Vasoactive intestinal peptide is required in the maintenance of immune regulatory competency of immune regulatory monocytes.

Dysfunction of the immune regulatory system plays an important role in the pathogenesis of rheumatoid arthritis (RA). Vasoactive intestinal peptide (VIP) has multiple bioactivities. This study aims to investigate the role of VIP in the maintenance of the immune regulatory capacity of monocytes (Mos). Human peripheral blood samples were collected from RA patients and healthy control (HC) subjects. Mos and CD14+ CD71- CD73+ CD25+ regulatory Mos (RegMos) were isolated from the blood samples and characterized by flow cytometry. A rat RA model was developed to test the role of VIP in the maintenance of the immune regulatory function of Mos. The results showed that RegMos of HC subjects had immune suppressive functions. RegMos of RA patients expressed less interleukin (IL)-10 and showed an incompetent immune regulatory capacity. Serum levels of VIP were lower in RA patients, which were positively correlated with the expression of IL-10 in RegMos. In-vitro experiments showed that the IL-10 mRNA decayed spontaneously in RegMos, which could be prevented by the presence of VIP in the culture. VIP suppressed the effects of tristetraprolin (TTP) on inducing IL-10 mRNA decay in RegMos. Administration of VIP inhibited experimental RA in rats through restoring the IL-10 expression in RegMos. RegMos have immune suppressive functions. VIP is required in maintaining IL-10 expression in RegMos. The data suggest that VIP has translational potential in the treatment of immune disorders such as RA.

Correction to: CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation.

Following publication of their article "CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation", the authors reported an error in Fig.6b. α-Tubulin image of rCCN2 treatment  (upper panel in CL1-5) only showed eight lanes, when there should be nine.

Manganese-Enhanced T1 Mapping in the Myocardium of Normal and Infarcted Hearts.

Background: Manganese-enhanced MRI (MEMRI) has the potential to identify viable myocardium and quantify calcium influx and handling. Two distinct manganese contrast media have been developed for clinical application, mangafodipir and EVP1001-1, employing different strategies to mitigate against adverse effects resulting from calcium-channel agonism. Mangafodipir delivers manganese ions as a chelate, and EVP1001-1 coadministers calcium gluconate. Using myocardial T1 mapping, we aimed to explore chelated and nonchelated manganese contrast agents, their mechanism of myocardial uptake, and their application to infarcted hearts. Methods: T1 mapping was performed in healthy adult male Sprague-Dawley rats using a 7T MRI scanner before and after nonchelated (EVP1001-1 or MnCl2 (22 µmol/kg)) or chelated (mangafodipir (22-44 µmol/kg)) manganese-based contrast media in the presence of calcium channel blockade (diltiazem (100-200 µmol/kg/min)) or sodium chloride (0.9%). A second cohort of rats underwent surgery to induce anterior myocardial infarction by permanent coronary artery ligation or sham surgery. Infarcted rats were imaged with standard gadolinium delayed enhancement MRI (DEMRI) with inversion recovery techniques (DEMRI inversion recovery) as well as DEMRI T1 mapping. A subsequent MEMRI scan was performed 48 h later using either nonchelated or chelated manganese and T1 mapping. Finally, animals were culled at 12 weeks, and infarct size was quantified histologically with Masson's trichrome (MTC). Results: Both manganese agents induced concentration-dependent shortening of myocardial T1 values. This was greatest with nonchelated manganese, and could be inhibited by 30-43% with calcium-channel blockade. Manganese imaging successfully delineated the area of myocardial infarction. Indeed, irrespective of the manganese agent, there was good agreement between infarct size on MEMRI T1 mapping and histology (bias 1.4%, 95% CI -14.8 to 17.1 P>0.05). In contrast, DEMRI inversion recovery overestimated infarct size (bias 11.4%, 95% CI -9.1 to 31.8 P=0.002), as did DEMRI T1 mapping (bias 8.2%, 95% CI -10.7 to 27.2 P=0.008). Increased manganese uptake was also observed in the remote myocardium, with remote myocardial ∆T1 inversely correlating with left ventricular ejection fraction after myocardial infarction (r=-0.61, P=0.022). Conclusions: MEMRI causes concentration and calcium channel-dependent myocardial T1 shortening. MEMRI with T1 mapping provides an accurate assessment of infarct size and can also identify changes in calcium handling in the remote myocardium. This technique has potential applications for the assessment of myocardial viability, remodelling, and regeneration.

Vitamin D receptor interacts with NLRP3 to restrict the allergic response.

