ABSTRACT
Langerhans cell histiocytosis (LCH) involving the gastrointestinal tract is a rare condition for which clinical experience is limited. We describe the cases of two patients who initially presented with chronic diarrhoea, hypoproteinaemia, and intermittent fever. These findings suggest that in cases of refractory diarrhoea accompanied by recurrent hypoalbuminaemia, especially with abdominal rash, LCH should be considered. Gastrointestinal endoscopy, biopsy, and imaging studies are essential for obtaining a definitive diagnosis. This approach might be helpful for the early recognition of gastrointestinal tract involvement in LCH.
Subject(s)
Histiocytosis, Langerhans-Cell , Hypoalbuminemia , Child , Humans , Hypoalbuminemia/complications , Hypoalbuminemia/pathology , Histiocytosis, Langerhans-Cell/complications , Histiocytosis, Langerhans-Cell/diagnosis , Histiocytosis, Langerhans-Cell/pathology , Gastrointestinal Tract/pathology , Biopsy , Diarrhea/complicationsABSTRACT
In a prior study, our group found that chorionic villus-derived mesenchymal stem cells (CV-MSCs) were capable of promoting trophoblast proliferative and invasive activity. The mechanistic basis for this activity, however, has yet to be clarified. As such, an RNA-Seq analysis was conducted using trophoblasts that were treated with or without CV-MSC-conditioned media. Of the differentially expressed genes identified when comparing these two groups of cells, 23 proliferation-associated genes were identified and knocked down to test their functional roles in trophoblasts. These analyses revealed that inhibiting neuregulin 1 (NRG1) expression was sufficient to suppress proliferation and induce cell cycle arrest in trophoblasts. Placental samples from patients with preeclampsia exhibited significantly increased NRG1 expression relative to samples from healthy pregnancies. Following treatment with CV-MSC-conditioned media, NRG1 was upregulated in trophoblasts at the mRNA and protein levels. Relative to control trophoblasts, those in which NRG1 had been knocked down exhibited significantly impaired proliferation and DNA replication with the inactivation of the NF-κB signaling pathway. In contrast, overexpressing NRG1 yielded the opposite trophoblast phenotypes. Even in cells overexpressing NRG1, inhibition of NF-κB signaling was sufficient to significantly suppress trophoblast proliferation (P < 0.05). These results indicate that elevated NRG1 expression may play a role in the ability of CV-MSCs to induce proliferative activity in trophoblasts through the NF-κB signaling axis.
ABSTRACT
BACKGROUND: Patients with abnormally invasive placenta (AIP) are at high risk of massive postpartum hemorrhage. Resuscitative endovascular balloon occlusion of the aorta (REBOA), as an adjunct therapeutic strategy for hemostasis, offers the obstetrician an alternative for treating patients with AIP. This study aimed to evaluate the role of REBOA in hemorrhage control in patients with AIP. METHODS: This was a historical cohort study with prospectively collected data between January 2014 to July 2021 at a single tertiary center. According to delivery management, 364 singleton pregnant AIP patients desiring uterus preservation were separated into two groups. The study group (balloon group, n = 278) underwent REBOA during cesarean section, whereas the reference group (n = 86) did not undergo REBOA. Surgical details and maternal outcomes were collected. The primary outcome was estimated blood loss and the rate of uterine preservation. RESULTS: A total of 278 (76.4%) participants experienced REBOA during cesarean section. The patients in the balloon group had a smaller blood loss during cesarean Sect. (1370.5 [752.0] ml vs. 3536.8 [1383.2] ml; P < .001) and had their uterus salvaged more often (264 [95.0%] vs. 23 [26.7%]; P < .001). These patients were also less likely to be admitted to the intensive care unit after delivery (168 [60.4%] vs. 67 [77.9%]; P = .003) and had a shorter operating time (96.3 [37.6] min vs. 160.6 [45.5] min; P < .001). The rate of neonatal intensive care unit admission (176 [63.3%] vs. 52 [60.4%]; P = .70) and total maternal medical costs ($4925.4 [1740.7] vs. $5083.2 [1705.1]; P = .13) did not differ between the two groups. CONCLUSIONS: As a robust hemorrhage-control technique, REBOA can reduce intraoperative hemorrhage in patients with AIP. The next step is identifying associated risk factors and defining REBOA inclusion criteria to identify the subgroups of AIP patients who may benefit more.
