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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,459 records · Page 81
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

The human aortic endothelium undergoes dose-dependent DNA methylation in response to transient hyperglycemia

Glycemic control is a strong predictor of long-term cardiovascular risk in patients with diabetes mellitus, and poor glycemic control influences long-term risk of cardiovascular disease even decades after optimal medical management. This phenomenon, termed glycemic memory, has been proposed to occur due to stable programs of cardiac and endothelial cell gene expression. This transcriptional remodeling has been shown to occur in the vascular endothelium through a yet undefined mechanism of cellular reprogramming.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

RACGAP1 modulates ECT2-Dependent mitochondrial quality control to drive breast cancer metastasis

Most cancer deaths are due to the colonization of tumor cells in distant organs. More evidence indicates that overexpression of RACGAP1 plays a critical role in cancer metastasis. However, the underlying mechanism still remains poorly understood. Here we found that RACGAP1 promoted breast cancer metastasis through regulating mitochondrial quality control. Overexpression of RACGAP1 in breast cancer cells led to the fragmentation of mitochondria, increased mitophagy intensity, mitochondrial turnover, and aerobic glycolysis ATP production. We showed that RACGAP1 promoted mitochondrial fission through recruiting ECT2 during anaphase and subsequently had activated ERK-DRP1 pathway. We further demonstrated the phosphorylation of RACGAP1 is essential for its ability of binding with ECT2 and its downstream effects. RACGAP1 overexpression also increased the expression of PGC-1a, a key mitochondrial biogenesis regulator, presumably by the increased mitophagy intensity induced by RACGAP1. PGC-1a increased the enrichment of DNMT1 in mitochondria, mitochondrial DNMT1 augmented mitochondrial DNA methylation and upregulated mitochondrial genome transcription. Our data indicated that RACGAP1 simultaneously facilitated mitophagy and mitochondrial biogenesis through regulating DRP1 phosphorylation and PGC-1a expression, eventually improved mitochondrial quality control in breast cancer cells. Our study provided a new angle in understanding the RACGAP1-overexpression related malignancy in breast cancer patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

PCGF3 promotes the proliferation and migration of non-small cell lung cancer cells via the PI3K/AKT signaling pathway

Highlights: • PCGF3 is highly expressed in non-small cell lung cancer (NSCLC) tissues. • PCGF3 overexpression positively correlates with lymph node metastasis and p-TNM staging. • PCGF3 promotes NSCLC cells proliferation by regulating CyclinB1, CyclinD1, and CDK4. • PCGF3 promotes NSCLC cells migration by regulating RhoA, RhoC, and CDC42. • PCGF3 promotes malignant behavior in NSCLC by positively regulating the PI3K/AKT signaling pathway. The Polycomb Group Ring Finger 3 (PCGF3) protein has been reported to be significantly upregulated in pancreatic islet tumors and related to signal transduction; however, its detailed mechanisms and biological roles in other tumors, including non-small cell lung cancer (NSCLC), remain unclear. This study investigated the function of PCGF3 in NSCLC and further elucidated its mechanism of action. The immunohistochemical analysis of 86 selected lung cancer tissues revealed that PCGF3 was highly expressed in NSCLC tissues and positively correlated with lymph node metastasis and p-TNM staging. Additionally, PCGF3 promoted cell proliferation in lung cancer by regulating CyclinB1, CyclinD1, and CDK4 expression, and also promoting their migration by regulating RhoA, RhoC, and CDC42. Furthermore, PCGF3 affected both the proliferation and migration of lung cancer cells by regulating the PI3K/AKT pathway, as verified by inhibiting this pathway using LY294002. The findings of this study suggested that PCGF3 is associated with poor prognosis in patients with NSCLC and could therefore be an important biomarker for treating and preventing NSCLC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

BAP1 antagonizes WWP1-mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression

Accumulating evidence revealed the abnormal expression of KLF5 in human cancers while its role in melanoma remains uncharacterized. This study aimed to explore the role of KLF5 in the proliferation and metastasis of melanoma. Bioinformatics analysis was performed to detect WWP1, BAP1 and KLF5 expression in melanoma, followed by expression determination on clinical tissues from melanoma patients and cancer cells. The cancer cells were infected with lentivirus expressing KLF5 or BAP1 while PI3K, AKT and mTOR expression was detected and autophagy was observed. Treated cells were injected to mice when tumor growth was measured and autophagy-related protein was detected. Plasmids expressing WWP1 and Ub-K48 were co-transfected into treated melanoma cells while immunoprecipitation assay was performed to determine the interaction among KLF5, WWP1, and BAP1. WWP1 was poorly expressed in melanoma cells and tissues whereas KLF5 was highly expressed and was positively correlated to poor prognosis. KLF5 promoted melanoma cell malignant phenotypes as well as inhibited autophagy. Interestingly, KLF5 contributed to activation of PI3K-AKT-mTOR signaling pathway, thereby inhibiting autophagy in melanoma cells. WWP1 mediated K48-linked ubiquitination of KLF5 to promote its degradation, and BAP1 antagonized this modification and stabilized KLF5 protein expression. Besides, BAP1 promoted KLF5-mediated growth of melanoma in vivo. Taken altogether, BAP1 antagonized WWP1-mediated ubiquitination of KLF5 to inhibit autophagy and promote melanoma development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A dehydrated, aseptically-processed human amnion/chorion allograft accelerates healing in a delayed murine excisional wound model

Since chronic, non-healing wounds represent an increasing source of economic and temporal burden for patients who suffer from them and healthcare professionals that treat them, therapeutic modalities that promote closure of delayed and non-healing wounds are of utmost importance. Recent clinical results of allografts derived from amnion and chorion placental layers encourage further investigation of the mechanisms underlying clinical efficacy of these products for treatment of wounds. Here, we utilized a diabetic murine splinted excisional wound model to investigate the effects of a dehydrated human amnion/chorion-derived allograft (dHACA) on delayed wound healing, as well as the effects of dehydrated allograft derived solely from amnion tissue of the same donor. We examined wound healing by histological endpoint analysis, and we assessed other parameters relevant to functional wound healing in the wound bed including angiogenesis, macrophage phenotypes, proliferative activity, and gene expression. Herein we demonstrate that application of dHACA to a murine diabetic model of delayed wound progression results in better macroscale wound resolution outcomes, including rate of closure, compared to unaided wound progression, while dehydrated human amnion allograft (dHAA) fails to improve outcomes. Improved gross wound resolution observed with dHACA was accompanied by increased granulation tissue formation, proliferation and vascular ingrowth observed in the wound bed, early macrophage polarization towards anti-inflammatory phenotypes, and downregulation of pro-fibrotic gene expression. Overall, our data suggest that improvements in the rates of delayed wound closure observed from combined amnion/chorion allografts are associated with modulation of critical cellular and tissue processes commonly found to be dysregulated in delayed healing wounds, including proliferation, vascularization, inflammation, and re-epithelialization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Organotypic platform for studying cancer cell metastasis

Highlights: • Liver and brain slices can be stable, realistic in vitro 3D models. • Cell stiffness and adhesion to the tissue play determinant roles in cellular invasion in 3D. • MEK inhibitors can lead to increased cell stiffness and adhesion forces, and consequently reduced cancer cell invasion. • MDA-MB-231 breast cancer cells migrate faster and deeper into brain tissue compared to liver tissue. Metastasis is the leading cause of mortality in cancer patients. To migrate to distant sites, cancer cells would need to adapt their behaviour in response to different tissue environments. Thus, it is essential to study this process in models that can closely replicate the tumour microenvironment. Here, we evaluate the use of organotypic liver and brain slices to study cancer metastasis. Morphological and viability parameters of the slices were monitored daily over 3 days in culture to assess their stability as a realistic 3D tissue platform for in vitro metastatic assays. Using these slices, we evaluated the invasion of MDA-MB-231 breast cancer cells and of a subpopulation that was selected for increased motility. We show that the more aggressive invasion of the selected cells likely resulted not only from their lower stiffness, but also from their lower adhesion to the surrounding tissue. Different invasion patterns in the brain and liver slices were observed for both subpopulations. Cells migrated faster in the brain slices (with an amoeboid-like mode) compared to in the liver slices (where they migrated with mesenchymal or collective migration-like modes). Inhibition of the Ras/MAPK/ERK pathway increased cell stiffness and adhesion forces, which resulted in reduced invasiveness. These results illustrate the potential for organotypic tissue slices to more closely mimic in vivo conditions during cancer cell metastasis than most in vitro models.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