Vitamin D receptor (VDR) mediates various biochemical activities between the cytoplasm and the nucleus in the cell. The nucleotide-binding, oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) protein is involved in the T helper type 2 (Th2) response. This study tests a hypothesis that VDR interacts with NLRP3 to restrict the Th2-biased response. In this study, VDR-/- mice and WT (WT) mice were used. Th2 cell differentiation between VDR-/- mice and WT mice was observed. We observed that CD4+ T cell activation was higher in VDR-/- mice. The VDR-/-CD4+ T cells were prone to Th2 polarization. VDR-/- mice produced more immunoglobulin (Ig)E. VDR bound NLRP3 to prevent Th2 differentiation by restricting IL4 gene transcription. Th2 biased inflammation spontaneously developed in the intestine of VDR-/- mice. In conclusion, VDR binds NLRP3 to restrict IL4 gene transcription and prevent biased Th2 polarization.

Long-term effects: Galectin-1 and specific immunotherapy for allergic responses in the intestine.

BACKGROUND AND AIMS: Mast cell activation interferes with the effects of allergen-specific immunotherapy (SIT). Galectin-1 (Gal-1) is capable of regulating immune cells' functions. This study tests the hypothesis that administration of Gal-1 promotes and prolongs the efficacy of SIT via suppressing mast cell activation. METHODS: An intestinal allergy mouse model was developed. The coadministration of SIT and Gal-1 on suppression of the allergic responses, prevention of mast cell activation, and generation of antigen-specific regulatory T cells (Treg) in the intestine was observed in sensitized mice. RESULTS: The coadministration of Gal-1 and SIT markedly suppressed the allergic responses in the mouse intestine vs the use of either SIT alone or Gal-1 alone. The Gal-1 binds to the IgE/FcɛRI complexes on the surface of mast cells to prevent mast cell activation during SIT. Gal-1 promoted the SIT-generated allergen-specific Tregs in the intestine of sensitized mice. Coadministration of Gal-1 and SIT significantly enhanced the efficacy of immunotherapy in suppressing allergic responses in the intestine, which lasted for at least for 12 months. CONCLUSIONS: Long-term effects of specific immunotherapy on intestinal allergy can be achieved with Gal-1/SIT therapy by inhibiting mast cell activation and facilitating Treg development.

Targeting histone-acetyltransferase Tat-interactive protein 60 inhibits intestinal allergy.

BACKGROUND: The overproduction of IgE plays a critical role in the pathogenesis of allergy; the mechanism is unclear. Histone-acetyltransferase (HAT) activities are required in gene transcription of a large number of molecules in the immune system of the body. OBJECTIVES: This study tests a hypothesis that HAT Tat-interactive protein 60 (Tip60) plays an important role in the initiation of IgE-mediated allergy. METHODS: The effects of Tip60 on regulating IgE expression were assessed with B cells. An intestinal allergy mouse model was developed to assess the role of Tip60 in the induction of IgE-mediated allergic inflammation. RESULTS: High levels of Tip60 were observed in the peripheral B cells of patients with FA. Tat-interactive protein 60 (Tip60) was required in the expression of IgE and IgG1 in B cells by inducing the chromatin remolding at the gene locus, in which histone acetylation, signal transducer and activator of transcription 6 (STAT6), and nuclear factor-κB at the locus of Iε promoter were markedly increased. Blocking Tip60 significantly attenuated the allergic inflammation in the mouse intestinal mucosa. CONCLUSIONS: Tat-interactive protein 60 (Tip60) plays an important role in the induction of IgE in B cells. Blocking Tip60 inhibits the allergic inflammation in the intestine, suggesting Tip60 inhibitor may be a potential anti-allergy drug.

GSK3ß controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug.

This corrects the article DOI: 10.1038/onc.2013.279.

[Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China].

