Recent advances in the combinations of plant-sourced natural products for the prevention of mycotoxin contamination in food.

Mycotoxins, secondary metabolites produced by mycotoxigenic fungi, are a major problem affecting food safety and security, because of their adverse health effects, their socio-economic impact and the difficulty of degradation or removal by conventional food processing methods. Plant-sourced natural products are a novel and effective control method for fungal infestation and mycotoxin production, with the advantages of biodegradability and acceptability for food use. However, development of resistance, low and inconsistent efficacy, and a limited range of antifungal activities hinder the effective application of single plant natural products for controlling mycotoxin contamination. To overcome these limitations, combinations of plant natural products have been tested extensively and found to increase efficacy, often synergistically. However, this extensive and promising research area has seen little development of practical applications. This review aims to provide up-to-date information on the antifungal, anti-mycotoxigenic and synergistic effects of combinations of plant natural products, as well as their mechanisms of action, to provide a reference source for future research and encourage application development.

How should preoperative examinations be chosen for infants with a ventricular septal defect: transthoracic echocardiography, cardiac CTA, or a combination of these two technologies?

OBJECTIVE: To evaluate the accuracy of transthoracic echocardiography (TTE) and cardiac computed tomography angiography (CTA) in detecting the size and location of ventricular septal defects (VSD) in infants. METHODS: Data from 258 infants diagnosed with VSD between January 2020 and December 2022 were retrospectively analyzed. All infants underwent both TTE and cardiac CTA. The accuracy of these imaging modalities was assessed by comparing their findings with intraoperative observations of VSD size and location. RESULTS: Intraoperatively, the average VSD size was 6.1 ± 2.5 mm. The defects were classified as committed VSD (Type 1) in 45 patients, noncommitted VSD (Type 2) in 198 patients, inlet VSD (Type 3) in 12 patients, and muscular VSD (Type 4) in 3 patients. Echocardiography estimated the average VSD size at 5.6 ± 2.7 mm, with 42 patients identified as Type 1, 203 as Type 2, 10 as Type 3, and 3 as Type 4. Cardiac CTA estimated the average size at 5.9 ± 3.2 mm, with 48 patients identified as Type 1, 196 as Type 2, 11 as Type 3, and 3 as Type 4. The accuracy rates of TTE and cardiac CTA in diagnosing VSD location were 98.1% and 98.8%, respectively. A survey of surgeons indicated that 80% believe both TTE and cardiac CTA are essential preoperative evaluations. CONCLUSIONS: TTE accurately diagnoses the size and location of VSD, while cardiac CTA serves as a valuable complementary method to TTE. Most surgeons advocate for the combined use of these examinations for preoperative assessment.

A Multifunctional N-Doped Cu-MOFs (N-Cu-MOF) Nanomaterial-Driven Electrochemical Aptasensor for Sensitive Detection of Deoxynivalenol.

Deoxynivalenol (DON) is one of the most common mycotoxins in grains, causing gastrointestinal inflammation, neurotoxicity, hepatotoxicity and embryotoxicity, even at a low quantity. In this study, a facile electrochemical aptasensor was established for the rapid and sensitive determination of DON based on a multifunctional N-doped Cu-metallic organic framework (N-Cu-MOF) nanomaterial. The N-Cu-MOF, with a large specific surface area and good electrical conductivity, served not only as an optimal electrical signal probe but also as an effective supporting substrate for stabilizing aptamers through the interactions of amino (-NH2) and copper. Under the optimal conditions, the proposed sensor provided a wide linear concentration range of 0.02-20 ng mL-1 (R2 = 0.994), showing high sensitivity, with a lower detection limit of 0.008 ng mL-1, and good selectivity. The sensor's effectiveness was also verified in real spiked wheat samples with satisfactory recoveries of 95.6-105.9%. The current work provides a flexible approach for the rapid and sensitive analysis of highly toxic DON in food samples and may also be easily extended to detect other hazardous substances with alternative target-recognition aptamers.

Molecularly Imprinted Poly(thionine)-Based Electrochemical Sensing Platform for Fast and Selective Ultratrace Determination of Patulin.

