Dysregulation of pericellular proteolysis is often required for tumor invasion and cancer progression. It has been shown that down-regulation of hepatocyte growth factor activator inhibitor-2 (HAI-2) ...results in activation of matriptase (a membrane-anchored serine protease), human prostate cancer cell motility and tumor growth. In this study, we further characterized if HAI-2 was a cognate inhibitor for matriptase and identified which Kunitz domain of HAI-2 was required for inhibiting matriptase and human prostate cancer cell motility. Our results show that HAI-2 overexpression suppressed matriptase-induced prostate cancer cell motility. We demonstrate that HAI-2 interacts with matriptase on cell surface and inhibits matriptase proteolytic activity. Moreover, cellular HAI-2 harnesses its Kunitz domain 1 (KD1) to inhibit matriptase activation and prostate cancer cell motility although recombinant KD1 and KD2 of HAI-2 both show an inhibitory activity and interaction with matriptase protease domain. The results together indicate that HAI-2 is a cognate inhibitor of matriptase, and KD1 of HAI-2 plays a major role in the inhibition of cellular matritptase activation as well as human prostate cancer invasion.
The dynamic cell–cell communication is essential for tissue homeostasis in normal physiological circumstances and contributes to a diversified tumor microenvironment. Although exosomes are ...extracellular vesicles that actively participate in cell–cell interaction by shutting cellular components, impacts of tumor exosomes in the context of cancer stemness remain elusive. Here, we expand colorectal cancer stem cells (CRCSCs) as cancer spheroids and demonstrate that the β‐catenin/Tcf‐4‐activated RAB27B expression is required for the secretion of CRCSC exosomes. In an exosomal RNA sequencing analysis, a switch of exosomal RNA species from retrotransposons to microRNAs (miRNAs) is identified upon expanding CRCSCs. miRNA‐146a‐5p (miR‐146a) is the major miRNA in CRCSC exosomes and exosomal miR‐146a promotes stem‐like properties and tumorigenicity by targeting Numb in recipient CRC cells. Among 53 CRC patients, those with abundant exosomal miR‐146a expression in serum exhibits higher miR‐146aHigh/NumbLow CRCSC traits, an increased number of tumor‐filtrating CD66(+) neutrophils and a decreased number of tumor‐infiltrating CD8(+) T cells. Our study elucidates a unique mechanism of tumor exosome‐mediated stemness expansion.
What's new?
The tumor microenvironment (TME) is composed of heterogeneous tumor cells and host cells interacting with each other to promote disease progression. However, diagnostic and prognostic biomarkers to monitor the cancer stem cells (CSCs)‐host interplay are lacking. Here, the authors explore the role of tumor exosomes in cancer stemness and demonstrate that RAB27B‐assisted secretion of miRNA‐dominant exosomes is one critical feature of CSCs. Importantly, they show that colorectal cancer stem cells release miR‐146a‐loaded oncogenic exosomes for reprogramming non‐CSC cells and demonstrate the clinical relevance of exosomal miR‐146a in predicting the TME of CRC patients.
TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor ...for execution of proteolytically biologic function; however, TMPRSS2's cognate inhibitor is still elusive. To identify the cognate inhibitor of TMPRSS2, in this study, we applied co-immunoprecipitation and LC/MS/MS analysis and isolated hepatocyte growth factor activator inhibitors (HAIs) to be potential inhibitor candidates for TMPRSS2. Moreover, the recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1, and recombinant HAI-2 proteins had a high affinity to form a complex with TMPRSS2. The immunofluorescence images further showed that TMPRSS2 was co-localized to HAI-2. Both KD1 and KD2 domain of HAI-2 showed comparable inhibitory effects on TMPRSS2 proteolytic activity. In addition, HAI-2 overexpression could suppress the induction effect of TMPRSS2 on pro-HGF activation, extracellular matrix degradation and prostate cancer cell invasion. We further determined that the expression levels of TMPRSS2 were inversely correlated with HAI-2 levels during prostate cancer progression. In orthotopic xenograft animal model, TMPRSS2 overexpression promoted prostate cancer metastasis, and HAI-2 overexpression efficiently blocked TMPRSS2-induced metastasis. In summary, the results together indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in human prostate cancer cells and may serve as a potential factor to suppress TMPRSS2-mediated malignancy.