MiR-205–5p suppresses angiogenesis in gastric cancer by downregulating the expression of VEGFA and FGF1

Highlights: • MiR-205-5p was commonly downregulated in GC tissues from TCGA database and our hospital, and these events were associated with a worse TNM stagedistant metastasis and poor survival. • MiR-205-5p and CD31 expressions were negatively inter-related within GC tissues from TCGA database and our hospital. • GC cell lines expressed lower level of miR-205-5p significantly as compared with the normal gastric cell line. • MiR-205-5p upregulation significantly impaired proliferation and colony formation of GC cells and neovascularization induced by GC cells in vitro and in vivo. • The angiogenesis and ERK-signaling were depressed by VEGFA and FGF1 downregulation induced by miR-205-5p overexpression. The miR-205-5p inhibitor promoted malignant phenotypes by enhancing VEGFA and FGF1 expressions, as well as the activation of ERK-signaling. Anti-angiogenic therapy represents one of the most promising treatment modalities for human cancers. However, the response to antiangiogenic therapy in gastric cancer (GC) remains dismal. To help identify new strategies for antiangiogenic therapy in GC, we evaluated miR-205–5p expression in GC tissues from TCGA database and our hospital, and its functions in angiogenesis were explored in vitro and in vivo. We investigated miR-205–5p expression and microvessel densities (MVDs) in GC tissues and liver metastases from patients. The function and mechanisms of miR-205–5p were examined in human cell lines and in xenograft mouse models. Associations between miR-205–5p expression and clinical characteristics were analyzed using either Pearson's χ{sup 2} test or Fisher's exact test. Differences in overall survival (OS) distributions were evaluated using the log-rank test. Differences in measurement data were compared using Student's t-test and one-way ANOVA. We found that miR-205–5p expression was downregulated in GC tissues and was negatively correlated with CD31 expression in both TCGA and our clinical samples. GC cell lines expressed low levels of miR-205–5p, and miR-205–5p upregulation significantly impaired the proliferation and angiogenesis of GC cells. Moreover, vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 1 (FGF1) expression and activation of extracellular-related kinase (ERK) signaling were suppressed by miR-205–5p. MiR-205–5p inhibition promoted malignant phenotypes by enhancing VEGFA and FGF1 expression, as well as the activation of ERK signaling. Angiogenesis and ERK signaling were decreased in response to VEGFA and FGF1 downregulation induced by miR-205–5p overexpression. The dual-luciferase reporter assay showed that VEGFA and FGF1 were direct targets of miR-205–5p. Xenograft mouse models revealed that miR-205–5p suppressed tumor growth by inhibiting neovascularization. Altogether, these results demonstrate that miR-205–5p suppresses angiogenesis in GC by attenuating the expression of VEGFA and FGF1, indicating that upregulation of miR-205–5p may represent as an antiangiogenic therapy for GC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Evidence that Maackia amurensis seed lectin (MASL) exerts pleiotropic actions on oral squamous cells with potential to inhibit SARS-CoV-2 infection and COVID-19 disease progression