Subject(s)
Balloon Occlusion , Postpartum Hemorrhage , Infant, Newborn , Humans , Pregnancy , Female , Cohort Studies , Cesarean Section/adverse effects , Aorta , Postpartum Hemorrhage/prevention & control , Postpartum Hemorrhage/etiology , Placenta , Resuscitation/methods , Balloon Occlusion/methods , Retrospective StudiesABSTRACT
Background: The extensive spread of coronavirus disease 2019 (COVID-19) has led to a rapid increase in global mortality. Preeclampsia is a commonly observed pregnancy ailment characterized by high maternal morbidity and mortality rates, in addition to the restriction of fetal growth within the uterine environment. Pregnant individuals afflicted with vascular disorders, including preeclampsia, exhibit an increased susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection via mechanisms that have not been fully delineated. Additionally, the intricate molecular mechanisms underlying preeclampsia and COVID-19 have not been fully elucidated. This study aimed to discern commonalities in gene expression, regulators, and pathways shared between COVID-19 and preeclampsia. The objective was to uncover potential insights that could contribute to novel treatment strategies for both COVID-19 and preeclampsia. Method: Transcriptomic datasets for COVID-19 peripheral blood (GSE152418) and preeclampsia blood (GSE48424) were initially sourced from the Gene Expression Omnibus (GEO) database. Subsequent to that, we conducted a subanalysis by selecting females from the GSE152418 dataset and employed the "Deseq2" package to identify genes that exhibited differential expression. Simultaneously, the "limma" package was applied to identify differentially expressed genes (DEGs) in the preeclampsia dataset (GSE48424). Following that, an intersection analysis was conducted to identify the common DEGs obtained from both the COVID-19 and preeclampsia datasets. The identified shared DEGs were subsequently utilized for functional enrichment analysis, transcription factor (TF) and microRNAs (miRNA) prediction, pathway analysis, and identification of potential candidate drugs. Finally, to validate the bioinformatics findings, we collected peripheral blood mononuclear cell (PBMC) samples from healthy individuals, COVID-19 patients, and Preeclampsia patients. The abundance of the top 10 Hub genes in both diseases was assessed using real-time quantitative polymerase chain reaction (RT-qPCR). Result: A total of 355 overlapping DEGs were identified in both preeclampsia and COVID-19 datasets. Subsequent ontological analysis, encompassing Gene Ontology (GO) functional assessment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, revealed a significant association between the two conditions. Protein-protein interactions (PPIs) were constructed using the STRING database. Additionally, the top 10 hub genes (MRPL11, MRPS12, UQCRH, ATP5I, UQCRQ, ATP5D, COX6B1, ATP5O, ATP5H, NDUFA6) were selected based on their ranking scores using the degree algorithm, which considered the shared DEGs. Moreover, transcription factor-gene interactions, protein-drug interactions, co-regulatory networks of DEGs and miRNAs, and protein-drug interactions involving the shared DEGs were also identified in the datasets. Finally, RT-PCR results confirmed that 10 hub genes do exhibit distinct expression profiles in the two diseases. Conclusion: This study successfully identified overlapping DEGs, functional pathways, and regulatory elements between COVID-19 and preeclampsia. The findings provide valuable insights into the shared molecular mechanisms and potential therapeutic targets for both diseases. The validation through RT-qPCR further supports the distinct expression profiles of the identified hub genes in COVID-19 and preeclampsia, emphasizing their potential roles as biomarkers or therapeutic targets in these conditions.
Subject(s)
COVID-19 , MicroRNAs , Pre-Eclampsia , Female , Pregnancy , Humans , Leukocytes, Mononuclear , Pre-Eclampsia/genetics , COVID-19/genetics , SARS-CoV-2 , Gene Expression Profiling , MicroRNAs/genetics , Transcription FactorsABSTRACT
Wind noise is notorious for its detrimental impacts on audio devices. This letter evaluates the influence of wind noise on the active noise control performance of headphones in a wind tunnel, and the noise reduction is found to decrease with wind speeds. To improve the performance of noise control systems in windy environments, the filtered-x least mean squares algorithm is modified based on the total least squares technique, taking the characteristics of wind noise into account. Computer simulations with real-recorded data demonstrate that the proposed algorithm could improve the noise reduction by approximately 3 dB in windy conditions.