The suppressive regulatory T cells (Treg) are frequently upregulated in cancer patients. This study aims to demonstrate the hypothesis that arecoline could induce the secretion of mitochondrial (mt) ...DNA D-loop and programmed cell death-ligand 1 (PD-L1) in extracellular vesicles (EVs), and attenuate T-cell immunity by upregulated Treg cell numbers. However, the immunosuppression could be reversed by whole glucan particle (WGP) β-glucan in oral squamous cell (OSCC) patients. Arecoline-induced reactive oxygen specimen (ROS) production and cytosolic mtDNA D-loop were analyzed in OSCC cell lines. mtDNA D-loop, PD-L1, IFN-γ, and Treg cells were also identified for the surgical specimens and sera of 60 OSCC patients. We demonstrated that higher mtDNA D-loop, PD-L1, and Treg cell numbers were significantly correlated with larger tumor size, nodal metastasis, advanced clinical stage, and areca quid chewing. Furthermore, multivariate analysis confirmed that higher mtDNA D-loop levels and Treg cell numbers were unfavorable independent factors for survival. Arecoline significantly induced cytosolic mtDNA D-loop leakage and PD-L1 expression, which were packaged by EVs to promote immunosuppressive Treg cell numbers. However, WGP β-glucan could elevate CD4
and CD8
T-cell numbers, mitigate Treg cell numbers, and promote oral cancer cell apoptosis. To sum up, arecoline induces EV production carrying mtDNA D-loop and PD-L1, and in turn elicits immune suppression. However, WGP β-glucan potentially enhances dual effects on T-cell immunity and cell apoptosis and we highly recommend its integration with targeted and immune therapies against OSCC.
Senescence is a state of cell cycle arrest that plays an important role in embryogenesis, wound healing and protection against cancer. Senescent cells also accumulate during aging and contribute to ...the development of age‐related disorders and chronic diseases, such as atherosclerosis, type 2 diabetes, osteoarthritis, idiopathic pulmonary fibrosis, and liver disease. Molecules that induce apoptosis of senescent cells, such as dasatinib, quercetin, and fisetin, produce health benefits and extend lifespan in animal models. We describe here the mechanism of action of senolytics and senomorphics, many of which are derived from plants and fungi. We also discuss the possibility of using such compounds to delay aging and treat chronic diseases in humans.
Obesity is one of the most important public health issues worldwide. Moreover, an extreme phenotype, morbid obesity (MO) has insidiously become a global problem. Therefore, we aimed to document the ...prevalence trend and to unveil the epidemiological characteristics of MO in Taiwan.
Nationally representative samples aged 19 years and above from three consecutive waves of Nutrition and Health survey in Taiwan: 1993-1996, 2005-2008, and 2013-2014 (n = 3,071; 1,673; and 1,440; respectively) were analyzed for prevalence trend. And 39 MO (BMI ≥35 kg/m2) cases from the two recent surveys compared with 156 age, gender, and survey-matched normal weight controls (BMI: 18.5-24 kg/m2) for epidemiological characteristics study. The reduced rank regression analysis was used to find dietary pattern associated with MO.
The prevalence of overweight and obesity together (BMI ≥24 kg/m2) was stabilized in the recent two surveys, but that of MO (0.4%, 0.6%, to 1.4%) and obesity (BMI ≥27 kg/m2) (11.8%, 17.9%, to 22.0%) increased sharply. MO cases tended to have lower levels of education, personal income, and physical activity. Furthermore, their dietary pattern featured with a higher consumption frequency of red meat, processed animal products, and sweets/sweetened beverage, but lower frequencies of fresh fruits, nuts, breakfast cereal, and dairy products.
This study documents a polarization phenomenon with smaller proportion of overweight people at the center and higher proportions of normal weight and obesity subjects at two extremes. MO was associated with low socioeconomic status and poor dietary pattern. The obesogenic dietary pattern became more prevalent in later time.
Introduction
Malignant germ cell tumors (MGCTs) can develop either extracranially or intracranially. Growing teratoma syndrome (GTS) may develop in these patients following chemotherapy. Reports on ...the clinical characteristics and outcomes of GTS in children with MGCTs are limited.
Methods
We retrospectively collected the data, including the clinical characteristics and outcomes of five patients in our series and 93 pediatric patients selected through a literature review of MGCTs. This study aimed to analyze survival outcomes and risk factors for subsequent events in pediatric patients with MGCTs developing GTS.
Results
The sex ratio was 1.09 (male/female). In total, 52 patients (53.1%) had intracranial MGCTs. Compared with patients with extracranial GCTs, those with intracranial GCTs were younger, predominantly boys, had shorter intervals between MGCT and GTS, and had GTS mostly occurring over the initial site (all p < 0.001). Ninety‐five patients (96.9%) were alive. However, GTS recurrence (n = 14), GTS progression (n = 9), and MGCT recurrence (n = 19) caused a substantial decrease in event‐free survival (EFS). Multivariate analyses showed that the only significant risk factors for these events were incomplete GTS resection and different locations of GCT and GTS. Patients without any risk had a 5‐year EFS of 78.8% ± 7.8%, whereas those with either risk had 41.7% ± 10.2% (p < 0.001).
