Isthmin-1 promotes growth and progression of colorectal cancer through the interaction with EGFR and YBX-1.

While previous studies have indicated the involvement of Isthmin 1 (ISM1), a secreted protein, in cancer development, the precise mechanisms have remained elusive. In this study, we unveiled that ISM1 is significantly overexpressed in both the blood and tissue samples of colorectal cancer (CRC) patients, correlating with their poor prognosis. Functional experiments demonstrated that enforced ISM1 expression significantly enhances CRC proliferation, migration, invasion and tumor growth. Notably, our investigation reveals an interaction of ISM1 with epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family of CRC cells. The binding of ISM1 triggered EGFR activation and initiate downstream signaling pathways. Meanwhile, intracellular ISM1 interacted with Y-box binding protein 1 (YBX1), enhancing its transcriptional regulation on EGFR. Furthermore, our research uncovered the regulation of ISM1 expression by the hypoxia-inducible transcription factor HIF-1α in CRC cells. Mechanistically, we identified HIF-1α as a direct regulator of ISM1, binding to a hypoxia response element on its promoter. This novel mechanism illuminated potential therapeutic targets, offering insights into restraining HIF-1α/ISM1/EGFR-driven CRC progression and metastasis.

A Self-Homing and Traceable Cardiac Patch Leveraging Ferumoxytol for Spatiotemporal Therapeutic Delivery.

Mesenchymal stem cell (MSC)-based cardiac patches are envisioned to be a promising treatment option for patients with myocardial infarction. However, their therapeutic efficacy and duration are hampered due to their limited retention on the epicardium. We engineered a scaffold-free MSC sheet with an inherent ability to migrate into the infarcted myocardium, a strategy enabled by actively establishing a sustained intracellular hypoxic environment through the endocytosis of our FDA-approved ferumoxytol. This iron oxide nanoparticle stabilized hypoxia-induced factor-1α, triggering upregulation of the CXC chemokine receptor and subsequent MSC chemotaxis. Thus, MSCs integrated into 2/3 depth of the left ventricular anterior wall in a rat model of acute myocardial infarction and persisted for at least 28 days. This led to spatiotemporal delivery of paracrine factors by MSCs, enhancing cardiac regeneration and function. Ferumoxytol also facilitated the noninvasive MRI tracking of implanted MSCs. Our approach introduces a strategy for mobilizing MSC migration, holding promise for rapid clinical translation in myocardial infarction treatment.

Mixed-valence gold-porphyrin two-dimensional coordination networks for repurposing of chrysotherapy.

Catalytic gold nanomaterials typically exhibit antibacterial properties, albeit significantly weaker than ionic gold in chrysotherapy. The inherent stability of gold nanoparticles prevents the release of gold ions, limiting their ability to achieve efficient antibacterial therapy. To address this limitation, we propose a novel sustained ionic gold release strategy through the construction of a mixed-valence gold-porphyrin coordination network (Au-Por). By adjusting the ratio of Au to porphyrin molecule, an ultrathin two-dimensional Au-Por nanosheet was successfully synthesized, which contains 85.9 % of Au (III). In addition, the remaining gold existed in the form of uniformly distributed ultrasmall nanoclusters on the Au-Por nanosheet. Notably, the Au-Por nanosheet exhibited a sustained release of gold ions. Thus, a multimodal antibacterial therapy was achieved by integrating the direct bactericidal action of ionic gold and lethal reactive oxygen species (ROS) generated through the peroxidase (POD)-like activity of gold nanoclusters and photodynamic therapy (PDT) using porphyrins. The innovative Au-Por exerted broad-spectrum bactericidal activity against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus bacteria mediated by bacterial membrane disruption and DNA damage. Moreover, in vivo studies demonstrated the synergistic effect of Au-Por on combating skin wound infections and facilitating wound healing. Comprehensive safety evaluations proved that Au-Por exhibited no hematotoxicity or hepatorenal toxicity, and it also displayed rapid renal clearance after treatment, indicating favorable biocompatibility. The repurposing of chrysotherapy has revolutionized the antibacterial strategy of nanoscale gold, resulting in a dramatic boost in antibacterial activity and valuable insights for designing highly efficient nanoscale antibacterial agents.