ABSTRACT
Human chorionic villous mesenchymal stem cells (CV-MSCs) are a promising and effective therapeutic option for tissue injury. Vascular dysfunction during pregnancies is significantly involved in the pathogenesis of preeclampsia (PE). This work aims to investigate how CV-MSCs regulate the function of vascular endothelial cells. In this study, RNA-seq analysis was used to examine the changes in HUVECs treated with CV-MSC conditioned medium (CM). We examined the levels of ABCA9 and AKT signaling in human umbilical vein endothelial cells (HUVECs) by immunohistochemistry, western blotting, and qRT-PCR assays. CCK-8, colony formation, and tube formation assays were used to understand the role of ABCA9 in HUVEC proliferation and angiogenesis mediated by CV-MSCs. The CV-MSC treatment significantly enhanced the HUVEC proliferation and angiogenesis. Furthermore, a significant increase in the ABCA9 expression and AKT pathway activation was observed in CV-MSCs -treated HUVECs. Consistent with these findings, ABCA9 overexpression exhibited the same proliferation-and angiogenesis-promoting effect in HUVECs as induced by CV-MSC CM, also accompanied the AKT signaling activation. In addition, inhibition of ABCA9 inactivated the AKT signaling in HUVECs and reduced the HUVEC proliferation and angiogenesis. Importantly, the elevation of proliferation and angiogenesis induced by ABCA9 overexpression in HUVECs could be reversed by AKT pathway inhibition. Our results suggest that ABCA9-dependent AKT signaling activation mediated by CV-MSCs could promote HUVEC proliferation and angiogenesis.
Subject(s)
Mesenchymal Stem Cells , Proto-Oncogene Proteins c-akt , ATP-Binding Cassette Transporters/metabolism , Angiogenesis Inducing Agents/metabolism , Cell Proliferation , Coculture Techniques , Culture Media, Conditioned/metabolism , Culture Media, Conditioned/pharmacology , Female , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Mesenchymal Stem Cells/metabolism , Neovascularization, Pathologic/metabolism , Neovascularization, Physiologic , Pregnancy , Proto-Oncogene Proteins c-akt/metabolism , Sincalide/metabolism , Sincalide/pharmacologyABSTRACT
Preeclampsia (PE), a pregnancy disorder that affects 5-7% of pregnant women, is among the primary causes for maternal and perinatal mortality. PE is believed to be associated with insufficient invasion of villous and extravillous trophoblasts (EVTs), which hampers uterine spiral artery remodeling and finally induces PE. But the mechanism responsible for reduction of trophoblast invasion remains unclear. In this study, placental tissues taken from healthy donors and PE patients were used to evaluate the miR-326 expression; CCK8 and colony formation assays were used to confirm the effect of miR-326 on cell proliferation; transwell assay was used to demonstrate the effect of miR-326 on cell invasion capability; western blot was used to investigate the underlying mechanism; and luciferase assay was used to detect the effect of miR-326 on YAP/TAZ-mediated transcription activity. It was revealed the miR-326 expression was higher in placentas from PE patients than from healthy donors. After transfection of miR-326 mimics, trophoblast proliferation and invasion were impaired. Using TargetScan, we speculated that PAX8 was a target of miR-326, which was later confirmed by western blot. The YAP/TAZ expression was also downregulated after transfection with miR-326. Luciferase assay demonstrated that overexpression of miR-326 suppressed YAP/TAZ-mediated transcription activity by targeting PAX8. Overexpression of PAX8 could partly rescue miR-326-induced suppression of trophoblast proliferation and invasion. Taken together, our result indicated that miR-326 suppresses trophoblast growth, invasion, and migration by means of targeting PAX8 via the Hippo pathway.