An innovative approach based on a surface functional monomer-directing strategy for the construction of a sensitive and selective molecularly imprinted electrochemical sensor for patulin recognition is described. A patulin imprinted platinum nanoparticle (PtNP)-coated poly(thionine) film was grown on a preformed thionine tailed surface of PtNP-nitrogen-doped graphene (NGE) by electropolymerization, which provided high capacity and fast kinetics to uptake patulin molecules. Thionine acted not only as a functional monomer for molecularly imprinted polymer (MIP), but also as a signal indicator. Enhanced sensitivity was obtained by combining the excellent electric conductivity of PtNPs, NGE, and thionine with multisignal amplification. The designed sensor displayed excellent performance for patulin detection over the range of 0.002-2 ng mL-1 (R2 = 0.995) with a detection limit of 0.001 ng mL-1 for patulin. In addition, the resulting sensor showed good stability and high repeatability and selectivity. Furthermore, the feasibility of its applications has also been demonstrated in the analysis of real samples, providing novel tactics for the rational design of MIP-based electrochemical sensors to detect a growing number of deleterious substances.

Knockdown of pseudogene derived from lncRNA DUXAP10 inhibits cell proliferation, migration, invasion, and promotes apoptosis in pancreatic cancer.

Current evidence suggests that pseudogene derived lncRNAs may be important players in human cancer progression. Our previous study showed that DUXAP10 could promote cell proliferation in colorectal cancer. However, the clinical significance and potential role of DUXAP10 in human pancreatic cancer (PC) has not been uncovered. In this study, we found that DUXAP10 was overexpressed in PC tissues compared with normal tissues. DUXAP10 expression was significantly higher in patients with an advanced TNM stage and positive lymph node metastasis. Bioinformatic analysis showed that cell cycle progression was increased in patients with high DUXAP10 expression. In vitro and in vivo assays of DUXAP10 alterations revealed a complex integrated phenotype affecting cell growth, apoptosis, migration, and invasion. Mechanistic studies revealed that DUXAP10 has a crucial role in G2/M arrest. We further showed that DUXAP10 regulated PC cell proliferation through interact with RNA-binding protein EZH2 and LSD1. Overall, our findings indicates that DUXAP10 is an oncogenic lncRNA that promotes PC proliferation and metastasis.

Synthesis and anticancer activity of novel rapamycin C-28 containing triazole moiety compounds.

Rapamycin is an mTOR allosteric inhibitor with multiple functions such as immunosuppressive, anticancer, and lifespan prolonging activities. Its C-43 semi-synthetic derivatives temsirolimus and everolimus have been used as mTOR targeting anticancer drugs in the clinic. Following our previous research on antitumor rapalogs modified on the C-43 position, 13 novel rapamycin triazole hybrids (6a-g, 7a-f) were designed and synthesized on the C-28 position of rapamycin via Huisgen's reaction. Anticancer assays indicated that the targeted derivatives containing phenyl and 4-methylphenyl groups showed an obvious raise in anticancer activity. On the contrary, the compounds with methoxyl, amine, and halogen groups on the benzene ring displayed lower anticancer activity. Compound 6c, as the most active compound, showed a stronger inhibition effect as compared with rapamycin for almost all of the tested cell lines (p < 0.01), except PC-3. Meanwhile, the effect of 6c on inducing apoptosis and cell cycle arrest in A549 cells was more powerful than that of rapamycin. In addition, 6c inhibited the phosphorylation of mTOR and its downstream key kinases 4EBP1 and p70S6K1 in A549 cells, indicating that 6c also effectively inhibits the mTORC1 signaling pathway as rapamycin. On the basis of these findings, 6c may have the potential to be developed as a new mTOR inhibitor against specific cancers.

miR218-5p regulates the proliferation of gastric cancer cells by targeting TFF1 in an Erk1/2-dependent manner.