COVID-19 was declared an international public health emergency in January, and a pandemic in March of 2020. There are over 125 million confirmed COVID-19 cases that have caused over 2.7 million deaths worldwide as of March 2021. COVID-19 is caused by the SARS-CoV-2 virus. SARS-CoV-2 presents a surface “spike” protein that binds to the ACE2 receptor to infect host cells. In addition to the respiratory tract, SARS-Cov-2 can also infect cells of the oral mucosa, which also express the ACE2 receptor. The spike and ACE2 proteins are highly glycosylated with sialic acid modifications that direct viral-host interactions and infection. Maackia amurensis seed lectin (MASL) has a strong affinity for sialic acid modified proteins and can be used as an antiviral agent. Here, we report that MASL targets the ACE2 receptor, decreases ACE2 expression and glycosylation, suppresses binding of the SARS-CoV-2 spike protein, and decreases expression of inflammatory mediators by oral epithelial cells that cause ARDS in COVID-19 patients. In addition, we report that MASL also inhibits SARS-CoV-2 infection of kidney epithelial cells in culture. This work identifies MASL as an agent with potential to inhibit SARS-CoV-2 infection and COVID-19 related inflammatory syndromes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Exosomes derived from hypoxic bone marrow mesenchymal stem cells rescue OGD-induced injury in neural cells by suppressing NLRP3 inflammasome-mediated pyroptosis

Exosomes have been shown to have therapeutic potential for cerebral ischemic diseases. In this study, we investigated the neuroprotective effects of normoxic and hypoxic bone marrow mesenchymal stromal cells-derived exosomes (N-BM-MSCs-Exo and H-BM-MSCs-Exo, respectively) on oxygen-glucose deprivation (OGD) injury in mouse neuroblastoma N2a cells and rat primary cortical neurons. The proportions of dead cells in N2a and primary cortical neurons after OGD injury were significantly increased, and N-BM-MSCs-Exo (40 μg/ml) could reduce the ratios, noteworthily, the protective effects of H-BM-MSCs-Exo (40 μg/ml) were more potent. Western blotting analysis indicated that N-BM-MSCs-Exo decreased the expression of NLRP3, ASC, Caspase-1, GSDMD-N, cleaved IL-1β and IL-18 in N2a cells. However, H-BM-MSCs-Exo (40 μg/ml) was more powerful in inhibiting the expression of these proteins in comparison with N-BM-MSCs-Exo. Similar results were obtained in primary cortical neurons. Immunofluorescence assays showed that after N-BM-MSCs-Exo and H-BM-MSCs-Exo treatment, the co-localization of NLRP3, ASC, Caspase-1 and the GSDMD translocation from the nucleus to the cytoplasm and membrane after OGD injury were reduced in N2a cells and primary cortical neurons, and H-BM-MSCs-Exo had a more obvious effect. In addition, N-BM-MSCs-Exo and H-BM-MSCs-Exo significantly reduced lactate dehydrogenase (LDH) release and the IL-18 levels in cell culture medium in N2a cells and primary cortical neurons. Once again H-BM-MSCs-Exo induced these effects more potently than N-BM-MSCs-Exo. All of these results demonstrated that N-BM-MSCs-Exo and H-BM-MSCs-Exo have significant neuroprotective effects against NLRP3 inflammasome-mediated pyroptosis. H-BM-MSCs-Exo has a more pronounced protective effect than N-BM-MSCs-Exo and may be used to ameliorate the progression of cerebral ischemia and hypoxia injury in patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Knockdown of NLE1 inhibits development of malignant melanoma in vitro and in vivo NLE1 promotes development of malignant melanoma

Melanoma, which originates from neural crest derived melanocytes, causes severe pain and even death to numerous patients. Previous studies reported that Notchless Homolog 1 (NLE1) plays an important role in cell proliferation, transcription and signal transduction. However, the clinical significance and biological behavior of NLE1 in melanoma remain a mystery. Thus, the role of NLE1 in melanoma was investigated in vitro and in vivo. The expression of NLE1 in melanoma was elevated and the expression level was positively correlated with lymphatic metastasis and tumor stage. In addition, NLE1 knockdown by shRNA specifically inhibited proliferation, enhanced the apoptotic sensitivity and hindered migration of melanoma cells in vitro. Mice xenograft model further showed that NLE1 knockdown could inhibit the tumor formation of melanoma in vivo. Additionally, the induction of apoptosis of melanoma cells by NLE1 knockdown required the participation of a series of apoptosis-related proteins. Besides, NLE1 can activate the PI3K/AKT signaling pathway. In summary, NLE1 was involved in the development and progression of melanoma, which may be a novel potential target for molecular therapy of melanoma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Deubiquitinating enzyme USP46 suppresses the progression of hepatocellular carcinoma by stabilizing MST1