Stage Shift Improves Lung Cancer Survival: Real-World Evidence.

INTRODUCTION: Lung cancer is the global leading cause of cancer death. Taiwan initiated several health policies including smoking cessation, precision therapy, and low-dose computed tomography (LDCT) screening in 1997. We aimed to investigate the effect of public policies on lung cancer survival. METHODS: We retrieved the nationwide cancer registry from the Ministry of Health and Welfare to evaluate the smoking prevalence and lung cancer incidence and mortality from 1994 to 2020. We also conducted a retrospective analysis of clinical characteristics and survival on 17,298 patients with lung cancer from 2006 to 2019 using the National Taiwan University Hospital database. RESULTS: Taiwan initiated an anti-smoking campaign in 1997, reimbursed tyrosine kinase inhibitors since 2004, and conducted an LDCT screening trial in 2015. Lung cancer incidence keeps rising but the annual percent change in mortality rate gradually decreased from 0.41% to -2.41%. The National Taiwan University Hospital data revealed that the 5-year survival substantially improved from 22.1% in 2006 to 2011 to 54.9% in 2015 to 2020. Improvement was observed in all stages, especially late stages (stage III: from 17.2% to 35.2%; stage IV: from 7.9% to 16.5%). Furthermore, a remarkable shift in cancer stage was observed (stage 0, I, and IIincreased from 19.3% to 62.8%, and stage III and IV decreased from 70.9% to 33.8%). The prominent improvement in survival was primarily driven by the stage shift from advanced to localized, potentially curable disease. CONCLUSIONS: This real-world evidence suggested an association between improved survival and LDCT screening and the diagnostic shift from late to early-stage of lung cancer, highlighting the importance of early detection for lung cancer control.

HOXB9 a miR-122-5p regulated gene, suppressed the anticancer effects of brusatol by upregulating SCD1 expression in melanoma.

Brusatol (Bru), a Chinese medicine Brucea javanica extract, has a variety of antitumour effects. However, its role and underlying mechanism in melanoma have not been fully elucidated. In this study, we found that brusatol inhibited melanoma cell proliferation and migration and promoted cell apoptosis in vitro, in addition to suppressing melanoma cell tumorigenesis in vivo. Further studies on the mechanism revealed that brusatol significantly downregulated the expression of stearoyl-CoA desaturase 1 (SCD1). Increased SCD1 expression could impair the antitumour effects of brusatol on melanoma cells. Subsequently, we found that HOXB9, an important transcription factor, was directly bound to the promoter of SCD1, facilitating its transcription. Overexpression of HOXB9 inhibited brusatol-induced SCD1 reduction and promoted cell survival. Furthermore, our results revealed that miR-122-5p was significantly increased in response to brusatol treatment and led to a decrease in HOXB9 in melanoma. Collectively, our data suggested that the miR-122-5p/HOXB9/SCD1 axis might play an important role in the antitumour effects of brusatol and that brusatol might have potential clinical implications in melanoma therapy.

mTOR Signalling Pathway: A Potential Therapeutic Target for Ocular Neurodegenerative Diseases.

Recent advances in the research of the mammalian target of the rapamycin (mTOR) signalling pathway demonstrated that mTOR is a robust therapeutic target for ocular degenerative diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. Although the exact mechanisms of individual ocular degenerative diseases are unclear, they share several common pathological processes, increased and prolonged oxidative stress in particular, which leads to functional and morphological impairment in photoreceptors, retinal ganglion cells (RGCs), or retinal pigment epithelium (RPE). mTOR not only modulates oxidative stress but is also affected by reactive oxygen species (ROS) activation. It is essential to understand the complicated relationship between the mTOR pathway and oxidative stress before its application in the treatment of retinal degeneration. Indeed, the substantial role of mTOR-mediated autophagy in the pathogenies of ocular degenerative diseases should be noted. In reviewing the latest studies, this article summarised the application of rapamycin, an mTOR signalling pathway inhibitor, in different retinal disease models, providing insight into the mechanism of rapamycin in the treatment of retinal neurodegeneration under oxidative stress. Besides basic research, this review also summarised and updated the results of the latest clinical trials of rapamycin in ocular neurodegenerative diseases. In combining the current basic and clinical research results, we provided a more complete picture of mTOR as a potential therapeutic target for ocular neurodegenerative diseases.

