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Results for “EMT”

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 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
DOE OSTI2013

Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis. Interestingly, the mechanism by which rapamycin diminished RMS tumor growth involved simultaneous inhibition of mTOR and hedgehog (Hh) pathways. Diminution in these pathways in this model of RMS also inhibited epithelial mesenchymal transition (EMT) which then dampened the invasiveness of these tumors. Our data provide bases for using rapamycin either alone or in combination with traditional chemotherapeutic drugs to block the pathogenesis of high risk RMS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

miR-612 suppresses the stemness of liver cancer via Wnt/β-catenin signaling

Highlights: • miR-612 suppresses tumorsphere and clone formation of HCC cells. • miR-612 reduces drug resistance of HCC cells. • miR-612 suppresses tumorigenesis of HCC in NOD/SCID mice. • miR-612 inhibits an invasive frontier of HCC xenografts. • miR-612 suppresses Wnt/β-catenin signaling. - Abstract: Previous research showed that microRNA-612 (miR-612) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of hepatocellular carcinoma (HCC). AKT2 was confirmed to be a direct target of miR-612, through which the epithelial–mesenchymal transition (EMT) and metastasis of HCC were inhibited. Our present findings reveal that miR-612 is able to suppress the stemness of HCC by reducing the number and size of tumorspheres as well as clone formation in soft agar, and to relieve drug resistance to cisplatin and 5-fluorouracil. In addition, miR-612 hampered the capacity of tumorigenesis in NOD/SCID mice and redistributed the tumor invasive frontier of miR-612-modulating cells. Finally, our findings suggest that Wnt/β-catenin signaling is required in the regulation of EMT-associated stem cell-like traits by miR-612.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Thymosin β4 induces invasion and migration of human colorectal cancer cells through the ILK/AKT/β-catenin signaling pathway

Highlights: • Tβ4 is overexpressed in human colorectal cancer cells. • The overexpression of Tβ4 is correlated with stage of colorectal cancer. • Tβ4 stimulates cell adhesion, invasion, migration and EMT. • Tβ4 activates the ILK/AKT/β-catenin signaling pathway. - Abstract: Thymosin β4 (Tβ4) is a 43-amino-acid peptide involved in many biological processes. However, the precise molecular signaling mechanism(s) of Tβ4 in cell invasion and migration remain unclear. In this study, we show that Tβ4 was significantly overexpressed in colorectal cancer tissues compared to adjacent normal tissues and high levels of Tβ4 were correlated with stage of colorectal cancer, and that Tβ4 expression was associated with morphogenesis and EMT. Tβ4-upregulated cancer cells showed increased adhesion, invasion and migration activity, whereas Tβ4-downregulated cells showed decreased activities. We also demonstrated that Tβ4 interacts with ILK, which promoted the phosphorylation and activation of AKT, the phosphorylation and inactivation of GSK3β, the expression and nuclear localization of β-catenin, and integrin receptor activation. These results suggest that Tβ4 is an important regulator of the ILK/AKT/β-catenin/Integrin signaling cascade to induce cell invasion and migration in colorectal cancer cells, and is a potential target for cancer treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

The role of microRNA-1274a in the tumorigenesis of gastric cancer: Accelerating cancer cell proliferation and migration via directly targeting FOXO4