Subject(s)
MicroRNAs/physiology , PAX8 Transcription Factor/genetics , Trophoblasts/physiology , Adult , Cell Movement/genetics , Cell Proliferation/genetics , Cells, Cultured , Down-Regulation/genetics , Female , Gene Expression Regulation , Hippo Signaling Pathway/physiology , Humans , PregnancyABSTRACT
BACKGROUND: Children with intestinal failure (IF) have frequent catheter-related bloodstream infections (CRBSIs). This study aimed to analyze the clinical presentation and laboratory parameters of CRBSIs in children with IF. METHODS: This 6-year retrospective study was conducted among IF children with CRBSIs at an intestinal rehabilitation center in China. Clinical data were collected, including data of temperature and gastrointestinal symptoms. Blood/catheter culture, fecal tests, and calculation of inflammatory index were performed, which were obtained within 1 week since CRBSI onset. RESULTS: Fifty children with 87 CRBSIs were identified, of which there were 17 suspected and 70 confirmed cases. Seventy-two pathogens were cultured from 70 positive blood cultures: 63% were Gram-positive organisms, 23% were Gram-negative organisms, and 11% were fungal organisms. Overall, 48.6% were enteric organisms; 47.2% of bacterial pathogens were consistent between fecal and blood cultures. Moreover, 46.3% fecal routines showed abnormalities including increased white blood cells, occult blood positive and the presence of fat droplets. The consistent symptom at onset of CRBSIs was fever and gastrointestinal symptoms including increased stool output, abdominal distension, or both. C-reactive protein (CRP) and procalcitonin (PCT) were elevated, i.e., 16.5 mg/L [interquartile range (IQR) 8.7-44.7] and 0.48 ng/mL (IQR 0.2-1.76), respectively. CONCLUSIONS: IF children had a high rate of CRBSIs, of which larger proportions were due to Gram-positive and enteric organisms. Fever and/or gastrointestinal symptoms, combined with elevated CRP and PCT, is conducive to the early diagnosis of CRBSIs in IF patients.
Subject(s)
Bacteremia , Catheter-Related Infections , Intestinal Failure , Bacteremia/diagnosis , Bacteremia/epidemiology , Catheter-Related Infections/diagnosis , Catheter-Related Infections/epidemiology , Catheters , Child , Fever , Humans , Rehabilitation Centers , Retrospective StudiesABSTRACT
Preeclampsia is a significant contributor for maternal or fetal morbidity and mortality, which is characterized by reduced invasion capacity of trophoblasts and is regulated by extracellular matrix (ECM). It is still under investigation whether chorionic villus-derived mesenchymal stem cells (CVMSC) could affect the functionality of trophoblasts. In this study, CVMSC-derived exosomes were isolated; their effect on trophoblasts was investigated based on the CCK8 assay, migration assay, and apoptosis detection. And the underlying mechanism of this effect was investigated using mRNA sequencing, western blot, co-immunoprecipitation, luciferase report assay, and ubiquitination assay. The results show that CVMSC-derived exosomes promote migration and proliferation of trophoblasts, and also reduce cell apoptosis. mRNA sequencing confirmed that after treatment of CVMSC-derived exosomes, Tripartite Motif Containing 72 (TRIM72) expression was upregulated and Tumor Protein P53 (P53) expression was downregulated, both significantly in trophoblasts. Subsequent study confirms that TRM72 can directly interact with P53 and promote P53 ubiquitination and proteasomal degradation, reducing apoptosis rate and elevating proliferation and migration in trophoblasts. Our study confirms that CVMSC-derived exosomes promote trophoblast migration and proliferation by upregulating TRIM72 expression, and subsequently advance P53 ubiquitination and proteasomal degradation.
Subject(s)
Chorionic Villi/metabolism , Exosomes/metabolism , Mesenchymal Stem Cells/metabolism , Tripartite Motif Proteins/metabolism , Trophoblasts/metabolism , Tumor Suppressor Protein p53/metabolism , Ubiquitination , Apoptosis , Cell Movement , Cell Proliferation , Chorionic Villi/growth & development , Female , Humans , Mesenchymal Stem Cells/cytology , Pregnancy , Tripartite Motif Proteins/genetics , Trophoblasts/cytology , Tumor Suppressor Protein p53/geneticsABSTRACT
BACKGROUND: Trophoblast dysfunction during pregnancy is fundamentally involved in preeclampsia. Several studies have revealed that human chorionic villous mesenchymal stem cells (CV-MSCs) could regulate trophoblasts function. RESULTS: To understand how human chorionic villous mesenchymal stem cells (CV-MSCs) regulate trophoblast function, we treated trophoblasts with CV-MSC supernatant under hypoxic conditions. Treatment markedly enhanced proliferation and invasion and augmented autophagy. Transcriptome and pathway analyses of trophoblasts before and after treatment revealed JAK2/STAT3 signalling as an upstream regulator. In addition, STAT3 mRNA and protein levels increased during CV-MSC treatment. Consistent with these findings, JAK2/STAT3 signalling inhibition reduced the autophagy, survival and invasion of trophoblasts, even in the presence of CV-MSCs, and blocking autophagy did not affect STAT3 activation in trophoblasts treated with CV-MSCs. Importantly, STAT3 overexpression increased autophagy levels in trophoblasts; thus, it positively regulated autophagy in hypoxic trophoblasts. Human placental explants also proved our findings by showing that STAT3 was activated and that LC3B-II levels were increased by CV-MSC treatment. CONCLUSION: In summary, our data suggest that CV-MSC-dependent JAK2/STAT3 signalling activation is a prerequisite for autophagy upregulation in trophoblasts.