Secular Trends of Clinical Characteristics and Survival of Hepatocellular Carcinoma in Taiwan from 2011 to 2019.

Hepatocellular carcinoma (HCC) is a major cause of cancer death in Taiwan, and in the past 30-40 years, Taiwan has been committed to its prevention and treatment. We aimed to investigate the secular trends of characteristics and the survival of HCC in recent decades after making increased efforts. Between 2011 and 2019, a total of 73,817 cases were enrolled from the TCR database. The overall male-to-female ratio was 7/3. The overall, male and female mean ages increased from 63.8 to 66.1 years, 62.0 to 64.3 years and 68.3 to 70.4 years, respectively. After dividing by viral etiologies and gender, the mean age showed increasing trends in all subgroups. The proportions of HBV-HCC, HCV-HCC, HBV+HCV-HCC and Non-HBV+non-HCV-HCC were 48.3%, 25.2%, 5.3% and 21.3% in males, compared with 25.5%, 48.6%, 5.3% and 20.5% in females, respectively. The 5-year survival rates of BCLC stages 0, A, B, C and D were 70%, 58%, 34%, 11% and 4%, respectively. The proportion of BCLC stage 0 increased from 6.2% to 11.3%. Multivariate analysis showed that being female, older age, diagnostic year, BCLC stages, hospital level, body mass index, smoking, alcohol consumption, AFP, Child-Pugh classification and HBV/HCV status were independent predictors for survival. In recent decades, the overall survival of HCC in Taiwan has been improving and might be partly associated with increased BCLC 0 and Child-Pugh A patients, while with the consequent age of patients increasing over time. The proportion of viral-related HCC is decreasing, while nonviral-related HCC is increasing.

Factors Related to Blood Pressure Response after Community-Based Exercise Program in the Elderly Population.

Exercise has been recommended for blood pressure (BP) control, but not every individual can improve BP and reduce the risk of cardiovascular disease effectively by exercise. This study aimed to evaluate the BP response after 12-week exercise intervention and then identify the potential factors of responders on BP (R-BP) control. This was a retrospective cohort study from a project of Taipei City Government. Subjects completed the original program were included for further analysis. Sociodemographic factors, health-related behaviors, and cardiovascular risks were extracted as potential factors. The results were categorized into R-BP control, i.e., BP under optimal level (systolic BP (SBP) < 140 mmHg; and diastolic BP (DBP) < 90 mmHg) or a significant BP reduction (SBP ↓10 mmHg or DBP ↓5 mmHg) after intervention, or non-responder on BP control, i.e., subjects who failed to achieve the targets. There were 81.62% R-BP subjects. R-BP showed lower SBP and lower risk of hypertension at baseline. Active lifestyle could quadruple the number of R-BP. Higher educational level or more prescription medications were likely to be R-BP in subjects with diagnosed hypertension. Active lifestyle combined with exercise could benefit R-BP in the elderly population. Health-related factors also need to be considered for BP control.

Anti-Warburg effect by targeting HRD1-PFKP pathway may inhibit breast cancer progression.