MicroRNAs (miRNAs) are a series of 18–25 nucleotides length non-coding RNAs, which play critical roles in tumorigenesis. Previous study has shown that microRNA-1274a (miR-1274a) is upregulated in human gastric cancer. However, its role in gastric cancer progression remains poorly understood. Therefore, the current study was aimed to examine the effect of miR-1274a on gastric cancer cells. We found that miR-1274a was overexpressed in gastric cancer tissues or gastric cancer cells including HGC27, MGC803, AGS, and SGC-7901 by qRT-PCR analysis. Transfection of miR-1274a markedly promoted gastric cancer cells proliferation and migration as well as induced epithelial–mesenchymal transition (EMT) of cancer cells. Our further examination identified FOXO4 as a target of miR-1274a, which did not influence FOXO4 mRNA expression but significantly inhibited FOXO4 protein expression. Moreover, miR-1274a overexpression activated PI3K/Akt signaling and upregulated cyclin D1, MMP-2 and MMP-9 expressions. With tumor xenografts in mice models, we also showed that miR-1274a promoted tumorigenesis of gastric cancer in vivo. In all, our study demonstrated that miR-1274a prompted gastric cancer cells growth and migration through dampening FOXO4 expression thus provided a potential target for human gastric cancer therapy. - Highlights: • MiR-1274a expression was augmented in gastric cancer. • MiR-1274a promoted proliferation, migration and induced EMT in cancer cells. • MiR-1274a directly targeted FOXO4 expression. • MiR-1274a triggered PI3K/Akt signaling in cancer cells. • MiR-1274a significantly increased tumor xenografts growth.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Over-expression of TRIM37 promotes cell migration and metastasis in hepatocellular carcinoma by activating Wnt/β-catenin signaling

Hepatocellular carcinoma (HCC) is the most common cancer in the world especially in East Asia and Africa. Advanced stage, metastasis and frequent relapse are responsible for the poor prognosis of HCC. However, the precise mechanisms underlying HCC remained unclear. So it is urgent to identify the pathological processes and relevant molecules of HCC. TRIM37 is an E3 ligase and has been observed deregulated expression in various tumors. Recent studies of TRIM37 have implicated that TRIM37 played critical roles in cell proliferation and other processes. In the present study, we demonstrated that TRIM37 expression was notably up-regulated in HCC samples and was associated with advanced stage and tumor volume, which all indicating the poor outcomes. We also found that TRIM37 could serve as an independent prognostic factor of HCC. During the course of in vitro and in vivo work, we showed that TRIM37 promoted HCC cells migration and metastasis by inducing EMT. Furthermore, we revealed that the effect of TRIM37 mediated EMT in HCC cells was achieved by the activation of Wnt/β-catenin signaling. These finding may provide insight into the understanding of TRIM37 as a novel critical factor of HCC and a candidate target for HCC treatment. - Highlights: • Highly expression of TRIM37 is found in HCC samples compared with nontumorous samples. • TRIM37 expression is correlated with advanced HCC stages and could be an independent prognostic factor. • TRIM37 promotes cell proliferation and metastasis. • We report an E3 ligase TRIM37 affects Wnt/β-catenin signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Del-1 overexpression potentiates lung cancer cell proliferation and invasion

Developmental endothelial locus-1 (Del-1) is an endogenous anti-inflammatory molecule that is highly expressed in the lung and the brain and limits leukocyte migration to these tissues. We previously reported that the expression of Del-1 is positively regulated by p53 in lung endothelial cells. Although several reports have implicated the altered expression of Del-1 gene in cancer patients, little is known about its role in tumor cells. We here investigated the effect of Del-1 on the features of human lung carcinoma cells. Del-1 mRNA was found to be significantly decreased in the human lung adenocarcinoma cell lines A549 (containing wild type of p53), H1299 (null for p53) and EKVX (mutant p53), compared to in human normal lung epithelial BEAS-2B cells and MRC-5 fibroblasts. The decrease of Del-1 expression was dependent on the p53 activity in the cell lines, but not on the expression of p53. Neither treatment with recombinant human Del-1 protein nor the introduction of adenovirus expressing Del-1 altered the expression of the apoptosis regulators BAX, PUMA and Bcl-2. Unexpectedly, the adenovirus-mediated overexpression of Del-1 gene into the lung carcinoma cell lines promoted proliferation and invasion of the lung carcinoma cells, as revealed by BrdU incorporation and transwell invasion assays, respectively. In addition, overexpression of the Del-1 gene enhanced features of epithelial–mesenchymal transition (EMT), such as increasing vimentin while decreasing E-cadherin in A549 cells, and increases in the level of Slug, an EMT-associated transcription regulator. Our findings demonstrated for the first time that there are deleterious effects of high levels of Del-1 in lung carcinoma cells, and suggest that Del-1 may be used as a diagnostic or prognostic marker for cancer progression, and as a novel therapeutic target for lung carcinoma. - Highlights: • Developmental Endothelial Locus-1 (Del-1) expression is downregulated in human lung cancer cells. • Overexpression of the Del-1 gene potentiates proliferation and invasion of lung carcinoma cells. • Del-1 may be used as a diagnostic or prognostic marker for lung cancer progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Activation of IRE1α-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma

Cell proliferation and tumor metastasis are considered as the main reasons for death in colorectal carcinoma (CRC). IRE1α-XBP1 pathway is the most conserved UPR pathways, which are activated during ER stress caused by the accumulation of unfolded or misfolded protein in the lumen of ER. Here, we demonstrated the critical role of IRE1α-XBP1 pathway and underlying molecular mechanism in cell proliferation and tumor metastasis in CRC. By the use of tissue microarray analysis of samples from 119 patients with CRC, IRE1α was determined to be an independent predictor of overall survival as higher expression of IRE1α in CRC patients showed lower survival rates (p = 0.0041). RNA interference and ectopic expression of IRE1α were applied to determine the molecular effects of IRE1α in CRC cells. The silencing of IRE1α inhibited the proliferation and blocked the invasion of CRC cells in vitro, while ectopic expression of IRE1α in turn promoted cell proliferation and invasion. IRE1α-XBP1 pathway regulated the mitosis of CRC cells through the directly binding of XBP1s to Cyclin D1 promoter to activate Cyclin D1 expression. Our results reveal that IRE1α-XBP1 pathway plays an important role in tumor progression and epithelial-to-mesenchymal transition (EMT), and IRE1α could be employed as a novel prognostic marker and a promising therapeutic target for CRC. - Highlights: • IRE1 was determined to be an independent predictor of overall survival in CRC patient. • IRE1-XBP1 pathway promoted CRC cell proliferation through regulating Cyclin D1 expression. • IRE1-XBP1 pathway played important role in EMT of CRC cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Hand1 overexpression inhibits medulloblastoma metastasis

Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current treatment includes surgery, radiation and chemotherapy. However, ongoing treatment in patients is further classified according to the presence or absence of metastasis. Since metastatic medulloblastoma are refractory to current treatments, there is need to identify novel biomarkers that could be used to reduce metastatic potential, and more importantly be targeted therapeutically. Previously, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus. We further demonstrated that uPAR protein act as cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand1. Among the histological subtypes classical and desmoplastic subtypes account for the majority while large cell/anaplastic variant is most commonly associated with metastatic disease. In this present study using immunohistochemical approach and patient data mining for the first time, we demonstrated that Hand1 expression is observed to be downregulated in all the subtypes of medulloblastoma. Previously we showed that Hand1 overexpression regulated medulloblastoma angiogenesis and here we investigated the role of Hand1 in the context of Epithelial-Mesenchymal Transition (EMT). Moreover, UW228 and D283 cells overexpressing Hand1 demonstrated decreased-expression of mesenchymal markers (N-cadherin, β-catenin and SOX2); metastatic marker (SMA); and increased expression of epithelial marker (E-cadherin). Strikingly, human pluripotent stem cell antibody array showed that Hand1 overexpression resulted in substantial decrease in pluripotency markers (Nanog, Oct3/4, Otx2, Flk1) suggesting that Hand1 expression may be essential to attenuate the EMT and our findings underscore a novel role for Hand1 in medulloblastoma metastasis. - Highlights: • Hand1 expression is downregulated in Medulloblastoma. • Hand1 over expression reduce the expression of signaling from WNT, SHH and Group 3 medulloblastoma subgroups. • Hand1 overexpression reduced metastatic abilities by reducing the expression of β-catenin and N-cadherin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