ABSTRACT
The use of multiple spatially distributed microphones allows performing spatial filtering along with conventional temporal filtering, which can better reject the interference signals, leading to an overall improvement of the speech quality. In this paper, we propose a novel dual-microphone generalized sidelobe canceller (GSC) algorithm assisted by a bone-conduction (BC) sensor for speech enhancement, which is named BC-assisted GSC (BCA-GSC) algorithm. The BC sensor is relatively insensitive to the ambient noise compared to the conventional air-conduction (AC) microphone. Hence, BC speech can be analyzed to generate very accurate voice activity detection (VAD), even in a high noise environment. The proposed algorithm incorporates the VAD information obtained by the BC speech into the adaptive blocking matrix (ABM) and adaptive noise canceller (ANC) in GSC. By using VAD to control ABM and combining VAD with signal-to-interference ratio (SIR) to control ANC, the proposed method could suppress interferences and improve the overall performance of GSC significantly. It is verified by experiments that the proposed GSC system not only improves speech quality remarkably but also boosts speech intelligibility.
Subject(s)
Speech Perception , Voice , Algorithms , Noise , SpeechABSTRACT
Our previous studies have shown that the Adipose-derived mesenchymal stem cells (ADSCs) can regulate metastasis and development of ovarian cancer. However, its specific mechanism has yet to be fully revealed. In this study, an RNA-seq approach was adopted to compare the differences in mRNA levels in ovarian cancer cells being given or not given ADSCs. The mRNA level of paired box 8 (PAX8) changed significantly and was confirmed as an important factor in tumour-inducing effect of ADSCs. In comparison with the ovarian cancer cells cultured in the common growth medium, those cultured in the medium supplemented with ADSCs showed a significant increase of the PAX8 level. Moreover, the cancer cell growth could be restricted, even in the ADSC-treated group (P < .05), by inhibiting PAX8. In addition, an overexpression of PAX8 could elevate the proliferation of ovarian cancer cells. Moreover, Co-IP assays in ovarian cancer cells revealed that an interaction existed between endogenous PAX8 and TAZ. And the PAX8 levels regulated the degradation of TAZ. The bioluminescence images captured in vivo manifested that the proliferation and the PAX8 expression level in ovarian cancers increased in the ADMSC-treated group, and the effect of ADSCs in promoting tumours was weakened through inhibiting PAX8. Our findings indicate that the PAX8 expression increment could contribute a role in promoting the ADSC-induced ovarian cancer cell proliferation through TAZ stability regulation.