Trefoil factor 1 (TFF1), a member of the trefoil peptide family, is not only associated with mucosal protection and restoration but is also correlated with tumorigenesis of the gastrointestinal tract. In an early study, we performed sequence analysis and identified one potential miR423-5p binding site within the 3'-untranslated region of TFF1 using microRNA target prediction tools. In the current study, we demonstrated that the coding DNA region within TFF1 is also a candidate for miR218-5p targeting. We used real-time PCR and in situ hybridization to analyze the correlation between miR218-5p and TFF1 expression in tumor lesions and paracancerous tissue in gastric cancer (GC) samples. Additionally, endogenous and exogenous TFF1 were suppressed by miR218-5p in gastric cancer cells and influenced the progression of GC in an Erk1/2-dependent manner. Targeting miR218-5p may provide a novel strategy for the treatment of GC.

The cost-effectiveness of zolbetuximab in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma.

Aim: To estimate the cost-effectiveness of zolbetuximab plus capecitabine/oxaliplatin (CAPOX) in CLDN18.2-positive, HER2-negative, mG/GEJ adenocarcinoma from the perspective of Chinese payers. Materials & methods: A partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER) of zolbetuximab plus CAPOX versus placebo plus CAPOX. Sensitivity analyses were performed to test the robustness of model. Results: Zolbetuximab plus CAPOX gained an additional cost of $91,551 and an extra health benefit of 0.24 QALY over placebo plus CAPOX, producing an ICER of $388,186/QALY, which exceeded the willingness-to-pay threshold of $38,223/QALY. Sensitivity analysis shows that the model was generally robust. Conclusion: Zolbetuximab plus CAPOX would not be a cost-effective first-line treatment regimen in CLDN18.2-positive, HER2-negative, mG/GEJ adenocarcinoma in China.

[Box: see text].

Vicious Cycle-Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis.

During liver fibrogenesis, the reciprocal crosstalk among capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (HSCs), and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating the disease condition and weakening therapeutic effect. Limited by the malignant cellular interactions, the previous single-cell centric treatment approaches show unsatisfactory efficacy and fail to meet clinical demand. Herein, a vicious cycle-breaking strategy is proposed to target and repair pathological cells separately to terminate the malignant progression of liver fibrosis. Chondroitin sulfate-modified and vismodegib-loaded nanoparticles (CS-NPs/VDG) are designed to efficiently normalize the fenestrae phenotype of LSECs and restore HSCs to quiescent state by inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid-modified and silybin-loaded nanoparticles (GA-NPs/SIB) are prepared to restore hepatocytes function by relieving oxidative stress. The results show successful interruption of vicious cycle as well as distinct fibrosis resolution in two animal models through multiregulation of the pathological cells. This work not only highlights the significance of modulating cellular crosstalk but also provides a promising avenue for developing antifibrotic regimens.

Fe3O4@COF(TAPT-DHTA) Nanocomposites as Magnetic Solid-Phase Extraction Adsorbents for Simultaneous Determination of 9 Mycotoxins in Fruits by UHPLC-MS/MS.

In this study, a simple and efficient magnetic solid-phase extraction (MSPE) strategy was developed to simultaneously purify and enrich nine mycotoxins in fruits, with the magnetic covalent organic framework nanomaterial Fe3O4@COF(TAPT-DHTA) as an adsorbent. The Fe3O4@COF(TAPT-DHTA) was prepared by a simple template precipitation polymerization method, using Fe3O4 as magnetic core, and 1,3,5-tris-(4-aminophenyl) triazine (TAPT) and 2,5-dihydroxy terephthalaldehyde (DHTA) as two building units. Fe3O4@COF(TAPT-DHTA) could effectively capture the targeted mycotoxins by virtue of its abundant hydroxyl groups and aromatic rings. Several key parameters affecting the performance of the MSPE method were studied, including the adsorption solution, adsorption time, elution solvent, volume and time, and the amount of Fe3O4@COF(TAPT-DHTA) nanomaterial. Under optimized MSPE conditions, followed by analysis with UHPLC-MS/MS, a wide linear range (0.05-200 µg kg-1), low limits of detection (0.01-0.5 µg kg-1) and satisfactory recovery (74.25-111.75%) were achieved for the nine targeted mycotoxins. The established method was further successfully validated in different kinds of fruit samples.