The up-regulation of long non-coding RNA CCAT2 indicates a poor prognosis for prostate cancer and promotes metastasis by affecting epithelial-mesenchymal transition

Recently, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in human cancer biology. LncRNA CCAT2 is a novel identified lncRNA that was previously reported to be up-regulated in different cancers, however, its role in prostate cancer remains unclear. The aim of this study was to investigate the expression and role of lncRNA CCAT2 in prostate cancer. The expression levels of lncRNA CCAT2 in PCa tissues and cell lines (DU145 and 22RV1) were evaluated by quantitative real-time PCR (qRT-PCR), and its association with prognosis of patients was analyzed by statistical analysis. Furthermore, the effect of CCAT2 on proliferation, migration, and invasion was studied in PCa cells. We found that the expression level of CCAT2 was higher in PCa tissues and cells compared to adjacent non-tumor tissues and normal prostate stromal immortalized cells WPMY-1. Kaplan-Meier survival analysis revealed that patients with high CCAT2 expression level had poorer overall survival and progression-free survival than those with low CCAT2 expression. Furthermore, multivariate analysis showed that the status of CCAT2 expression was an independent prognostic indicator for this disease. We also found that knockdown of CCAT2 could inhibit cell growth, migration, and invasion in vitro. In addition, knockdown of CCAT2 stimulated epithelial-mesenchymal transition (EMT) through abrogating N-cadherin, vimentin expression and intensifing the expression levels of E-cadherin. In conclusion, our data suggested that lncRNA CCAT2 was a novel molecule involved in PCa progression, which provided a potential prognostic biomarker and therapeutic target for new therapies in patients with prostate cancer. - Highlights: • LncRNA CCAT2 is identified with overexpression in prostate cancer tissues and cell lines. • High expression of lncRNA CCAT2 can be an independent prognostic factor for overall survival and progression-free survival. • Knockdown of lncRNA CCAT2 can inhibit cell growth, migration, and invasion in vitro study. • Knockdown of lncRNA CCAT2 stimulates metastasis of prostate cancer cell through regulating EMT-associated gene expression including N-cadherin, Vimentin and E-cadherin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

miR-1236-3p suppresses the migration and invasion by targeting KLF8 in lung adenocarcinoma A549 cells

MicroRNAs (miRNAs) have a great effect on regulating tumor cell migration, invasion, proliferation and prognosis. However, the mechanism of miR-1236-3p on regulating carcinogenesis is still unknown. In this study, the expression of miR-1236-3p was lower in lung adenocarcinoma tissues than that in adjacent normal tissue. In lung adenocarcinoma A549 cell line, miR-1236-3p decreased ability of cell invasion and migration, furthermore, we show that KLF8 is targeted by miR-1236-3p, and expression of miR-1236-3p is negatively correlated with KLF8. Additionally, miR-1236-3p suppressed the expression of KLF8 and EMT (epithelial mesenchymal transition)-related genes. Overexpression of KLF8 can promote EMT-related genes at protein level. In conclusion, our results support the fact that miR-1236-3p acts as a tumor inhibitor in lung adenocarcinoma by suppressing the activity of KLF8, and it may play a critical role in the diagnosis and treatment of lung cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3