Highlights: • Low USP46 level is correlated with poor prognosis in HCC. • USP46 suppresses the proliferation and metastasis of HCC. • USP46 suppress the progression of HCC by inhibiting the expression of YAP1. • MST1 mediates the regulation of USP46 on YAP1. • USP46 stabilized MST1 protein through inhibiting its ubiquitination and degradation. The deubiquitinating enzyme USP46 (ubiquitin-specific protease 46) is implicated in various cancers. However, its role and regulatory mechanism in HCC (hepatocellular carcinoma) are still unknown. In this study, we showed that USP46 is downregulated in HCC tissues and that low USP46 levels are associated with poor prognosis in HCC patients. In functional experiments, overexpression of USP46 impaired proliferation and metastasis of HCC cells, whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo. Furthermore, we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1. Ectopic expression of YAP1 rescued the inhibition of cell proliferation and metastasis caused by USP46 overexpression. Mechanistically, USP46 promotes the degradation of YAP1 by increasing expression of MST1, and the increase in MST1 protein antagonizes YAP1 to suppress HCC progression. Finally, we demonstrated that USP46 stabilizes the MST1 protein by directly binding to it and decreasing its ubiquitination. Taken together, our results demonstrated that USP46 may be a novel tumor suppressor in HCC. Moreover, USP46 acts as a deubiquitinating enzyme of MST1 to potentiate MST1 kinase activity to suppress tumor growth and metastasis, indicating that USP46 activation may represent a potential treatment strategy for HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Metformin attenuates expression of angiogenic and inflammatory genes in human endometriotic stromal cells

Highlights: • Metformin reduced cell migration, and proliferation of endometriotic stromal cells. • Metformin attenuated the expression of angiogenic and inflammatory genes in human endometriotic stromal cells. • Metformin could be used as an effective adjuvant in endometriosis treatment. Endometriosis is a benign gynecological disease that is manifested by the presence and growth of endometrial cells and glands outside the uterine. Active angiogenesis, migration, and invasion of endometrial tissue outside the uterine are critical for the development of endometriosis and lead to the survival and growth of endometriotic lesions. Metformin, as an anti-diabetic agent, represents anti-angiogenic property. Here, we performed a study using human normal endometrial stromal cells (N-ESCs) from healthy endometrial tissue and human eutopic endometrial stromal cells (EU-ESCs) and ectopic endometrial stromal cells (ECT-ESCs) from endometriosis patients. ESCs were cultured and treated with different concentrations of Metformin (0–20 mmol/l) for 72 h to evaluate Metformin effect on cell viability, proliferation, migration was measured by methyl thiazolyl tetrazolium (MTT) assay and scratch test respectively as well as expression of angiogenesis and migration markers. The Metformin reduced cell migration, and proliferation of endometriotic stromal cells in a time and concentration dependently manner. Furthermore, Metformin attenuated the expression of angiogenic and inflammatory genes in human endometriotic stromal cells. The direct anti-proliferative effect on ECT-ESCs combined with the effects of Metformin on inflammatory and angiogenesis-related genes expression supports its therapeutic potential for endometriosis. Metformin could be used as an effective adjuvant in endometriosis treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Glucocorticoids activate Yes-associated protein in human vocal fold fibroblasts

Fibrosis of the vocal folds poses a substantive clinical challenge potentially underlying the rapid proliferation of direct steroid injections into the upper airway. The variable clinical response to glucocorticoids (GCs) in the vocal folds is likely related to diversity inherent to GCs and patient-specific, and upstream, cell-specific responses to GCs. Broadly, we hypothesize the disparity in clinical outcomes are due to undesirable effects of GCs on resident fibroblasts. Transcriptome analysis identified significant GC-mediated modulation of Hippo signaling, a known regulator of fibrotic gene expression. Subsequent analysis confirmed GC-mediated YAP activation, a transcriptional co-factor in the Hippo signaling pathway. YAP inhibition attenuated ACTA2 expression in GC-treated human vocal fold fibroblasts. Nuclear localization and phosphorylation at Ser211, however, was not affected by YAP inhibition, suggesting nuclear translocation of YAP is indirectly driven by GR. RNA-seq analysis confirmed the influence of GCs on Wnt signaling, and canonical Wnt signaling target genes were upregulated by GCs. These data implicate YAP and its downstream targets as putative mediators of a pro-fibrotic response to GCs. Therapeutic YAP inhibition may ultimately be clinically relevant and warrants further consideration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Dexamethasone reduces the formation of thoracic aortic aneurysm and dissection in a murine model