Using Revolution™ CT Angiography to Assess Complex Coarctation of the Aorta in Infants and Its Association with a Prolonged Postoperative Cardiac ICU Stay.

OBJECTIVE: To investigate the accuracy of aortic dimensions measured by Revolution™ computed tomography (CT) in infants with complex coarctation of the aorta (CoA) and to further analyze the utility of the degree of CoA in predicting the risk of prolonged postoperative cardiac intensive care unit stay. METHODS: A total of 30 infants with complex CoA who underwent surgical correction from January 2020 to July 2022 were retrospectively enrolled. General demographic data, preoperative imaging, and perioperative outcomes were collected. Univariate and multivariate analyses were performed to investigate predictors of prolonged postoperative cardiac intensive care unit stay, and the reliability of the CT measurements was assessed by the intraclass correlation coefficient. RESULTS: All infants were divided into a mild or severe CoA group. The duration of mechanical ventilation and cardiac intensive care unit stay in the mild CoA group were significantly lower than those in the severe CoA group. After multivariate analysis, we found that the degree of CoA and age at surgery were significant predictors of prolonged postoperative cardiac intensive care unit stay. The intraclass correlation coefficient between CT measurements and intraoperative measurements was between 0.937 and 0.975, and the measurement results had good reliability. CONCLUSION: CT angiography can provide a comprehensive and accurate preoperative evaluation of aortic dimensions measured in infants with complex CoA. The degree of CoA is an independent risk factor for prolonged postoperative cardiac intensive care unit stay in infants with complex CoA.

[Simultaneous determination of 36 mycotoxins in fruits by QuEChERS coupled with ultra performance liquid chromatography-tandem mass spectrometry].

Mycotoxins are secondary metabolites produced by toxigenic fungi under specific environmental conditions. Fruits, owing to their high moisture content, rich nutrition, and improper harvest or storage conditions, are highly susceptible to various mycotoxins, such as ochratoxin A (OTA), zearalenone (ZEN), patulin (PAT), Alternaria toxins, etc. These mycotoxins can cause acute and chronic toxic effects (teratogenicity, mutagenicity, and carcinogenicity, etc) in animals and humans. Given the high toxicity and wide prevalence of mycotoxins, establishing an efficient analytical method to detect multiple mycotoxins simultaneously in different types of fruits is of great importance. Conventional mycotoxin detection methods rely on high performance liquid chromatography (HPLC) coupled with mass spectrometry (MS). However, fruit sample matrices contain large amounts of pigments, cellulose, and minerals, all of which dramatically impede the detection of trace mycotoxins in fruits. Therefore, the efficient enrichment and purification of multiple mycotoxins in fruit samples is crucial before instrumental analysis. In this study, a reliable method based on a QuEChERs sample preparation approach coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established to determine 36 mycotoxins in fruits. In the optimal extraction method, 2.0 g of a sample was extracted with 10 mL of acetic acid-acetonitrile-water (1∶79∶20, v/v/v) in a 50 mL centrifuge tube, vortexed for 30 s, and ultrasonicated for 40 min. The mixture was then salted out with 2.0 g of anhydrous MgSO4 and 0.5 g of NaCl and centrifuged for 5 min. Next, 6 mL of the supernatant was purified using 85 mg of octadecylsilane-bonded silica gel (C18) and 15 mg of N-propylethylenediamine (PSA). After vigorous shaking and centrifugation, the supernatant was collected and dried with nitrogen at 40 ℃. Finally, the residues were redissolved in 1 mL of 5 mmol/L ammonium acetate aqueous solution-acetonitrile (50∶50, v/v) and passed through a 0.22 µm nylon filter before analysis. The mycotoxins were separated on a Waters XBridge BEH C18 column using a binary gradient mixture of ammonium acetate aqueous solution and methanol. The injection volume was 3 µL. The mycotoxins were analyzed in multiple reaction monitoring (MRM) mode under both positive and negative electrospray ionization. Quantitative analysis was performed using an external standard method with matrix-matched calibration curves. Under optimal conditions, good linear relationships were obtained in the respective linear ranges, with correlation coefficients (R2) no less than 0.990. The limits of detection (LODs) and quantification (LOQs) were 0.02-5 and 0.1-10 µg/kg, respectively. The recoveries of the 36 mycotoxins in fruits ranged from 77.0% to 118.9% at low, medium, and high spiked levels, with intra- and inter-day precisions in the range of 1.3%-14.9% and 0.2%-17.3%, respectively. The validated approach was employed to investigate mycotoxin contamination in actual fruit samples, including strawberry, grape, pear, and peach (15 samples of each type). Eleven mycotoxins, namely, altenuene (ALT), altenusin (ALS), alternariol-methyl ether (AME), tenuazonic acid (TeA), tentoxin (Ten), OTA, beauvericin (BEA), PAT, zearalanone (ZAN), T-2 toxin (T2), and mycophenolic acid (MPA), were found in the samples; three samples were contaminated with multiple mycotoxins. The incidence rates of mycotoxins in strawberry, grape, pear, and peach were 27%, 40%, 40%, and 33%, respectively. In particular, Alternaria toxins were the most frequently found mycotoxins in these fruits, with an incidence of 15%. The proposed method is simple, rapid, accurate, sensitive, reproducible, and stable; thus, it is suitable for the simultaneous detection of the 36 mycotoxins in different fruits.