Highlights: • The expression patterns and prognostic roles of VEGFR2 and PD-L1 in osteosarcoma are investigated. • Apatinib reduces the migration and invasion of osteosarcoma cells in vitro and in vivo. • Apatinib suppresses EMT and PD-L1 expression in osteosarcoma cells in vitro and in vivo. The cure rate of osteosarcoma has not improved in the past 30 years. The new treatments and drugs is urgently needed, especially for metastatic osteosarcoma. Anti-angiogenesis therapy and immunotherapy has got promising anti-tumor effects in various tumors. It is hypothesised that combining checkpoint inhibitor immunotherapies with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. However, its underlying mechanism remain largely uninvestigated. To investigate the clinical significance of vascular endothelial growth factor receptor-2 (VEGFR2) and programmed death ligand-1 (PD-L1) in osteosarcoma, we analyzes their expression levels in 93 osteosarcoma specimens by immunohistochemistry. Meanwhile, we analyzes their correlation with the metastatic behavior and overall survival (OS). We also investigate the effects of Apatinib on migration and invasion of osteosarcoma cells and its underlying mechanism in vitro and in vivo. In our study, the positive rates of the VEGFR2 and PD-L1 expression are 64.5% (60/93) and 35.5% (33/93), respectively. A significant correlation is detected between VEGFR2 and PD-L1 expression (P = 0.009). Receiver-operating characteristic (ROC) curves analysis indicates the predictive value of the two markers in tumor metastasis, and both PD-L1 and VEGFR2 are negatively correlated with OS. Transwell assays reveals that VEGFR2 inhibition attenuates migration and invasion of osteosarcoma cells. Mechanistically, we demonstrate that Apatinib attenuates migration and invasion by suppressing epithelial-mesenchymal transition (EMT) and inactivating STAT3. Additionally, Apatinib reduces PD-L1 expression in osteosarcoma cells. Apatinib markedly weakens pulmonary metastatic potential of osteosarcoma in vivo. In conclusion, our study reveals a pro-metastatic functional mechanism for VEGFR2 in osteosarcoma. Furthermore, we demonstrate that Apatinib exerts anti-tumor effect not only through antiangiogenic effect, but also via suppressing immune escape, which may represent a potential therapeutic target for metastatic osteosarcoma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

NK cell and IFN signatures are positive prognostic biomarkers for resectable pancreatic cancer

Highlights: • Integrative immunomonitoring was undertaken in resected pancreatic cancer patients. • Immunomonitoring employed flow cytometry, multiplex-bead assays and RMA-Seq. • Higher NK cell % in peripheral blood are associated with better prognosis. • Type I and II IFN signatures in the tumor are associated with better prognosis. • Epithelial mesenchymal transition is associated with early recurrence. To establish prognostic biomarkers and to identify potential novel therapeutic targets, we performed integrative immunomonitoring of blood and tumor in patients with resectable pancreatic cancer. Flow cytometry (FC) was employed for phenotyping immune cells, multiplex bead assays for plasma cytokine and chemokine determination, and RNA-Seq for the analysis of gene expression in the tumor. Nineteen pancreatic cancer patients were stratified into those with longer or shorter than median recurrence-free survival after surgery (median, 426 days). There were no significant differences between the two groups for clinical parameters including age, sex, surgical procedure, stage, or postoperative adjuvant therapy. However, we found that the percentages of NK cells as assessed by FC in peripheral blood mononuclear cells were higher in patients with late recurrence (P = .037). RNA-Seq data indicated no differences in the amount of immune cells or stromal cells between the two groups, although NK cells in the tumor did tend to be higher in patients with late recurrence (P = .058). Type I and II IFN signatures were enriched in late-recurring tumors (FDR q-value <0.001), while genes related to KRAS signaling and the epithelial mesenchymal transition (EMT) were enriched in early recurrence. We conclude that tumor-intrinsic properties of metastasis and recurrence influence prognosis, whereas NK cells that might contribute to prevent metastasis are associated with longer recurrence-free survival. Therefore, enhancement of NK cell activity and inhibition of the EMT and KRAS signaling might represent appropriate therapeutic targets following surgical resection of pancreatic cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long noncoding RNA LNC473 inhibits the ubiquitination of survivin via association with USP9X and enhances cell proliferation and invasion in hepatocellular carcinoma cells