Conclusion
For patients with high‐risk features, every effort should be made to closely monitor, completely remove, and pathologically prove any newly developed mass to guide relevant treatment. Further studies incorporating the risk factors into treatment strategies may be required to optimize adjuvant therapy.
Caloric restriction, intermittent fasting, and exercise activate defensive cellular responses such as autophagy, DNA repair, and the induction of antioxidant enzymes. These processes improve health ...and longevity by protecting cells and organs against damage, mutations, and reactive oxygen species. Consuming a diet rich in vegetables, fruits, and mushrooms can also improve health and longevity. Phytochemicals such as alkaloids, polyphenols, and terpenoids found in plants and fungi activate the same cellular processes as caloric restriction, fasting, and exercise. Many of the beneficial effects of fruits and vegetables may thus be due to activation of stress resistance pathways by phytochemicals. A better understanding of the mechanisms of action of phytochemicals may provide important insights to delay aging and prevent chronic diseases.
Biological stress such as caloric restriction, intermittent fasting, and physical exercise extends lifespan and improves health markers in model organisms by activating stress resistance pathways.Phytochemicals from fruits, vegetables, and mushrooms produce beneficial effects on health and longevity by modulating stress resistance pathways in a manner similar to caloric restriction, intermittent fasting, and exercise.Phytochemicals also promote intestinal homeostasis by improving gut barrier integrity and short-chain fatty acid production and by modulating the composition of the gut microbiota.Common sources of phytochemicals include not only fruits, vegetables, and mushrooms, but also organic foods and dietary supplements.
Mutations in genes involved in the production, migration, or differentiation of cortical neurons often lead to malformations of cortical development (MCDs). However, many genetic mutations involved ...in MCD pathogenesis remain unidentified. Here we developed a genetic screening paradigm based on transposon-mediated somatic mutagenesis by in utero electroporation and the inability of mutant neuronal precursors to migrate to the cortex and identified 33 candidate MCD genes. Consistent with the screen, several genes have already been implicated in neural development and disorders. Functional disruption of the candidate genes by RNAi or CRISPR/Cas9 causes altered neuronal distributions that resemble human cortical dysplasia. To verify potential clinical relevance of these candidate genes, we analyzed somatic mutations in brain tissue from patients with focal cortical dysplasia and found that mutations are enriched in these candidate genes. These results demonstrate that this approach is able to identify potential mouse genes involved in cortical development and MCD pathogenesis.
The past decade has witnessed tremendous advances in synthesis of metal halide perovskites and their use for a rich variety of optoelectronics applications. Metal halide perovskite has the general ...formula ABX
3
, where A is a monovalent cation (which can be either organic (
e.g.
, CH
3
NH
3
+
(MA), CH(NH
2
)
2
+
(FA)) or inorganic (
e.g.
, Cs
+
)), B is a divalent metal cation (usually Pb
2+
), and X is a halogen anion (Cl
−
, Br
−
, I
−
). Particularly, the photoluminescence (PL) properties of metal halide perovskites have garnered much attention due to the recent rapid development of perovskite nanocrystals. The introduction of capping ligands enables the synthesis of colloidal perovskite nanocrystals which offer new insight into dimension-dependent physical properties compared to their bulk counterparts. It is notable that doping and ion substitution represent effective strategies for tailoring the optoelectronic properties (
e.g.
, absorption band gap, PL emission, and quantum yield (QY)) and stabilities of perovskite nanocrystals. The doping and ion substitution processes can be performed during or after the synthesis of colloidal nanocrystals by incorporating new A′, B′, or X′ site ions into the A, B, or X sites of ABX
3
perovskites. Interestingly, both isovalent and heterovalent doping and ion substitution can be conducted on colloidal perovskite nanocrystals. In this review, the general background of perovskite nanocrystals synthesis is first introduced. The effects of A-site, B-site, and X-site ionic doping and substitution on the optoelectronic properties and stabilities of colloidal metal halide perovskite nanocrystals are then detailed. Finally, possible applications and future research directions of doped and ion-substituted colloidal perovskite nanocrystals are also discussed.
Doping and ion substitution in colloidal metal halide perovskite nanocrystals and their implication on compositions, properties, and applications.
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