Subject(s)
Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/chemistry , Mesenchymal Stem Cells/cytology , Ovarian Neoplasms/pathology , PAX8 Transcription Factor/metabolism , Animals , Apoptosis , Biomarkers, Tumor/genetics , Cell Movement , Cell Proliferation , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , PAX8 Transcription Factor/genetics , Transcriptional Coactivator with PDZ-Binding Motif Proteins , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Human amnion-derived mesenchymal stem cells (AD-MSCs) have been reported as a promising effective treatment to repair tissue. Trophoblast dysfunction during pregnancy is significantly involved in the pathogenesis of preeclampsia (PE). To understand how AD-MSCs regulated trophoblast function, we treated trophoblasts with AD-MSC-derived exosomes under hypoxic conditions. The treatment markedly enhanced the trophoblast proliferation and autophagy. Furthermore, significant decrease of EZH2 levels and inactivation of mTOR signaling were observed in AD-MSC exosomes-treated trophoblasts. Consistent with these findings, overexpression of EZH2 activated the mTOR signaling in trophoblasts, and reduced the autophagy and survival of trophoblasts, even in the presence of AD-MSC-derived exosomes. In addition, EZH2 inhibition exhibited the same trophoblast autophagy-promoting effect as induced by AD-MSC-derived exosomes, also accompanied by the inactivation of mTOR signaling. Importantly, when EZH2 was overexpressed in trophoblasts treated with PQR620, a specific mTOR signaling inhibitor, the autophagy and proliferation in trophoblasts were decreased. Studies on human placental explants also confirmed our findings by showing that the expression levels of EZH2 and mTOR were decreased while the autophagy-associated protein level was increased by AD-MSC-derived exosome treatment. In summary, our results suggest that EZH2-dependent mTOR signaling inactivation mediated by AD-MSC-derived exosomes is a prerequisite for autophagy augmentation in hypoxic trophoblasts.
ABSTRACT
BACKGROUND: Ovarian cancer is the fifth most common cause of cancer-related deaths and accounts for 3% of cancer cases occurring in women. Therefore, determining the underlying genes that can promote ovarian cancer progression is of great urgency. It has been reported that RHPN2 promotes tumour progression in various types of cancer, but its role in ovarian cancer pathogenesis remains unknown. MATERIALS AND METHODS: In this study, bioinformatic datasets were used to predict the expression of RHPN2 in clinical samples and determine the relationship between RHPN2 and the prognosis of ovarian cancer patients. Clinical samples were used to verify the prediction. RHPN2-targeting shRNA was used to investigate the effect of RHPN2 on ovarian cancer cells, and following RHPN2 knockdown, the proliferative and migratory capacities of ovarian cancer cells were tested. To determine the downstream signalling target of RHPN2, a luciferase reporter assay was conducted, and an animal experiment was carried out to confirm the effect of RHPN2 in vivo. RESULTS: The public datasets indicated that ovarian cancer tissues showed significantly higher RHPN2 expression than para-cancer normal tissues, and poor prognosis was observed in patients with higher RHPN2 expression, which was further confirmed in clinical samples. After RHPN2 was knocked down, the proliferation and migration of ovarian cancer cells were significantly impaired; a luciferase reporter assay indicated that the STAT3 signalling pathway was the most highly affected, and RHPN2 downregulation inhibited STAT3 nuclear translocation. STAT3 inhibitors partially rescued the tumour-promoting effect induced by RHPN2 overexpression, which was further confirmed by animal experiments. CONCLUSION: Collectively, our results indicate that RHPN2 promotes malignant behaviours in ovarian cancer by activating STAT3 signalling.
ABSTRACT
OBJECTIVES: Homosapien collagen beta (1-O) galactosyl transferase 2 (COLGALT2) is an important enzyme during collagen glycosylation, yet its biological functions in cancer are incompletely understood. Our previous study revealed that in the osteosarcoma microenvironment, adipose-derived mesenchymal stem cells (ADSCs) demonstrate cancer-promoting effects, but the exact mechanisms remain unclear. The aim of this study was to investigate the role of COLGALT2 in the osteosarcoma-fostering effects of ADSCs. MATERIALS AND METHODS: In this study, we compared COLGALT2 expression between primary and metastatic osteosarcoma tissues and found that metastatic tissues expressed significantly higher COLGALT2 levels. Then, we isolated and identified exosomes secreted by ADSCs. Additionally, we assessed the roles of ADSC exosomes and COLGALT2 in the osteosarcoma-promoting effects of ADSCs. RESULTS: Our results showed that ADSC exosomes could foster the invasion, migration, and proliferation of osteosarcoma cells, together with increasing COLGALT2 expression. COLGALT2 inhibition in MG63 cells suppressed the ADSC exosome-mediated fostering of osteosarcoma cell invasion, migration and proliferation in vitro. Conversely, COLGALT2 overexpression promoted U-2OS cell invasion, migration and proliferation in vitro. Additionally, COLGALT2 inhibition attenuated metastasis and tumor growth, and ADSC exosomes promoted tumor progression, as demonstrated in a nude mouse model of osteosarcoma. CONCLUSION: According to these data, ADSC exosomes foster osteosarcoma progression by increasing COLGALT2 expression in osteosarcoma cells.