BACKGROUND: Our previous studies have shown that the E3 ubiquitin ligase of HMG-CoA reductase degradation 1 (HRD1) functions as a tumor suppressor, as overexpression of HRD1 suppressed breast cancer proliferation and invasion. However, its role in breast cancer cell glucose metabolism was unclear. Here, our aim was to uncover the role and molecular mechanisms of HRD1 in regulating aerobic glycolysis in breast cancer. METHODS: The effect of HRD1 on robic glycolysis in breast cancer cells were assessed. Then the proliferation, colony formation ability, invasion and migration of breast cancer cells were evaluated. The relationship between HRD1 and PFKP was validated by Mass spectrometry analysis, immunofluorescence and co-immunoprecipitation. The level of PFKP ubiquitination was measured using ubiquitylation assay. Furthermore, the tumor growth and metastasis in mice xenografts were observed. RESULTS: We found that upregulation of HRD1 clearly decreased aerobic glycolysis, and subsequently inhibited breast cancer proliferation and invasion. Mass spectrometry analysis results revealed a large HRD1 interactome, which included PFKP (platelet isoform of phosphofructokinase), a critical enzyme involved in the Warburg Effect in breast cancer. Mechanistically, HRD1 interacted and colocalized with PFKP in the cytoplasm, targeted PFKP for ubiquitination and degradation, and ultimately reduced PFKP expression and activity in breast cancer cells. HRD1 inhibited breast cancer growth and metastasis in vivo through a PFKP-dependent way CONCLUSIONS: Our findings reveal a new regulatory role of HRD1 in Warburg effect and provide a key contributor in breast cancer metabolism. Video abstract.

CircNR3C2 promotes HRD1-mediated tumor-suppressive effect via sponging miR-513a-3p in triple-negative breast cancer.

BACKGROUND: E3 ubiquitin ligase HRD1 (HMG-CoA reductase degradation protein 1, alias synoviolin with SYVN1 as the official gene symbol) was found downregulated and acting as a tumor suppressor in breast cancer, while the exact expression profile of HRD1 in different breast cancer subtypes remains unknown. Recent studies characterized circular RNAs (circRNAs) playing an regulatory role as miRNA sponge in tumor progression, presenting a new viewpoint for the post-transcriptional regulation of cancer-related genes. METHODS: Examination of the expression of HRD1 protein and mRNA was implemented using public microarray/RNA-sequencing datasets and breast cancer tissues/cell lines. Based on public RNA-sequencing results, online databases and enrichment/clustering analyses were used to predict the specific combinations of circRNA/miRNA that potentially govern HRD1 expression. Gain-of-function and rescue experiments in vitro and in vivo were executed to evaluate the suppressive effects of circNR3C2 on breast cancer progression through HRD1-mediated proteasomal degradation of Vimentin, which was identified using immunoblotting, immunoprecipitation, and in vitro ubiquitination assays. RESULTS: HRD1 is significantly underexpressed in triple-negative breast cancer (TNBC) against other subtypes and has an inverse correlation with Vimentin, inhibiting the proliferation, migration, invasion and EMT (epithelial-mesenchymal transition) process of breast cancer cells via inducing polyubiquitination-mediated proteasomal degradation of Vimentin. CircNR3C2 (hsa_circ_0071127) is also remarkably downregulated in TNBC, negatively correlated with the distant metastasis and lethality of invasive breast carcinoma. Overexpressing circNR3C2 in vitro and in vivo leads to a crucial enhancement of the tumor-suppressive effects of HRD1 through sponging miR-513a-3p. CONCLUSIONS: Collectively, we elucidated a bona fide circNR3C2/miR-513a-3p/HRD1/Vimentin axis that negatively regulates the metastasis of TNBC, suggesting that circNR3C2 and HRD1 can act as potential prognostic biomarkers. Our study may facilitate the development of therapeutic agents targeting circNR3C2 and HRD1 for patients with aggressive breast cancer.

Facile fabrication of a low-cost and environmentally friendly inorganic-organic composite membrane for aquatic dye removal.