Objective: To construct the Markov models to reflect the reality of prevention and treatment interventions against hepatitis B virus (HBV) infection, simulate the natural history of HBV infection in different age groups and provide evidence for the economics evaluations of hepatitis B vaccination and population-based antiviral treatment in China. Methods: According to the theory and techniques of Markov chain, the Markov models of Chinese HBV epidemic were developed based on the national data and related literature both at home and abroad, including the settings of Markov model states, allowable transitions and initial and transition probabilities. The model construction, operation and verification were conducted by using software TreeAge Pro 2015. Results: Several types of Markov models were constructed to describe the disease progression of HBV infection in neonatal period, perinatal period or adulthood, the progression of chronic hepatitis B after antiviral therapy, hepatitis B prevention and control in adults, chronic hepatitis B antiviral treatment and the natural progression of chronic hepatitis B in general population. The model for the newborn was fundamental which included ten states, i.e. susceptiblity to HBV, HBsAg clearance, immune tolerance, immune clearance, low replication, HBeAg negative CHB, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (HCC) and death. The susceptible state to HBV was excluded in the perinatal period model, and the immune tolerance state was excluded in the adulthood model. The model for general population only included two states, survive and death. Among the 5 types of models, there were 9 initial states assigned with initial probabilities, and 27 states for transition probabilities. The results of model verifications showed that the probability curves were basically consistent with the situation of HBV epidemic in China. Conclusion: The Markov models developed can be used in economics evaluation of hepatitis B vaccination and treatment for the elimination of HBV infection in China though the structures and parameters in the model have uncertainty with dynamic natures.

[Cost-effectiveness and affordability of strategy for preventing mother-to-child transmission of hepatitis B in China].

Objective: To evaluate the cost effectiveness of nationwide prevention of mother to child transmission (PMTCT) strategy for hepatitis B, and estimate the willing to pay and budget impacts on the PMTCT. Methods: The decision analytic Markov model for the PMTCT was constructed and a birth cohort of Chinese infants born in 2013 was used to calculate the cost-effectiveness of the PMTCT among them compared with those receiving no intervention. The parameters in the model were obtained from literatures of national surveys or Meta-analysis. The costs, cases of HBV-related diseases and quality-adjusted life-years (QALYs) were obtained from the societal and payer perspectives, respectively. The incremental cost-effectiveness ratio (ICER) was used as measures of strategy optimization. One-way and probability sensitivity analysis were performed to explore the uncertainty of the primary results. In addition, cost-effectiveness acceptability curve and cost-effectiveness affordability curves were drawn to illustrate the cost effectiveness threshold and financial budget of the PMTCT strategy. Results: The lifetime cost for PMTCT strategy was 4 063.5 yuan (RMB) per carrier, which was 37 829.7 yuan (RMB) lower compared with those receiving no intervention. Due to the strategy, a total of 24.516 1 QALYs per person would be gained, which was higher than that in those receiving no intervention. From societal perspective, the ICER was -59 136.6 yuan (RMB) per additional QALYs gained, indicating that the PMTCT is cost effective. The results were reliable indicated by one-way, multi-way and probability sensitivity analyses. By the CEAC, the willing to pay was much lower than the cost-effectiveness threshold. From the affordability curve of the PMTCT strategy, the annual budget ranged from 590.4 million yuan (RMB) to 688.8 million yuan (RMB), which was lower than the financial ability. Based on the results of cost-effectiveness affordability curves, the higher annual budget was determined, the higher probability of affordability for the PMTCT would be obtained under the same willing to pay state. Only when the annual budget reaches 688.8 million yuan (RMB), the goal of PMTCT would be fully realized. Conclusions: The PMTCT strategy in China was cost effective, and the cost is not beyond the financial budget needed and the willing to pay. The strategy, which is consistent with the global hepatitis B elimination efforts, should be conducted widely in China.

[Cost-effectiveness of community-based treatment of chronic hepatitis B in China].