Highlights: • Dexamethasone attenuated thoracic aortic aneurysm and dissection in a mouse model. • Dexamethasone reduced infiltration of inflammatory cell and apoptosis of vascular smooth muscle cell and fibroblast. • Dexamethasone partly alleviated degradation of collagen and phenotype switch. • DEX might ameliorate thoracic aortic aneurysm and dissection by suppressing NF-κB signaling pathway. Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease with no effective pharmaceutical therapies currently available. Inflammation plays a key role in the progression of aneurysms. Dexamethasone (DEX), a synthetic glucocorticoid, has showed alleviating effects on cells in vitro from TAAD patients. Here we performed a study aiming at investigating the protective role of DEX in a β-aminopropionitrile monofumarate (BAPN)-induced TAAD mouse model. DEX (dose: 0.04 mg/kg/day) treatment significantly reduced the aortic diameter and inhibited TAAD formation. DEX reduced infiltration of macrophages and neutrophils, apoptosis of vascular smooth muscle cells (VSMCs), expression of metalloproteinase 2/9, and extracellular matrix degradation in BAPN-treated TAAD mice. Furthermore, DEX therapy downregulated the expression of p-p65 in macrophages and VSMCs, which suggested that DEX might ameliorate BAPN-induced TAAD by suppressing NF-κB signaling. Therefore, DEX therapy attenuates the progression of BAPN-induced TAAD murine model and could be used as an effective adjuvant therapy for treating TAAD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

ANGPTL4 regulates CD163 expression and Kuppfer cell polarization induced cirrhosis via TLR4/NF-κB pathway

Angiopoietin like 4 (ANGPTL4) has been proved to play an important role in lipid and glucose metabolism disorders and related cardiovascular diseases, but its role in the formation of cirrhosis still needs to be further explored. Therefore, the aim of this study was to investigate the role of ANGPTL4 in the development of liver cirrhosis and its mechanism, as well as its effect on Kupffer cell polarization and hepatic stellate cell activation. The ELISA and RT-qPCR assay were used to detect the content of ANGPTL4 in serum and mRNA expression in cells and tissues respectively. The expression of ANGPTL4, Arg1 and Mrc2 in Kupffer cells was measured by Western blot. The percentage of CD163{sup +} and CD206{sup +} cells was measured by flow cytometry. Mice cirrhosis model was established, and the expression of ANGPTL4 was interfered by injecting sh-ANGPTL4 lentiviral vector into caudal vein. The results revealed that ANGPTL4 was significantly up-regulated in liver cirrhosis patients and HBV induced liver injury cell models. Further studies found that interference with ANGPTL4 regulated CD163 and inhibited the polarization and proinflammatory effects of KCsas well as inhibited the activation of hepatic stellate cells (HSCs) and fibrosis. More importantly, Interference with ANGPTL4 inhibits the progression of liver cirrhosis in mice. What's more, TLR4/NF-κB pathway was involved in the molecular mechanism of ANGPTL4 on Kupffer cells and hepatic stellate cells. It is suggested that the mechanism of sh-ANGPTL4 suppressing the polarization of KCs and the activation of hepatic stellate cells (HSCs) is to regulate the TLR4/NF-κB signaling pathways.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Tunicamycin-induced endoplasmic reticulum stress inhibits chemoresistance of FaDu hypopharyngeal carcinoma cells in 3D collagen I cultures and in vivo