This study reports a new inorganic-organic composite membrane fabricated by an electrostatic self-assembling method. The low-cost and eco-friendly porous geopolymer (PG) was chosen as a support, on which chitosan (CS), a "green" biomaterial, was used to form an active layer. With optimum dosage of CS (2.0 mL of 1.0% CS solution), the obtained CS/PG membrane exhibited a high porosity of 50.97% with an average pore diameter of 13.93 nm as well as a high water flux of 1663.82 ± 22.46 L/m2·h·bar. The effects of initial concentration, pH, flow rate and temperature of the feed solution on crystal violet (CV) removal by the CS/PG were evaluated in a continuous mode. The results indicated ~95% CV could be removed from water during continuous treating of 14 h. The effectiveness in CV removal by the CS/PG membrane was attributed to the synergistic effect of rejection and adsorption. Furthermore, the composite membrane could be easily regenerated for prolonged use. Overall, this work opens a new possibility of building cost-saving and eco-friendly composite membranes for practical applications in water purification.

Numerical Simulation, Machining and Testing of a Phase Change Heat Sink for High Power LEDs.

Thermal management is crucial to guarantee the normal operation of light-emitting diodes (LEDs) Phase change heat sink is superior to traditional metal solid heat sink due to very small thermal resistance. In this study, a new type of phase change heat sink for high power LEDs is first designed. Then, the fabrication process of boiling structures at the evaporation surface of the phase change heat sink is discussed and analyzed. To make a comparison and deep discussion, the machining process is simulated through the FEM (finite element analysis) software, DEFORM-3D. Last but not least, heat transfer performance of the fabricated phase change heat sink is tested. Results have shown that the designed new type of phase change heat sink has superior heat transfer performance and is suitable for heat dissipation of high-power LEDs.

DNA Methylation of miR-122 Aggravates Oxidative Stress in Colitis Targeting SELENBP1 Partially by p65NF-κB Signaling.

Aberrant microRNA (miRNA) expressions contribute to the development and progression of various diseases, including Crohn's disease (CD). However, the accurate mechanisms of miRNAs in CD are definitely unclear. We employed colonic tissue samples from normal volunteers and CD patients, an acute mice colitis model induced by 2,4,6-trinitro-benzene-sulfonic acid (TNBS), and a cellular oxidative stress model induced by H2O2 in HT-29 cells to determine the effects of oxidative stress on expressions of miR-122, selenium-binding protein 1 (SELENBP1, SBP1), p65 nuclear factor κB (p65NF-κB) signaling, and DNA methylation. We found that SBP1 was mainly located on epithelial cells and was significantly increased in patients with active CD. SBP1 was the target gene of miR-122. miR-122 expression was downregulated while SBP1 expression was upregulated under TNBS-induced colitis or oxidative stress. Pre-miR-122 or siRNA SBP1 (si-SBP1) treatment ameliorated acute TNBS-induced colitis and H2O2-induced oxidative stress. Cotreatment of pre-miR-122 and si-SBP1 enhanced these effects. Besides, pre-miR-122 and si-SBP1 obviously activated the p65NF-κB signaling by phosphorylation of IκBα. Bisulfite sequencing of the CpG islands in the promoter region of miR-122 showed that CpG methylation was significantly increased under oxidative stress. Treating cells with 5'-AZA which was well known as a DNA-demethylating agent significantly increased miR-122 expression. Our results suggest that oxidative stress-induced DNA methylation of miR-122 aggravates colitis targeting SELENBP1 partially by p65NF-κB signaling and may promote the progression of CD.

A Minimally Invasive Hollow Microneedle With a Cladding Structure: Ultra-Thin but Strong, Batch Manufacturable.

OBJECTIVE: A minimally invasive hollow in-plane microneedle with a cladding structure is designed to improve the mechanical strength. METHODS: The traditional weak stack structure has been changed into a cladding structure, and the effectiveness has been validated through finite element analysis. The prototypes of the microneedles were batch manufactured by the integrated micromachining process with no need to assemble. RESULTS: Compared to our previously reported microneedle with the weak stack structure, the cladding microneedle in this paper shows 263% improvement in bonding strength (6.4±0.30 N) and 36.5% improvement in buckling strength (2.8±0.07 N). In addition, the fabricated microneedle will not fail during insertion into the fresh and dehydrated pig skin with a satisfying safety factor (1.55). CONCLUSION: A novel structure of hollow microneedle was developed and fabricated by microfabrication technology. The improvement in mechanical strength is obvious. SIGNIFICANCE: The microneedle has great mechanical property and good potential for wider applications in human skin.