Antifungal Activity and Action Mechanisms of 2,4-Di-tert-butylphenol against Ustilaginoidea virens.

Ustilaginoidea virens is a destructive phytopathogenic fungus that causes false smut disease in rice. In this study, the natural product 2,4-di-tert-butylphenol (2,4-DTBP) was found to be an environmentally friendly and effective agent for the first time, which exhibited strong antifungal activity against U. virens, with an EC50 value of 0.087 mmol/L. The scanning electron microscopy, fluorescence staining, and biochemical assays indicated that 2,4-DTBP could destroy the cell wall, cell membrane, and cellular redox homeostasis of U. virens, ultimately resulting in fungal cell death. Through the transcriptomic analysis, a total of 353 genes were significantly upregulated and 367 genes were significantly downregulated, focusing on the spindle microtubule assembly, cell wall and membrane, redox homeostasis, mycotoxin biosynthesis, and intracellular metabolism. These results enhanced the understanding of the antifungal activity and action mechanisms of 2,4-DTBP against U. virens, supporting it to be a potential antifungal agent for the control of false smut disease.

DAB2IP suppresses invadopodia formation through destabilizing ALK by interacting with USP10 in breast cancer.

Invadopodia, being actin-rich membrane protrusions, play a vital role in tumor cell invasion and metastasis. Our previous studies have revealed some functions of the DOC-2/DAB2 interacting protein (DAB2IP) as a tumor suppressor. Nevertheless, the specific role and mechanism of DAB2IP in invadopodia formation remain unclear. Here, we find that DAB2IP effectively suppresses invadopodia formation and metastasis in breast cancer, both in vitro and in vivo. Additionally, DAB2IP could downregulate anaplastic lymphoma kinase (ALK), resulting in the inhibition of tyrosine phosphorylation of Cortactin and the prevention of invadopodia formation. DAB2IP competitively antagonizes the interaction between the deubiquitinating enzyme Ubiquitin-specific peptidase 10 (USP10) and ALK, leading to a decrease in the abundance of ALK protein. In summary, DAB2IP impairs the stability of ALK through USP10-dependent deubiquitination, suppressing Cortactin phosphorylation, thereby inhibiting invadopodia formation and metastasis of breast cancer cells. Furthermore, this study suggests a potential therapeutic strategy for breast cancer treatment.

Survey and toxigenic abilities of Aspergillus, Fusarium, and Alternaria fungi from wheat and paddy grains in Shanghai, China.

