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At least 145 records · Page 8

All sources NASA NTRS DOE OSTI

DOE OSTI2017

MicroRNA-144-3p suppresses gastric cancer progression by inhibiting epithelial-to-mesenchymal transition through targeting PBX3

MicroRNAs are aberrantly expressed in a wide variety of human cancers. The present study aims to elucidate the effects and molecular mechanisms of miR-144-3p that underlie gastric cancer (GC) development. It was observed that miR-144-3p expression was significantly decreased in GC tissues compared to that in paired non-tumor tissues; moreover, its expression was lower in tissues of advanced stage and larger tumor size, as well as in lymph node metastasis tissues compared to that in control groups. miR-144-3p expression was associated with depth of invasion (P = 0.030), tumor size (P = 0.047), lymph node metastasis (P = 0.047), and TNM stage (P = 0.048). Additionally, miR-144-3p significantly inhibited proliferation, migration, and invasion in GC cells. It also reduced F-actin expression and suppressed epithelial-to-mesenchymal transition (EMT) in GC cells. Furthermore, pre-leukemia transcription factor 3 (PBX3) was a direct target gene of miR-144-3p. PBX3 was overexpressed in GC tissues and promoted EMT in GC cells. The effects of miR-144-3p mimics or inhibitors on cell migration, invasion, and proliferation were reversed by PBX3 overexpression or downregulation respectively. These results suggest that miR-144-3p suppresses GC progression by inhibiting EMT through targeting PBX3. - Highlights: • miR-144-3p is downregulated in gastric cancer tissues and associated with malignant clinical factors. • miR-144-3p inhibits proliferation, migration, and invasion in gastric cancer cells. • PBX3 is a direct target of miR-144-3p and promotes EMT in gastric cancer. • miR-144-3p suppresses EMT in gastric cancer by regulating PBX3.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

GSK3β attenuates TGF-β1 induced epithelial–mesenchymal transition and metabolic alterations in ARPE-19 cells

While TGF-β1 is known to induce epithelial–mesenchymal transition (EMT), a major factor in the pathogenesis of proliferative vitreoretinopathy (PVR), in ARPE-19 cells. The molecular pathways involved in EMT formation have not yet to be fully characterized. In this study, we have found that TGF-β1-mediated induction of EMT in ARPE-19 cells varied in a dose- and time-dependent manner. Specifically, TGF-β1 inhibited GSK-3β by accelerating phosphorylation at ser9. GSK-3β inhibitor or knockdown of GSK-3β resulted in enhanced TGF-β1-mediated EMT, migration and collagen contraction in ARPE-19 cells, which were then abrogated by GSK-3β overexpression and PI3K/AKT inhibitor. Importantly, GSK-3β also mediated metabolic reprogramming in TGF-β1-treated cells. Our results indicate that GSK-3β plays a pivotal role in TGF-β1-mediated EMT in ARPE-19 cells. - Highlights: • GSK-3β mediates epithelial-mesenchymal transition in TGF-β1 treated ARPE-19 cells. • GSK-3β regulates cell migration and collagen contraction of ARPE-19 cells. • TGF-β1 induces extracellular metabolomic changes of ARPE-19 cells via a GSK-3β-dependent mechanism.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Alpha B-crystallin promotes the invasion and metastasis of colorectal cancer via epithelial-mesenchymal transition