ABSTRACT
Ovarian cancer (OC) is the deadliest gynecological malignancy. The pathogenesis of molecular in epithelial ovarian cancer (EOC), main histological type of OC, has not been completely defined. Enhancer of rudimentary homolog (ERH) had been reported to participate in transcriptional regulation, mRNA splicing, DNA repair and DNA synthesis by binding a variety of proteins. In this study, immunohistochemical staining revealed that the protein expression of ERH was associated with histological type, lymph node metastasis and pathological grade in EOC patients. To verify the association of ERH with the prognosis of OC, a GSE microarray dataset was downloaded from the Gene Expression Omnibus (GEO) database. Survival analysis suggested that ERH may be associated with poor prognosis of OC. In addition, shRNA was used to knockdown the protein and mRNA expression levels of ERH in the OC cell line SKOV3. Inhibition of ERH expression slowed proliferation, promoted apoptosis and inhibited metastasis and invasion by regulating epithelial-mesenchymal transition (EMT) in SKOV3 cells. These results indicate that ERH protein promotes the development of OC and provides an experimental basis for ERH as the potential target for ovarian cancer treatment.
Subject(s)
Carcinoma, Ovarian Epithelial/metabolism , Cell Cycle Proteins/metabolism , Epithelial-Mesenchymal Transition/physiology , Gene Expression Regulation, Neoplastic , Transcription Factors/metabolism , Carcinoma, Ovarian Epithelial/genetics , Cell Cycle Proteins/genetics , Cell Line, Tumor , Female , Gene Knockdown Techniques , Humans , Middle Aged , Transcription Factors/geneticsABSTRACT
BACKGROUND: Our previous study showed that human omental adipose-derived stem cells (ADSCs) promote ovarian cancer growth and metastasis. In this study, the role of autophagy in the ovarian cancer-promoting effects of omental ADSCs was further determined. METHODS: The growth and invasion of ovarian cancer cells were detected by CCK-8 and Transwell assays, respectively. The autophagy of ovarian cancer cells transfected with MRFP-GFP-LC3 adenoviral vectors was evaluated by confocal microscopy and western blot assay. Transfection of STAT3 siRNA was used to inhibit the expression of STAT3. RESULTS: Our results show that autophagy plays a vital role in ovarian cancer and is promoted by ADSCs. Specifically, we show that proliferation and invasion are correlated with autophagy induction by ADSCs in two ovarian cancer cell lines under hypoxic conditions. Mechanistically, ADSCs activate the STAT3 signalling pathway, thereby promoting autophagy. Knockdown of STAT3 expression using siRNA decreased hypoxia-induced autophagy and decreased the proliferation and metastasis of ovarian cancer cells. CONCLUSION: Taken together, our data indicate that STAT3-mediated autophagy induced by ADSCs promotes ovarian cancer growth and metastasis.
Subject(s)
Autophagy , Mesenchymal Stem Cells , Ovarian Neoplasms , STAT3 Transcription Factor/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Female , Humans , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , Omentum/cytology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Signal TransductionABSTRACT
Ovarian cancer metastasizes to organs in the abdominal cavity, such as the omentum that is a rich source of adipose-derived mesenchymal stem cells (ADSCs). In present, ADSCs have received more and more attention for their roles in the development of cancer. In this study, we examined α-smooth muscle actin (α-SMA) expression and carcinoma-associated fibroblast (CAF)-like differentiation capabilities in ADSCs from omentum of different patients. The effects of ADSCs on the proliferation and invasion of epithelial ovarian cancer cells (EOCCs) were also assessed in vitro and in vivo. Our results showed that ADSCs from omentum of ovarian cancer patients, no matter whether metastasis or not, expressed higher levels of α-SMA than ADSCs from patients with benign gynecologic disease. Using direct and indirect co-culture system, we found that EOCCs induced ADSCs to express CAF markers, including α-SMA and fibroblast activation protein, via the transforming growth factor beta 1 (TGF-ß1) signaling pathway. Moreover, co-cultured ADSCs exhibited functional properties similar to those of CAFs, including the ability to promote EOCCs proliferation, progression and metastasis both in vitro and in vivo. Furthermore, blocking the TGF-ß1 pathway can counteract the CAF-like differentiation and tumor promotion effect of ADSCs. Our results suggest that ADSCs are a source of CAFs and that they participate in the interaction between EOCCs and the omental microenvironment. EOCCs could induce ADSCs in the omentum to differentiate before ovarian cancer metastasis, which participate in the formation of omental metastatic niches and promote the proliferation and invasion of ovarian cancer.