A systematic study was carried out on 638 wheat and paddy grains (including fresh and stored samples) collected in 2021 from Shanghai, China, to identify the major mycobiota and their toxigenic abilities. A total of 349 fungi, namely, 252 Fusarium, 53 Aspergillus, and 44 Alternaria, were characterized by morphological and molecular identification. Fusarium and Aspergillus were more frequently isolated in paddy with Fusarium sambucinum species complex and Aspergillus section flavi as the predominant species, respectively. The genus Alternaria was the most frequently isolated fungal species in wheat. The toxin-producing potentials of the identified fungi were further evaluated in vitro. Deoxynevalenol (DON) was produced by 34.5% of Fusarium isolates and zearalenone (ZEN) was produced by 47.6% of them, and one isolate also processed the abilities for fumonisin B1 (FB1), B2 (FB2), and B3 (FB3) productions. Aflatoxin B1 (AFB1), B2 (AFB2), and G1 (AFG1) were only generated by Aspergillus section flavi, with the production rate of 65.5%, 27.6%, and 13.8%, respectively. Alternariol (AOH) was the most prevalent Alternaria toxin, which could be produced by 95.5% of the isolates, followed by alternariol monomethyl ether (AME) (72.7%), altenuene (ALT) (52.3%), tenuazonic acid (TeA) (45.5%), tentoxin (TEN) (29.5%), and altenusin (ALS) (4.5%). A combinational analysis of mycobiota and toxigenic ability allowed us to provide comprehensive information about the production mechanisms of mycotoxins in wheat and paddy in a specific geographic area, and will be helpful for developing efficient prevention and control programs.

Capsulized Fecal Microbiota Transplantation Induces Remission in Patients with Ulcerative Colitis by Gut Microbial Colonization and Metabolite Regulation.

Fecal microbiota transplantation (FMT) can induce clinical remission in ulcerative colitis (UC) patients. Enemas, nasoduodenal tubes, and colonoscopies are the most common routes for FMT administration. However, there is a lack of definitive evidence regarding the effectiveness of capsulized FMT treatment in UC patients. In this study, we administered capsulized FMT to 22 patients with active UC to assess the efficiency of capsulized FMT and determine the specific bacteria and metabolite factors associated with the response to clinical remission. Our results showed that the use of capsulized FMT was successful in the treatment of UC patients. Capsulized FMT induced clinical remission and clinical response in 57.1% (12 of 21) and 76.2% (16 of 21) of UC patients, respectively. Gut bacterial richness was increased after FMT in patients who achieved remission. Patients in remission after FMT exhibited enrichment of Alistipes sp. and Odoribacter splanchnicus, along with increased levels of indolelactic acid. Patients who did not achieve remission exhibited enrichment of Escherichia coli and Klebsiella and increased levels of biosynthesis of 12,13-DiHOME (12,13-dihydroxy-9Z-octadecenoic acid) and lipopolysaccharides. Furthermore, we identified a relationship between specific bacteria and metabolites and the induction of remission in patients. These findings may provide new insights into FMT in UC treatment and provide reference information about therapeutic microbial manipulation of FMT to enhance its effects. (This study has been registered at ClinicalTrails.gov under registration no. NCT03426683). IMPORTANCE Fecal microbiota transplantation has been successfully used in patients. Recently, capsulized FMT was reported to induce a response in patients with UC. However, limited patients were enrolled in such studies, and the functional factors of capsulized FMT have not been reported in the remission of patients with UC. In this study, we prospectively recruited patients with UC to receive capsulized FMT. First, we found that capsulized FMT could induce clinical remission in 57.1% of patients and clinical response in 76.2% after 12 weeks, which was more acceptable. Second, we found a relationship between the decrease of opportunistic pathogen and lipopolysaccharide synthesis in patients in remission after capsulized FMT. We also identified an association between specific bacteria and metabolites and remission induction in patients after capsulized FMT. These findings put forward a possibility for patients to receive FMT at home and provide reference information about therapeutic microbial manipulation of FMT to enhance its effects.

Novel biotin-linked amphiphilic calix[4]arene-based supramolecular micelles as doxorubicin carriers for boosted anticancer activity.

Supramolecular carrier-mediated chemotherapy is a highly attractive strategy for targeted drug delivery. In this study, four novel biotin-linked calix[4]arenes BPCA1-BPCA4 have been rationally designed to construct nano-complex with doxorubicin. The in vitro and in vivo assessments reveal that BPCA4-DOX with excellent stability are capable of affording significantly superior anti-tumor activity and lower side effects.