Objective: Since eliminating hepatitis B in China would need considerable public health resources, the economics problem of the strategy of community-based antiviral treatment for chronic hepatitis B (CHB) has become an important issue. The cost-effectiveness and affordability of the strategy were evaluated in this study. Methods: According to the advocacy on eliminating hepatitis B by WHO and the comprehensive protocol of community based prevention of major infectious diseases and the guideline for CHB prevention and treatment in China, the decision analytic Markov model was constructed with the parameters from national surveys or Meta-analysis. A cohort population aged 20-59 years was used as study subjects. The strategy of CHB antiviral treatment was compared with the strategies of hepatitis B vaccination and non-intervention, respectively. The costs and disability-adjusted life years (QALYs) of the strategies were calculated from the societal and payer perspectives. The incremental cost-effectiveness ratio (ICER) and the cost-effectiveness ratio (CER) were calculated for the comparison of the strategies. One-way and probability sensitivity analysis were performed for uncertainty of the results. And the cost-effectiveness and affordability curves were introduced to estimate the budget impact on the strategies. Results: In the Chinese aged 20-59 years, the ICER of CHB antiviral treatment was 37 598.6 yuan (RMB) per QALYs and the ICERs were smaller in the low age groups, indicating that the antiviral treatment strategy is cost-effective and low age groups should be the priority population. The ICER of hepatitis B vaccination was -64 000.0 yuan (RMB) per QALYs, indicating that hepatitis B vaccination is cost saving. The CER of CHB antiviral treatment ranged from 731.8 to 1 813.3 yuan (RMB) per QALYs compared with hepatitis B vaccination, and the CER of CHB antiviral treatment was higher than that of hepatitis B vaccination in all age groups, indicating that hepatitis B vaccination would be more cost-effective than CHB antiviral treatment. The price of antiviral drug, entercavir, can influence the cost effectiveness of CHB antiviral treatment. If the price of entercavir declined half, CHB antiviral treatment would be cost-saving. The probability sensitivity analysis showed that people's willing to pay for CHB antiviral treatment should not be ignored, although the results of economics evaluation of CHB antiviral treatment were reliable. The results of affordability analysis indicated that the antiviral treatment strategy could not be implemented with the budget lower than 30 million yuan (RMB), the probability of implementing the strategy was 42.6% if the budget reaches 127 million yuan (RMB), and only when the budget reaches 269 million yuan (RMB), the goal of CHB antiviral treatment strategy can be fully realized. Conclusions: Although the strategy of CHB antiviral treatment as prevention in Chinese aged 20-59 years is cost-effective, it is not an appropriate public health measure due to the high cost. The cost effectiveness would be higher by conducting hepatitis B vaccination and then antiviral treatment in susceptible population.

Protease-activated receptor-2 suppresses interleukin (IL)-10 expression in B cells via upregulating Bcl2L12 in patients with allergic rhinitis.

BACKGROUND AND AIMS: The function of interleukin (IL)-10-producing B cells (B10 cell) is compromised in patients with allergic diseases. Protease-activated receptor (PAR)-2 has immunoregulatory functions. This study aimed to elucidate the role of PAR2 in the suppression of IL-10 expression in peripheral B cells. METHODS: Peripheral blood B cells were collected from patients with allergic rhinitis (AR). A correlation between the expression of Bcl2-like protein 12 (Bcl2L12) and IL-10 in the B cells was analyzed. An AR mouse model was developed. RESULTS: We observed that the expression of IL-10 was lower in the peripheral B cells from patients with airway allergy. A negative correlation was identified between the expression of IL-10 and PAR2 in B cells. Activation of PAR2 of B cells increased the expression of Bcl2L12 and suppression of LPS-induced IL-10 expression, which were inhibited by knocking down the Bcl2L12 gene. Treating B cells from AR patients with Bcl2L12-shRNA-carrying liposomes reversed the capability of IL-10 expression and the immunosuppressive function. Administration of Bcl2L12 shRNA-carrying liposomes attenuated experimental AR in mice. CONCLUSIONS: Activation of PAR2 inhibits the expression of IL-10 in B cells, which can be reversed by treating B cells with Bcl2L12 shRNA-carrying liposomes. The data suggest that regulation of Bcl2L12 may be a novel approach in the treatment for AR.

Vitamin D regulates immunoglobulin mucin domain molecule-4 expression in dendritic cells.

BACKGROUND: Dendritic cell (DC)-derived immunoglobulin domain molecule (TIM)4 plays a critical role in the initiation of T helper (Th)2 polarization. Vitamin D (VitD) involves the regulation of a number of immune responses. OBJECTIVES: This study tests a hypothesis that VitD regulates TIM4 expression in DCs. METHODS: Peripheral blood samples were collected from patients with allergic rhinitis (AR) and healthy subjects. DCs were isolated from the samples and analyzed for the expression of TIM4. RESULTS: We observed that the levels of calcitriol, the active form of VitD3, in the sera of AR patients were lower than that in healthy subjects. The peripheral DC expressed higher levels of TIM4 and lower levels of VDR. A negative correlation was identified between the data of serum calcitriol and TIM4 in DCs. Exposure DCs to calcitriol in the culture increased the expression of VDR. We also found that VDR bound to the TIM4 promoter locus in DCs to repress the TIM4 gene transcription and expression. CONCLUSIONS AND CLINICAL RELEVANCE: VitD deficiency may contribute to the pathogenesis of AR by increasing the TIM4 expression. The results suggest that to regulate the serum calcitriol levels and the expression of VDR in DCs may be necessary to be taken into account in the treatment of AR.

Dust mite allergen, glutathione S-transferase, induces T cell immunoglobulin mucin domain-4 in dendritic cells to facilitate initiation of airway allergy.