Highlights: • LNC473 was overexpressed in HCC tissues and correlated with tumor size, BCLC stage, vascular invasion and poor prognosis. • LNC473 enhanced HCC cell proliferation and invasion and induced epithelial–mesenchymal transition (EMT) process. • LNC473 associated with oncoprotein survivin and regulates its stability. • LNC473 recruited USP9X to inhibit survivin ubiquitination and then increase its expression. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Recent studies reported that lncRNA LINC00473 (LNC473) was involved in cancer progression. However, the clinical significance and functional role of LNC473 in HCC progression is still unknown. In the present study, we found that the LNC473 expression was markedly elevated in HCC tissues and correlated with bigger tumor size, higher BCLC stage, vascular invasion and poor prognosis. Gain- and loss-of-function assay showed that LNC473 enhanced HCC cell proliferation and invasion and induced epithelial–mesenchymal transition (EMT) process. Mechanistically, LNC473 associated with oncoprotein survivin and regulates its stability. Moreover, LNC473 could recruit deubiquitinase USP9X to inhibit the ubiquitination level of survivin and then increase survivin expression. Therefore, our results suggest that LNC473 exerts its functions as an oncogene in HCC progression and may be a therapeutic target for HCC treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TGF beta inhibits expression of SP-A, SP-B, SP-C, but not SP-D in human alveolar type II cells

Highlights: • TGF beta inhibits expression of SP-A, SP-B, SP-C, Fatty acid synthase, and ABCA3. • TGF beta does not inhibit the expression of SP-D. • TGF beta does not induce EMT changes in highly differentiated type II cells. TGF beta is a multifunctional cytokine that regulates alveolar epithelial cells as well as immune cells and fibroblasts. TGF beta inhibits surfactant protein A, B and C expression in fetal human lung and can inhibit type II cell proliferation induced by FGF7 (KGF). However, little is known about direct effects of TGF beta on adult human type II cells. We cultured alveolar type II cells under air/liquid interface conditions to maintain their state of differentiation with or without TGF beta. TGF beta markedly decreased expression of SP-A, SP-B, SP-C, fatty acid synthase, and the phospholipid transporter ABCA3. However, TGF beta increased protein levels of SP-D with little change in mRNA levels, indicating that it is regulated independently from other components of surfactant. TGF beta is a negative regulator of both the protein and the phospholipid components of surfactant. TGF beta did not induce EMT changes in highly differentiated human type II cells. SP-D is an important host defense molecule and regulated independently from the other surfactant proteins. Taken together these data are the first report of the effect of TGF beta on highly differentiated adult human type II cells. The effects on the surfactant system are likely important in the development of fibrotic lung diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Knockout of NCOA5 impairs proliferation and migration of hepatocellular carcinoma cells by suppressing epithelial-to-mesenchymal transition

Highlights: • Generation of NCOA5-knockout HCC cell lines using CRISPR/Cas9. • Knockout of NCOA5 inhibits the proliferation and migration of HCC cells. • Knockout of NCOA5 depresses the tumor microsphere formation of HCC cells. • Knockout of NCOA5 suppresses EMT. Nuclear receptor coactivator 5 (NCOA5) plays important roles in the development of a variety of malignancies. However, the underlying mechanisms remain obscure. In this study, we successfully generated the NCOA5 knockout hepatocellular carcinoma (HCC) cells by CRISPR/Cas9 - mediated genome editing and found that knockout of NCOA5 inhibited the proliferation and tumor microsphere formation of HCC cells significantly. Moreover, the migration ability of NCOA5 knockout HCC cells declined. Mechanistic analyses indicated that knockout of NCOA5 can suppress the epithelial - mesenchymal transition (EMT) in HCC cells. In conclusion, our findings provide a mechanistic insight into the role of NCOA5 in HCC progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MiR-455-3p suppresses renal fibrosis through repression of ROCK2 expression in diabetic nephropathy