Subject(s)
Adipose Tissue/cytology , Carcinoma, Ovarian Epithelial/secondary , Cell Transformation, Neoplastic/pathology , Mesenchymal Stem Cells/pathology , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/secondary , Actins/metabolism , Adult , Animals , Cancer-Associated Fibroblasts/pathology , Cell Differentiation , Cells, Cultured , Coculture Techniques , Disease Progression , Endopeptidases , Female , Gelatinases/metabolism , Humans , Membrane Proteins/metabolism , Mice , Middle Aged , Myofibroblasts/pathology , Omentum/pathology , Primary Cell Culture , Serine Endopeptidases/metabolism , Transforming Growth Factor beta1/metabolism , Tumor Cells, Cultured , Tumor Microenvironment , Xenograft Model Antitumor AssaysABSTRACT
As shown in our previous studies, growth and metastasis of ovarian cancer can be regulated by adipose-derived mesenchymal stem cells (ADSCs). However, the underlying mechanism has not yet been revealed. In this study, a proteomics analysis was performed to compare protein expression treated with and without ADSCs in ovarian cancer cells. Protein levels were altered in ovarian cancer cells due to the treatment of ADSCs. Thymosin beta 4 X-linked (TMSB4X) levels changed dramatically, and this protein was identified as one of the most important candidate molecules contributing to the tumour-promoting effects of ADSCs. Compared with the cells that are cultured in the normal growth medium, the TMSB4X levels cultured in ADSC-conditioned medium increased significantly in ovarian cancer cells. Furthermore, the growth and invasion of cancer cells were decreased, even in the ADSC-conditioned medium treatment group (P < 0.05), by the inhibition of TMSB4X. As shown in the bioluminescence images captured in vivo, increased ovarian cancer's growth and metastasis, along with elevated TMSB4X expression, were observed in the group of ADSC-conditioned medium, and the tumour-promoting effect of ADSCs was attenuated by the inhibition of TMSB4X. Based on our findings, increased TMSB4X expression may play a role in accelerating the ADSC-mediated proliferation, invasion, and migration of ovarian cancers.
ABSTRACT
BACKGROUND: Spinal metastasis is a major challenge in patients with advanced lung cancer, but the mechanisms in the organotropism of metastasis are still unclear. Adipose-derived mesenchymal stem cells (ADSCs) exhibit cancer-promoting properties that influence the tumour microenvironment; however, there is no research on ADSCs from epidural fat thus far. METHODS: In this study, we isolated and identified ADSCs from epidural adipose tissue for the first time. We examined the activation of epidural ADSCs treated with lung cancer cell-conditioned medium by immunohistochemistry, western blot and qRT-PCR assays. The expression of interleukin (IL)-6 family cytokines in the supernatants of ADSCs were evaluated by enzyme-linked immunosorbent assay. The effects of epidural ADSCs on the growth and invasion of lung cancer cells were evaluated with the CCK-8 and Transwell assays. The expression of signal transducer and activator of transcription 3 (STAT3), matrix metalloprotease and epithelial-mesenchymal transition markers were measured by western blot assays. RESULTS: Our results showed that ADSCs treated with lung cancer cell-conditioned medium expressed higher levels of the myofibroblast marker α-smooth muscle actin and fibroblast activation protein than ADSCs cultured alone. Then, we found that lung cancer cells induced ADSCs to secrete high levels of IL-6 family cytokines and activate the STAT3 signalling pathway. Moreover, activated epidural ADSCs exhibited the ability to promote lung cancer cell proliferation and invasion by elevating matrix metalloprotease expression and epithelial-mesenchymal transition in cancer cells. Furthermore, blocking IL-6 can counteract the differentiation and tumour-promoting effects of ADSCs. CONCLUSION: Our results suggest that ADSCs respond to lung cancer cells and are involved in the crosstalk between primary tumours and pre-metastatic niches in epidural fat.