BACKGROUND: Allergens from dust mites play a critical role in the pathogenesis of airway allergy. The mechanism by which dust mite allergens induce allergic diseases is not fully understood yet. OBJECTIVE: This study tests a hypothesis that the eighth subtypes of Dermatophagoides farina allergen (Derf8) play an important role in the induction of airway allergy. METHODS: The protein of Derf8 was synthesized via molecular cloning approach. Dendritic cells (DC) were stimulated with Derf8 in the culture, and then, the expression of T cell immunoglobulin mucin domain 4 (TIM4) in dendritic cells (DC) was analysed. The role of Derf8 in the induction of airway allergy was evaluated with a mouse model. RESULTS: Exposure to Derf8 markedly induced the TIM4 expression in DCs by modulating the chromatin at the TIM4 promoter locus. Derf8 played a critical role in the expansion of the T helper 2 response in the mouse airway via inducing DCs to produce TIM4. Administration with Derf8-depleted dust mite extracts (DME) inhibited the allergic inflammation and induced regulatory T cells in mice with airway allergy. CONCLUSION: Derf8 plays an important role in the initiation of dust mite allergy. Vaccination with Derf8-deficient DME is more efficient to inhibit the dust mite allergic inflammation than using wild DME.

Vitamin D contributes to mast cell stabilization.

BACKGROUND AND AIMS: Mast cells are the major effector cells in allergic disorders and many other informatory disorders. The mechanism of mast cell stabilization is not fully understood. Cumulative reports indicate that vitamin D (VitD) contributes to the homeostasis in the body. This study tests a hypothesis that VitD is required in the maintenance of the stability of mast cells. METHODS: The stability of mast cell lines, HMC1 cells, RBL-2H3 cells, p815 cells, and mouse bone marrow-derived mast cells (BMMC) was tested in the presence or absence of VitD3. RESULTS: Mast cells activated automatically in a VitD-deficient environment. Exposure to calcitriol in the culture increased the expression of VitD receptor (VDR) in mast cells. VDR formed complexes with Lyn in mast cells to inhibit the binding of Lyn to the ß chain of FcεRI and MyD88, which decreased the phosphorylation of Syk, decreased the levels of MAPK and NF-κB. VDR bound to the promoter of TNF-α to decrease the acetylation of histone H3/H4, RNA polymerase II and OCT1 (a transcription factor of TNF-α) at the promoter locus and repressed the expression of TNF-α in mast cells. CONCLUSIONS: The data demonstrate that VitD is required to maintain the stability of mast cells. The deficiency of VitD results in mast cell activation.

Forkhead box protein-3 (Foxp3)-producing dendritic cells suppress allergic response.

BACKGROUND: The generation of the tolerogenic dendritic cells (DC) is not fully understood yet. Forkhead box protein-3 (Foxp3) is an important molecule in the immune tolerance. This study tests a hypothesis that DCs express Foxp3, which can be upregulated by Staphylococcal enterotoxin B (SEB). METHODS: The expression of Foxp3 by DCs was evaluated by real-time RT-PCR, Western blotting, flow cytometry, and chromatin immunoprecipitation assay. RESULTS: We observed that mice treated with SEB at 0.25-0.5 µg/mouse showed high frequencies of transforming growth factor (TGF)-ß-producing CD4+ T cells and TGF-ß-producing DCs in the intestine, while the IL-4+ CD4+ T cells and TIM4+ DCs were dominated in the intestine in mice treated with SEB at 1-10 µg/mouse. Treating DCs with SEB in the culture induced high levels of Foxp3 at the TGF-ß promoter locus. The function of Foxp3 was blocked by STAT6 (signal transducer and activator transcription-6); the latter was induced by exposing DCs to SEB in the culture at doses of 100-400 ng/ml. Treating allergic mice with specific immunotherapy (SIT) together with SEB significantly promoted the therapeutic effects on the allergic responses than treating with SIT alone. CONCLUSION: Dendritic cells have the capacity to express Foxp3, which can be upregulated by exposure to SEB.

[Cost-effectiveness and cost-benefit analysis on strategy for preventing mother-to-child transmission of hepatitis B virus].