Alpha B-crystallin (CRYAB, HSPB5) is a protein that was first discovered in the lens of the eye. It is a member of the small heat-shock protein family (sHsps). CRYAB functions primarily as a molecular chaperone to prevent the aggregation and degradation of damaged unfolded proteins due to cellular damage resulting from heat shock, radiation, oxidative stress, and other insults, thereby promoting cell survival and preventing apoptosis. In recent years, the role of CRYAB in tumorigenesis, tumor invasion, and metastasis has received increasing attention. CRYAB is highly expressed in a variety of cancers, including breast cancer, head and neck cancer, and kidney cancer, and is likely associated with the prognosis of cancer. However, few studies have examined CRYAB in colorectal cancer (CRC). To study the effect of CRYAB on CRC, we transfected the CRC cell line SW480, which expresses high levels of CRYAB, with a lentiviral vector that inhibits CRYAB expression. The messenger RNA (mRNA) and protein expression of CRYAB was examined in the transfected SW480 cells (Si-CRYAB) using quantitative real-time polymerase chain reaction (qPCR) and Western blotting (WB) assays. Moreover, a growth curve was plotted to examine the proliferation of Si-CRYAB cells, and transwell assays were used to examine the migration of Si-CRYAB cells. Apoptosis and the cell cycle were examined in Si-CRYAB cells using flow cytometry (FCM), and the tumorigenic capability of Si-CRYAB cells was assessed in a nude mouse tumor model. Immunohistochemistry (IHC) was employed to examine CRYAB protein expression and the markers of epithelial-mesenchymal transition (EMT), such as E-cadherin, fibronectin, vimentin, and slug, in tumor tissues from nude mice and clinical invasive CRC and hepatic metastasis specimens. The qPCR and WB results showed that CRYAB was downregulated at the protein and mRNA level in Si-CRYAB cells, and the growth curve indicated that the proliferation of Si-CRYAB cells was reduced. Moreover, Si-CRYAB cells exhibited reduced migration capability in the transwell assay as well as increased apoptosis and G1 arrest in the FCM assay. The tumorigenesis study in nude mice showed that Si-CRYAB cells formed smaller tumors, indicating decreased tumorigenic capability. IHC results showed reduced CRYAB expression and lower levels of EMT in Si-CRYAB cells, whereas clinical specimens of invasive CRC and hepatic metastases exhibited elevated CRYAB expression and enhanced levels of EMT. These results demonstrated that CRYAB promoted the invasion and metastasis of CRC tumor cells via EMT. - Highlights: • The CRC cell line SW480 experssed high levels of CRYAB. • Inhibition of CRYAB induced apoptosis and G1 arrest. • Inhibition of CRYAB exhibited decreased migration and tumorigenesis in nude mice. • CRYAB promoted CRC invasion and metastasis probably via EMT.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

The role of XBP1s in the metastasis and prognosis of hepatocellular carcinoma

Highlights: • The expression of XBP1s in HCC cell lines and tissue samplesis associated with poor prognosis. • XBP1s enhances the invasive and metastatic potential of HCC cells. • XBP1s promotes epithelial-mesenchymal transition in hepatocellular carcinoma. • XBP1s regulates EMT in HCC cells via Twist/Snail pathway. Tumor metastasis and recurrence are the primary contributors to poor prognosis in patients with hepatocellular carcinoma (HCC). The epithelial-mesenchymal transition (EMT) of tumor cells is the predominant mechanism of HCC progression. XBP1s is a newly discovered molecule involved in the endoplasmic reticulum (ER) stressresponse, which is an adaptive response and defense mechanism in cells that enablessurvival under adverse conditions. Abnormally high XBP1sexpression has been found in tumor cells, but the role of XBP1sin HCC progression remains unclear. We found that the expression of XBP1s in HCC cell lines and tissuesamples was higher than that in control cells and tissuesamples. Clinicopathological analysis showed that the expression of XBP1s was closely correlated with distant metastasis and poor prognosis in HCC. In vivo and invitro experiments confirmed that the overexpression of XBP1s promoted EMT and metastasis in HCC cells. XBP1ssilencing attenuated cellular migration and development of the EMT phenotypein vitro. Through further study to elucidate the molecular mechanism underlying the promotion ofEMT by XBP1s in HCC cells, we confirmed that XBP1s could mediate the expression of Twist. In HCC cells, XBP1s enhanced the expression of Twist and Snail, resulting in a subsequent reduction in the expression of E-cadherin, a contributor to cell-cell adhesion. Overall, this study reveals a novel XBP1s/Twist/Snail axis that mediates EMT in HCC cells and the invasion and metastasis of HCC.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

Disruption of canonical TGFβ-signaling in murine coronary progenitor cells by low level arsenic