Highlights: • 3D collagen I culture induces chemoresistance of FaDu hypopharyngeal carcinoma cells. • Tunicamycin-induced ER stress inhibits chemoresistance in collagen I cultures. • Tunicamycin-induced ER stress potentiates anticancer efficacy in vivo. • Tunicamycin-induced ER stress inhibits TGF-β1 and modifies integrin β1 glycosylation. The prognosis in patients with advanced head and neck squamous cell carcinoma (HNSCC) is widely affected by the resistance to chemotherapy. As a culture scaffold, collagen I was showed to promote CSC (cancer stem cell) properties of cancer cells which could be used as in vitro models to study the chemoresistance in HNSCC. Endoplasmic reticulum (ER) stress is a cellular stress condition which could affect tumor progression and promote the anti-tumor effects of certain drugs. However, the impact of ER stress on collagen I induced CSC properties and chemoresistance of HNSCC cells has not been addressed. In this study we investigated the effects of tunicamycin (TM) induced ER stress on the stemness and sensitivity to chemotherapeutic drugs of FaDu hypopharyngeal carcinoma cells in 3D (three-dimensional) collagen I cultures and mouse xenograft models. Our study revealed that Collagen I scaffold promoted CSC properties and increased G1 population of FaDu cells in 3D cultures, accompanied by maturation of integrin β1 and enhanced activated TGF-β1 concentration. Compared to 2D (two-dimensional) cultured cells, cells in 3D Collagen I scaffold exhibited significantly increased resistance to chemotherapeutic drugs of cisplatin and paclitaxel. Further analysis revealed that TM induced ER stress preferentially attenuated chemoresistance of FaDu cells in 3D collagen I, downregulated their CSC properties and TGF-β1 concentration and resulted in deglycosylation of integrin β1. TM was further evaluated in the mouse xenograft models and showed significant tumor growth inhibition in combination with paclitaxel than either TM or paclitaxel alone. Taken together, Our findings suggest that TM-induced ER stress potentiates anticancer efficacy of FaDu cells in 3D cultures and in vivo, and highlight implications for targeting chemotherapy-resistant cancer stem cells under ER stress conditions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Tumor-derived LIF promotes chemoresistance via activating tumor-associated macrophages in gastric cancers

Chemotherapy is the preferred clinical treatment for advanced stage gastric cancer (GC) patients, of which efficacy could be markedly impaired due to the development of chemoresistance. Alternatively activated or M2-type tumor associated macrophages (TAMs) are recruited under chemotherapy and are highly implicated in the chemoresistance development, but underlying molecular mechanism for TAM activation is largely unknown. Here, we present that tumor-derived Leukemia inhibitory factor (LIF) induced by chemo drugs represses the chemo sensitivity of gastric tumor cells in a TAM-dependent manner. Mechanistically, cisplatin-induced HIF1α signaling activation directly drive the transcription of LIF, which promotes the resistance of gastric tumors to chemo drug. Further study revealed that tumor cell-derived LIF stimulates macrophages into tumor-supporting M2-type phenotype via activating STAT3 signaling pathway. Therapeutically, blocking LIF efficiently elevates chemo sensitivity of tumor cells and further represses the growth rates of tumors under chemotherapy. Therefore, our study reveals a novel insight in understanding the cross talking between tumor cells and immune cells and provides new therapeutic targets for gastric cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Association of somatic mutations in BRCA2 BRC domain with chemotherapy sensitivity and survival in high grade serous ovarian cancer

Highlights: • BRCA2 BRC domain-associated mutation confers higher platinum sensitivity of HGSOC. • Somatic BRCA2 BRC domain mutation impairs BRCA2 HR in HGSOC. • BRCA2 BRC domain mutation at sites is crucial for HR repair of DNA DSB induced by platinums. • Somatic BRCA2 BRC domain missense mutations improve outcomes in patients with HGSOC. Mutations at sites crucial for the interaction between RAD51 and BRC domains impair the ability of BRCA2 homologous recombination. We aimed to clarify whether BRCA2 BRC domain-associated mutation correlates with sensibility of platinum-based chemotherapy and survival in high-grade serous ovarian cancer (HGSOC).

60 APPLIED LIFE SCIENCES↗