OBJECTIVE: Through cost-benefit analysis (CBA), cost-effectiveness analysis (CEA) and quantitative optimization analysis to understand the economic benefit and outcomes of strategy regarding preventing mother-to-child transmission (PMTCT) on hepatitis B virus. METHODS: Based on the principle of Hepatitis B immunization decision analytic-Markov model, strategies on PMTCT and universal vaccination were compared. Related parameters of Shenzhen were introduced to the model, a birth cohort was set up as the study population in 2013. The net present value (NPV), benefit-cost ratio (BCR), incremental cost-effectiveness ratio (ICER) were calculated and the differences between CBA and CEA were compared. RESULTS: A decision tree was built as the decision analysis model for hepatitis B immunization. Three kinds of Markov models were used to simulate the outcomes after the implementation of vaccination program. The PMTCT strategy of Shenzhen showed a net-gain as 38 097.51 Yuan/per person in 2013, with BCR as 14.37. The universal vaccination strategy showed a net-gain as 37 083.03 Yuan/per person, with BCR as 12.07. Data showed that the PMTCT strategy was better than the universal vaccination one and would end with gaining more economic benefit. When comparing with the universal vaccination program, the PMTCT strategy would save 85 100.00 Yuan more on QALY gains for every person. The PMTCT strategy seemed more cost-effective compared with the one under universal vaccination program. In the CBA and CEA hepatitis B immunization programs, the immunization coverage rate and costs of hepatitis B related diseases were the most important influencing factors. Outcomes of joint-changes of all the parameters in CEA showed that PMTCT strategy was a more cost-effective. CONCLUSIONS: The PMTCT strategy gained more economic benefit and effects on health. However, the cost of PMTCT strategy was more than the universal vaccination program, thus it is important to pay attention to the process of PMTCT strategy and the universal vaccination program. CBA seemed suitable for strategy optimization while CEA was better for strategy evaluation. Hopefully, programs as combination of the above said two methods would facilitate the process of economic evaluation.

HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms.

HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. This study demonstrated that HLJ1 inhibits epithelial-mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways. A screen of specimens from HLJ1-knockout mice and lung cancer patients validated that HLJ1 expression is inversely correlated with Src activity. Mechanistically, HLJ1 protein directly bound to catalytic and protein-binding domains of Src through its amino acid Y172 and the P301/P304 motif. Following Src-induced HLJ1 phosphorylation at Y172, HLJ1-Src interaction was elevated, resulting in Src inhibition and malignancy suppression. Interestingly, both Src-binding regions also occurred in other DNAJB family members and contributed to anti-invasive activities of DNAJB proteins. We conclude that HLJ1 is an endogenous Src inhibitor that can suppress cancer metastasis through complex interacting mechanisms. This HLJ1-Src complex might provide a promising molecular model for developing new anticancer strategies.

Slug is temporally regulated by cyclin E in cell cycle and controls genome stability.

The transcriptional repressor Slug is best known to control epithelial-mesenchymal transition (EMT) and promote cancer invasion/metastasis. In this study, we demonstrate that Slug is temporally regulated during cell cycle progression. At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. Non-phosphorylatable Slug is markedly stabilized at G1/S transition compared with wild-type Slug and greatly leads to downregulation of DNA synthesis and checkpoint-related proteins, including TOP1, DNA Ligase IV and Rad17, reduces cell proliferation, delays S-phase progression and contributes to genome instability. Our results indicate that Slug has multifaceted roles in cancer progression by controlling both EMT and genome stability.

A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis.

Myristoylated Alanine-Rich C Kinase Substrate (MARCKS), a substrate of protein kinase C, is a key regulatory molecule controlling mucus granule secretion by airway epithelial cells as well as directed migration of leukocytes, stem cells and fibroblasts. Phosphorylation of MARKCS may be involved in these responses. However, the functionality of MARCKS and its related phosphorylation in lung cancer malignancy have not been characterized. This study demonstrated elevated levels of MARCKS and phospho-MARCKS in highly invasive lung cancer cell lines and lung cancer specimens from non-small-cell lung cancer patients. siRNA knockdown of MARCKS expression in these highly invasive lung cancer cell lines reduced cell migration and suppressed PI3K (phosphatidylinositol 3'-kinase)/Akt phosphorylation and Slug level. Interestingly, treatment with a peptide identical to the MARCKS N-terminus sequence (the MANS peptide) impaired cell migration in vitro and also the metastatic potential of invasive lung cancer cells in vivo. Mechanistically, MANS peptide treatment resulted in a coordination of increase of E-cadherin expression, suppression of MARCKS phosphorylation and AKT/Slug signalling pathway but not the expression of total MARCKS. These results indicate a crucial role for MARCKS, specifically its phosphorylated form, in potentiating lung cancer cell migration/metastasis and suggest a potential use of MARCKS-related peptides in the treatment of lung cancer metastasis.