characterization of five varieties of L. japonica collected from different geographic locations of Southern China. A total of 147 bands of DNA fragments were obtained in RAPD-PCR by using 18 primers, and the band sizes ranged from approximately 300-2,000 bp, with 3-11 amplified bands for each primer. Based on the RAPD amplification profiles, cluster dendrogram was obtained, which showed that the similarity coefficients among five varieties of L. japonica ranged from 0.59 to 0.77. To our knowledge, this is the first report of genetic characterization of L. japonica using improved RAPD analysis which has been validated by ISSR analysis, and this characterization may be useful for the preservation of genetic diversity and Lonicera population identification. Moreover, as an option, the improved method could be employed for a variety of applications in genetic diversity and fingerprinting analyses.

Proteasome activity is frequently enhanced in cancer to accelerate metastasis and tumorigenesis. REGγ, a proteasome activator known to promote p53/p21/p16 degradation, is often overexpressed in cancer cells. Here we show that p53/TGF-β signalling inhibits the REGγ–20S proteasome pathway by repressing REGγ expression. Smad3 and p53 interact on the REGγ promoter via the p53RE/SBE region. Conversely, mutant p53 binds to the REGγ promoter and recruits p300. Importantly, mutant p53 prevents Smad3/N-CoR complex formation on the REGγ promoter, which enhances the activity of the REGγ–20S proteasome pathway and contributes to mutant p53 gain of function. Depletion of REGγ alters the cellular response to p53/TGF-β signalling in drug resistance, proliferation, cell cycle progression and proteasome activity. Moreover, p53 mutations show a positive correlation with REGγ expression in cancer samples. These findings suggest that targeting REGγ–20S proteasome for cancer therapy may be applicable to human tumours with abnormal p53/Smad protein status. Furthermore, this study demonstrates a link between p53/TGF-β signalling and the REGγ–20S proteasome pathway, and provides insight into the REGγ/p53 feedback loop.

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