TFF3 mediated induction of VEGF via hypoxia in human gastric cancer SGC-7901 cells.

Increasing evidence indicates that in gastric epithelial cells, induction of TFF3 by hypoxia is mediated by HIF-1. Since VEGF is one of the most important angiogenic factors on cancer progression, we have started to investigate the possible link among HIF-1α, VEGF, and TFF3 in gastric cancer cells. We induced the hypoxic condition in SGC-7901cells using hypoxia-mimetic agent of CoCI2. SGC7901 cells were transfected with pcPUR + U6 plasmid carrying RNAi targeted to human TFF3 and selected puromycin-resistant pools to establish the stable knockdown of TFF3 cells. Our results showed the induction of HIF-1a via hypoxia and consequences of increased expressions of the TFF3 and VEGF in gastric cancer SGC-7901 cells. Overexpression of TFF3 upregulated the mRNA expressions of VEGF and HIF-1a induced by hypoxia, and stable knockdown of TFF3 impaired the mRNA upregulations of VEGF and HIF-1a induced by hypoxia. Furthermore, knockdown of TFF3 reduced the VEGF protein secretion: as VEGF secretion was increased time dependent manner in response to the hypoxia induction in TFF3-WT cells; however, VEGF production was significantly decreased in TFF3-KD cells (621 ± 89 vs. 264 ± 73 at 6 h and 969 ± 97 vs. 508 ± 69 at 12 h, P < 0.05). Our data demonstrated the TFF3 mediated regulation of VEGF expression induced by hypoxia, and implicated that TFF3 might be applied as a potential anti-angiogenic target for treatment of gastric cancer.

YAP1 induces invadopodia formation by transcriptionally activating TIAM1 through enhancer in breast cancer.

Yes-associated protein 1 (YAP1), a central component of the Hippo pathway, plays an important role in tumor metastasis; however, the underlying mechanism remains to be elucidated. Invadopodia are actin-rich protrusions containing multiple proteases and have been widely reported to promote cell invasiveness by degrading the extracellular matrix. In the present study, we report that YAP1 induces invadopodia formation and promotes tumor metastasis in breast cancer cells. We also identify TIAM1, a guanine nucleotide exchange factor, as a target of the YAP1-TEAD4 complex. Our results demonstrate that YAP1 could promote TEAD4 binding to the enhancer region of TIAM1, which activates TIAM1 expression, subsequently increasing RAC1 activity and inducing invadopodia formation. These findings reveal the functional role of Hippo signaling in the regulation of invadopodia and provide potential molecular targets for preventing tumor metastasis in breast cancer.

DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer.

Increasing evidence has shown that DAB2IP acts as a tumor suppressor and plays an inhibitory role in many signals associated with tumorigenesis. However, the underlying mechanism of this function remains unclear. Our study shows that DAB2IP was positively associated with a good prognosis in patients with colorectal cancer and wild-type p53 expression. An in vitro assay showed that DAB2IP elicited potent tumor-suppressive effects by inhibiting cell invasiveness and colony formation and promoting cell apoptosis in wild-type p53 colon cancer cells. In addition, DAB2IP improved the stability of wild-type p53 by inhibiting its degradation in a ubiquitin-proteasome-dependent manner. Using mass spectrometry profiling, we revealed that DAB2IP and p53 interacted with the ubiquitin ligase-related protein GRP75. Mechanistically, DAB2IP is competitively bound to GRP75, thus reducing GRP75-driven p53 ubiquitination and degradation. Moreover, the Ras-GAP domain was required for the DAB2IP-GRP75 interaction and DAB2IP-mediated p53 ubiquitination. Finally, animal experiments revealed that DAB2IP inhibited tumor progression in vivo. In conclusion, our study presents a novel function of DAB2IP in GRP75-driven wild-type p53 degradation, providing new insight into DAB2IP-induced tumor suppression and a novel molecular interpretation of the p53 pathway.