Exposure to arsenic results in several types of cancers as well as heart disease. A major contributor to ischemic heart pathologies is coronary artery disease, however the influences by environmental arsenic in this disease process are not known. Similarly, the impact of toxicants on blood vessel formation and function during development has not been studied. During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types including smooth muscle cells which contribute to the coronary vessels. The TGFβ family of ligands and receptors is essential for developmental cardiac epithelial to mesenchymal transition (EMT) and differentiation into coronary smooth muscle cells. In this in vitro study, 18 hour exposure to 1.34 μM arsenite disrupted developmental EMT programming in murine epicardial cells causing a deficit in cardiac mesenchyme. The expression of EMT genes including TGFβ2, TGFβ receptor-3, Snail, and Has-2 are decreased in a dose-dependent manner following exposure to arsenite. TGFβ2 cell signaling is abrogated as detected by decreases in phosphorylated Smad2/3 when cells are exposed to 1.34 μM arsenite. There is also loss of nuclear accumulation pSmad due to arsenite exposure. These observations coincide with a decrease in vimentin positive mesenchymal cells invading three-dimensional collagen gels. However, arsenite does not block TGFβ2 mediated smooth muscle cell differentiation by epicardial cells. Overall these results show that arsenic exposure blocks developmental EMT gene programming in murine coronary progenitor cells by disrupting TGFβ2 signals and Smad activation, and that smooth muscle cell differentiation is refractory to this arsenic toxicity. - Highlights: • Arsenic blocks TGFβ2 induced expression of EMT genes. • Arsenic blocks TGFβ2 triggered Smad2/3 phosphorylation and nuclear translocation. • Arsenic blocks epicardial cell differentiation into cardiac mesenchyme. • Arsenic does not block TGFβ2 induced smooth muscle cell differentiation.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Epithelial-mesenchymal transition and cancer stem cells, mediated by a long non-coding RNA, HOTAIR, are involved in cell malignant transformation induced by cigarette smoke extract

The incidence of lung diseases, including cancer, caused by cigarette smoke is increasing, but the molecular mechanisms of gene regulation induced by cigarette smoke remain unclear. This report describes a long noncoding RNA (lncRNA) that is induced by cigarette smoke extract (CSE) and experiments utilizing lncRNAs to integrate inflammation with the epithelial-mesenchymal transition (EMT) in human bronchial epithelial (HBE) cells. The present study shows that, induced by CSE, IL-6, a pro-inflammatory cytokine, leads to activation of STAT3, a transcription activator. A ChIP assay determined that the interaction of STAT3 with the promoter regions of HOX transcript antisense RNA (HOTAIR) increased levels of HOTAIR. Blocking of IL-6 with anti-IL-6 antibody, decreasing STAT3, and inhibiting STAT3 activation reduced HOTAIR expression. Moreover, for HBE cells cultured in the presence of HOTAIR siRNA for 24 h, the CSE-induced EMT, formation of cancer stem cells (CSCs), and malignant transformation were reversed. Thus, IL-6, acting on STAT3 signaling, which up-regulates HOTAIR in an autocrine manner, contributes to the EMT and to CSCs induced by CSE. These data define a link between inflammation and EMT, processes involved in the malignant transformation of cells caused by CSE. This link, mediated through lncRNAs, establishes a mechanism for CSE-induced lung carcinogenesis. - Highlights: • STAT3 directly regulates the levels of LncRNA HOTAIR. • LncRNA HOTAIR mediates the link between inflammation and EMT. • LncRNA HOTAIR is involved in the malignant transformation of cells caused by CSE.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Augmenter of liver regeneration inhibits TGF-β1-induced renal tubular epithelial-to-mesenchymal transition via suppressing TβR II expression in vitro

Tubular epithelial-to-mesenchymal transition (EMT) plays a crucial role in the progression of renal tubular interstitial fibrosis (TIF), which subsequently leads to chronic kidney disease (CKD) and eventually, end-stage renal disease (ESRD). We propose that augmenter of liver regeneration (ALR), a member of the newly discovered ALR/Erv1 protein family shown to ameliorate hepatic fibrosis, plays a similar protective role in renal tubular cells and has potential as a new treatment option for CKD. Here, we showed that recombinant human ALR (rhALR) inhibits EMT in renal tubular cells by antagonizing activation of the transforming growth factor-β1 (TGF-β1) signaling pathway. Further investigation revealed that rhALR suppresses the expression of TGF-β receptor type II (TβR II) and significantly alleviates TGF-β1-induced phosphorylation of Smad2 and nuclear factor-κB (NF-κB). No apparent adverse effects were observed upon the addition of rhALR alone to cells. These findings collectively suggest that ALR plays a role in inhibiting progression of renal tubular EMT, supporting its potential utility as an effective antifibrotic strategy to reverse TIF in CKD. - Highlights: • ALR is involved in the pathological progression of renal EMT in NRK-52E cells. • ALR suppresses the expression of TβRII and the phosphorylation of Smad2 and NF-κB. • ALR plays a role in inhibiting progression of renal tubular EMT.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