Thermal Performance of Micro Hotplates with Novel Shapes Based on Single-Layer SiO2 Suspended Film.

In this paper, two kinds of suspended micro hotplate with novel shapes of multibeam structure and reticular structure are designed. These designs have a reliable mechanical strength, so they can be designed and fabricated on single-layer SiO2 suspended film through a simplified process. Single-layer suspended film helps to reduce power consumption. Based on the new film shapes, different resistance heaters with various widths and thicknesses are designed. Then, the temperature uniformity and power consumption of different micro hotplates are compared to study the effect of these variables and obtain the one with the optimal thermal performance. We report the simulations of temperature uniformity and give the corresponding infrared images in measurement. The experimental temperature differences are larger than those of the simulation. Experimental results show that the lowest power consumption and the minimum temperature difference are 43 mW and 50 °C, respectively, when the highest temperature on the suspended platform (240 × 240 µm²) is 450 °C. Compared to the traditional four-beam micro hotplate, temperature non-uniformity is reduced by about 30⁻50%.

DAPL1, a susceptibility locus for age-related macular degeneration, acts as a novel suppressor of cell proliferation in the retinal pigment epithelium.

The retinal pigment epithelium (RPE) forms a monolayer at the back of the vertebrate eye and is fundamental to retinal function and homoeostasis. During early development, RPE cells undergo rapid proliferation, but in the adult, they remain normally nonproliferative throughout life. Nevertheless, under pathological conditions such as in proliferative vitreoretinopathy or after retinal ablation, mature RPE cells can re-enter the cell cycle and form nodules or multiple cell layers. Here we show that Dapl1, whose human homolog represents a susceptibility locus for age-related macular degeneration (AMD), is highly up-regulated in quiescent but not proliferating RPE cells and that experimental overexpression of DAPL1 in proliferating RPE cells inhibits their proliferation. Consistent with this observation, the percent of Ki67-positive cells is significantly higher in E11.5 Dapl1 knockout mouse embryos compared to age-matched controls. In adult Dapl1-/- mice, which survive without showing any overt pathology, RPE overgrowth leads to multiple cell layers and/or cellular nodules. The antiproliferative effect of DAPL1 is associated with an increase in CDKN1A protein levels. Reduction of CDKN1A by siRNA in DAPL1-overexpressing RPE cells in vitro partially restores cell proliferation. Hence, we show that DAPL1 is a novel regulator of RPE cell proliferation that is important for the maintenance of the RPE as a monolayer. The findings suggest that DAPL1 dysregulation may be involved in abnormal RPE-related proliferative diseases and corresponding retinal dysfunctions in humans.

Effectiveness and Tolerability of Different Recommended Doses of PPIs and H2RAs in GERD: Network Meta-Analysis and GRADE system.

Proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are used for gastro-esophageal reflux disease (GERD); however, the clinical evidence for treatment is poor. We evaluated the effectiveness and tolerability of different doses of PPIs, H2RAs and placebo in adults with GERD. Six online databases were searched through September 1, 2016. All related articles were included and combined with a Bayesian network meta-analysis from randomized controlled trials (RCTs). The GRADE systems were employed to assess the main outcome. Ninety-eight RCTs were identified, which included 45,964 participants. Our analysis indicated that the full/standard dose of esomeprazole at 40 mg per day was the most efficient in healing among nine different dosages of PPIs and H2RAs. The main efficacy outcome did not change after adjustments for the area, age, level of disease from endoscopy, year of publication, pharmaceutical industry sponsorship, Intention-to-treat (ITT)/per-protocol (PP), withdrawal rate, pre-set select design bias, single blinded and unblinded studies, study origination in China, study arms that included zero events, inconsistency node or discontinued drug were accounted for in the meta-regressions and sensitivity analyses. This research suggests that the full/standard doses (40 mg per day) of esomeprazole should be recommended as first-line treatments for GERD in adults for short-term therapy.