Highlights: • Downregulation of miR-455-3p expression in DN. • ROCK2 as a target of miR-455-3p. • Re-introduction of ROCK2 attenuated the effect of miR-455-3p on cell proliferation, ECM accumulation and EMT in vitro. • Reductions in proinflammatory levels and renal fibrosis by miR-455-3p usages, in vivo. Emerging evidence has shown that microRNAs (miRNAs) play a mediatory role in the pathogenesis of diabetic nephropathy (DN), but the function of the involved miRNAs is still incomplete. Here, we found that miR-455-3p was down-regulated in the human mesangial cells (HMC) and human proximal tubule epithelial cells (HK-2) stimulated with high glucose (HG) or transforming growth factor beta 1 (TGF-β1). Rho-associated coiled coil-containing protein kinase 2 (ROCK2) was identified as a directed target of miR-455-3p. Overexpression of ROCK2 significantly attenuated the inhibitory effects of miR-455-3p on cell proliferation, extracellular matrix (ECM) synthesis and epithelial-mesenchymal transition (EMT) in HG-treated cells. Furthermore, the DN model was prepared by using high-fat feeding combined with Streptozotocin (STZ) induced rats, and the DN group was treated by injecting miR-455-3p agomir. The results of periodic acid-Schiff (PAS) and Masson staining showed that miR-455-3p overexpression improved the pathological changes of glomerular hypertrophy, mesangial amplification, and renal fibrosis. Additionally, miR-455-3p overexpression decreased ROCK2, proliferating cell nuclear antigen (PCNA) and Collagen I levels, and also reduced inflammatory cytokines TNF-α, MCP-1 and IL-1β levels in vivo. Altogether, these results suggest that miR-455-3p plays an essential role in the treatment of renal fibrosis through repressing ROCK2 expression; and miR-455-3p might be an effective therapy for DN.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

SALL4 suppresses reactive oxygen species in pancreatic ductal adenocarcinoma phenotype via FoxM1/Prx III axis

Highlights: • SALL4 promotes stemness traits and metastatic phenotype in vitro. • SALL4 expression positively impacts PDAC-derived tumor growth. • SALL4 regulates intracellular ROS via FoxM1/Prx III by activation of ERK1/2. Pancreatic ductal adenocarcinoma (PDAC) is a major malignant phenotype in pancreatic cancer, which is one of the most death causes by cancer in the world. PDAC developed from pancreatic intra-epithelial neoplasms (PanINs) and poorly diagnosed at early stages. Beside of high drug resistance, metastasis is the great concern during pancreatic cancer treatment. SALL4 expression is inherent in the upregulations of endothelial mesenchymal transition (EMT) genes and therefore promoting cancer metastasis. Furthermore, some of evidences indicated reactive oxygen species (ROS) is also influent to metastasis and self-antioxidant capacity seems a gold standard for successful metastasis rate. In this study, we have found the role Spalt like protein 4 (SALL4) to PDAC proliferation, mobility and its regulation to mitochondrial ROS via FoxM1/Prx III axis. It is possible that SALL4 mainly induces endothelial-mesenchymal transition (EMT) phenotype and favors ROS loss to facilitate metastasis efficiency in PDAC cells. Therefore, SALL4 might be a promising marker for PDAC treatment and targeting SALL4 would benefit anti-proliferative and anti-metastasis therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Rab3IP interacts with SSX2 and enhances the invasiveness of gastric cancer cells

RAB3A interacting protein (Rab3IP) has been determined to be involved in cancer progression; however, its expression pattern and function in gastric cancer remain unknown. The aim of this study was to determine the association between Rab3IP and gastric cancer, in addition to its functional role in this disease. Overexpression of Rab3IP in gastric cancer was verified at both transcriptional and translational levels. Analysis of clinical data indicated its role as an independent risk factor for survival. Cellular studies showed that Rab3IP could induce an aggressive phenotype in gastric cancer cells and that its expression was correlated with markers of the epithelial-mesenchymal transition (EMT). In addition, we verified the co-expression of and interplay between Rab3IP and SSX2 during gastric cancer progression. Thus, these findings elucidated the central role of Rab3IP in inducing an invasive phenotype in gastric cancer cells, in addition to its involvement in EMT. Our results could be exploited for the clinical prognosis and treatment of this important disease.

60 APPLIED LIFE SCIENCES↗