High YBX1 expression indicates poor prognosis and promotes cell migration and invasion in nasopharyngeal carcinoma

Highlights: • YBX1 overexpressed in cytoplasmic of nasopharyngeal carcinoma cells. • YBX1 expression associated with the EMT process in nasopharyngeal carcinoma. • TGF-β1 induced YBX1 expression in NPC cell lines. • TGF-β1/YBX1 signaling mediated the EMT process in NPC cell lines. Y-box binding protein-1 (YBX1) is a multifunctional protein and often acts as an indicator of poor prognosis in cancers. Increasing evidence has shown that the levels of YBX1 protein were closely associated with multidrug resistance, relapse, metastasis and poor prognosis in cancers. However, its role in nasopharyngeal carcinoma (NPC) metastasis remains unknown. In our study, we discovered that the expression of YBX1 was increased in nasopharyngeal carcinoma tissues. YBX1 protein levels positively correlated with T stage and metastasis of NPC patients. Moreover, expression of YBX1 was negatively correlated with membrane E-cadherin levels and positively correlated with Vimentin expression. In vitro, the expression of YBX1 was closely related to the invasive and migratory ability of nasopharyngeal carcinoma cells. Knockdown of YBX1 inhibited migration and invasion in 5–8 F cells, and over-expression of YBX1 promoted CNE1 cells migration and invasion. Transforming growth factor-β1 (TGF-β1) treatment led to epithelial-to-mesenchymal transition (EMT) in CNE1 cells accompanied by elevated YBX1 expression. On the contrary, knockdown of YBX1 partially inhibited the TGF-β1-induced CNE1 cell migration, together with changes of EMT-associated markers. Our study revealed that TGF-β1/YBX1 signaling might be one of novel mechanisms mediating EMT in NPC, providing a new target for the treatment of nasopharyngeal carcinoma.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Roles of genetic and microenvironmental factors in cancer epithelial-to-mesenchymal transition and therapeutic implication

Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells lose their cell-cell contacts resulting in the formation of mesenchymal cells with migratory properties. Increasing evidence indicate EMT plays a key role in the invasion, metastasis and therapeutic resistance of cancer and maintenance of the phenotype of cancer stem cells (CSCs), which makes the prognosis of patients worse. The progression of cancer from epithelial tissue towards a malignant phenotype is driven by multiple factors that remodel the tissue architecture. This review summarizes and analyzes current studies of genetic and microenvironmental factors in inducing and maintaining cancer EMT and therapeutic implications. This will enable a better understanding of the contribution of EMT-associated factors to cancer progression and highlights that genetic factors and tumor microenvironment responsible for EMT could be used as attractive targets for therapeutic intervention.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Cell transdifferentiation in ocular disease: Potential role for connexin channels

Highlights: • Cell transdifferentiation including EMT and EndMT is a pathological process in a number of ocular diseases. • Gap junction channels and connexin hemichannels play a role in cell transdifferentiation in ocular diseases. • Connexin-blocking therapies demonstrate efficacy in ocular disease models. • Future studies could explore connexin-based therapies for prevention and treatment of pathological transdifferentiation. Cell transdifferentiation is the conversion of a cell type to another without requiring passage through a pluripotent cell state, and encompasses epithelial- and endothelial-mesenchymal transition (EMT and EndMT). EMT and EndMT are well defined processes characterized by a loss of epithelial/endothelial phenotype and gain in mesenchymal spindle shaped morphology, which results in increased cell migration and decreased apoptosis and cellular senescence. Such cells often develop invasive properties. Physiologically, these processes may occur during embryonic development and can resurface, for example, to promote wound healing in later life. However, they can also be a pathological process. In the eye, EMT, EndMT and cell transdifferentiation have all been implicated in development, homeostasis, and multiple diseases affecting different parts of the eye. Connexins, constituents of connexin hemichannels and intercellular gap junctions, have been implicated in many of these processes. In this review, we firstly provide an overview of the molecular mechanisms induced by transdifferentiation (including EMT and EndMT) and its involvement in eye diseases. We then review the literature for the role of connexins in transdifferentiation in the eye and eye diseases. The evidence presented in this review supports the need for more studies into the therapeutic potential for connexin modulators in prevention and treatment of transdifferentiation related eye diseases, but does indicate that connexin channel modulation may be an upstream and unifying approach for regulating these otherwise complex processes.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Electromagnetic interference shielding effectiveness of polypropylene/conducting fiber composites