Sox10 regulates skin melanocyte proliferation by activating the DNA replication licensing factor MCM5.

BACKGROUND: The control of cell proliferation is a fundamental aspect of tissue formation in development and regeneration. A cell type that illustrates this point particularly well is the neural crest-derived melanocyte, the pigment cell of vertebrates, as melanocytes can be followed easily during development and their pigment is directly visible in the integument of the adult. In mammals, melanocytes undergo physiological cycles of loss and proliferative regeneration during the hair cycle, and their proliferation is also critical during wound healing, repigmentation of depigmented lesions, and in melanoma formation and progression. Hence, a thorough analysis of the molecular parameters controlling melanocyte proliferation is crucial for our understanding of the physiology of this cell type both in health and disease. OBJECTIVE: SOX10 is a critical regulator in melanocytes and melanoma cells, but its specific role in their proliferation is far from clear. In this study we analyze the role of SOX10 in regulating mammalian melanocyte proliferation in a mouse model. METHODS: The role of SOX10 in melanoblast proliferation was analyzed in Sox10/+ mice by co-staining for melanocyte-specific markers and cell proliferation. In vitro, the role of SOX10 was studied by manipulating its levels using RNAi and analyzing the effects on DNA synthesis and cell growth and on gene expression at the RNA and protein levels. RESULTS: Reduction of Sox10 gene dose led to a reduction in the number of melanoblasts. Knockdown of Sox10 in melanocytes led to inhibition of cell proliferation and a decrease in the expression of the minichromosome maintenance complex component 5 (MCM5). In fact, SOX10 directly activated MCM5 transcription by binding to conserved SOX10 consensus DNA sequences in the MCM5 promoter. Furthermore, the defect in cell proliferation could be rescued partially by overexpression of MCM5 in Sox10 knockdown melanocytes. CONCLUSION: The results suggest that the SOX10-MCM5 axis plays an important role in controlling melanocyte proliferation. Our findings provide novel insights into the regulatory mechanisms of melanocyte proliferation and may have implications for our understanding of the roles of SOX10 and MCM5 in abnormal melanocyte proliferation disorders such as cutaneous melanoma.

Cyclooxygenase-2 induced ß1-integrin expression in NSCLC and promoted cell invasion via the EP1/MAPK/E2F-1/FoxC2 signal pathway.

Cyclooxygenase-2 (COX-2) has been implicated in cell invasion in non-small-cell lung cancer (NSCLC). However, the mechanism is unclear. The present study investigated the effect of COX-2 on ß1-integrin expression and cell invasion in NSCLC. COX-2 and ß1-integrin were co-expressed in NSCLC tissues. COX-2 overexpression or Prostaglandin E2 (PGE2) treatment increased ß1-integrin expression in NSCLC cell lines. ß1-integrin silencing suppressed COX-2-mediated tumour growth and cancer cell invasion in vivo and in vitro. Prostaglandin E Receptor EP1 transfection or treatment with EP1 agonist mimicked the effect of PGE2 treatment. EP1 siRNA blocked PGE2-mediated ß1-integrin expression. EP1 agonist treatment promoted Erk1/2, p38 phosphorylation and E2F-1 expression. MEK1/2 and p38 inhibitors suppressed EP1-mediated ß1-integrin expression. E2F-1 silencing suppressed EP1-mediated FoxC2 and ß1-integrin upregulation. ChIP and Luciferase Reporter assays identified that EP1 agonist treatment induced E2F-1 binding to FoxC2 promotor directly and improved FoxC2 transcription. FoxC2 siRNA suppressed ß1-integrin expression and EP1-mediated cell invasion. Immunohistochemistry showed E2F-1, FoxC2, and EP1R were all highly expressed in the NSCLC cases. This study suggested that COX-2 upregulates ß1-integrin expression and cell invasion in NSCLC by activating the MAPK/E2F-1 signalling pathway. Targeting the COX-2/EP1/PKC/MAPK/E2F-1/FoxC2/ß1-integrin pathway might represent a new therapeutic strategy for the prevention and treatment of this cancer.