Electromagnetic released from the automotive electronic parts is harmful to human body. Electromagnetic interference (EMT) shielding refers to the reflection and/or adsorption of electromagnetic radiation by a material, which thereby acts as a shield against the penetration of the radiation through the shield. Polypropylene (PP)/conductive micro fiber composites containing various fiber contents and fiber length were injection-molded. The effect of fiber content and length on electrical properties of the composites was studied by electrical resistivity and EMT shielding measurements. The through-plane electrical conductivity and dielectric permittivity were obtained by measuring dielectric properties. The EMT shielding effectiveness (SE) was investigated by using S-parameter in the range of 100 ~ 1500 MHz. Reflection, absorption and multiple-reflection are the EMT attenuation mechanisms. From the measurement of S-Parameters, the absorption coefficient, reflection coefficient, and the shielding efficiency of the materials were calculated. The EMT SE of PP/conducing fiber composites is 40 dB over a wide frequency range up to 1.5 GHz, which is higher than that of PP/talc composite used automotive parts, viz. 0 dB.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

DOE OSTI2024

Sparse Linear Solvers for Large-scale Electromagnetic Transient Simulations

Linear solvers form the basis for electromagnetic transient (EMT) simulations. There is a need to speed up EMT simulations as larger regions are analyzed using EMT simulations. For the same, the performance of linear solvers plays an important role. Exploiting the sparsity of the matrices generated in EMT simulations could assist with speed-up. Scalability is also crucial as power grids expand, demanding solutions capable of accommodating the increasing system size. Recent studies from the North American Electric Reliability Corporation (NERC) increasingly emphasize that EMT simulation models of the power grid will grow larger with the inclusion of power electronics components. Parallelisms in sparsity patterns exploit modern central processing units (CPUs), multi-core CPUs, and graphics processing units (GPUs) architectures in sparse solver designs. Therefore, this paper explores publicly available existing linear solvers and investigates their efficiency in large-scale power grid simulations. A large-scale power grid is developed by increasing the size of the IEEE 39 bus test system to up to 39000 bus systems.

Hsu, Kuan-Chieh↗

DOE OSTI2025

Linear Solver for Electromagnetic Simulation of General Distribution Feeders

High-fidelity electromagnetic transient (EMT) modeling is required for accurate simulation and analysis of power system dynamics in modern distribution feeders. However, the high-fidelity of EMT models often leads to significant computational challenges, particularly in terms of computational resources and simulation time. This paper investigates the development and application of a detailed EMT model for general distribution feeders, with a focus on improving computational efficiency. A direct linear solver is proposed for a bordered block diagonal (BBD) matrix structure commonly encountered in a EMT model of distribution feeders. The solver integrates the Schur complement method with the block tridiagonal matrix algorithm to enhance the computational performance. The proposed solver is validated using the primary feeder of the IEEE 342-node test system, demonstrating its accuracy and efficiency in EMT simulations. Furthermore, the solver’s performance is benchmarked against MATLAB’s built-in linear solvers, showing significant improvements in computation time while maintaining high fidelity and accuracy in simulation results.

Choi, Jongchan [ORNL] (ORCID:000000025952455X)↗

DOE OSTI2018

Downregulation of HOXA13 sensitizes human esophageal squamous cell carcinoma to chemotherapy

Background Chemoresistance often develops in esophageal squamous cell carcinoma (ESCC), leading to poor prognosis. HOX genes play a crucial role in embryonic development and cell differentiation. Studies have recently linked HOX with chemoresistance, thus we explored whether HOXA13 is involved in ESCC chemoresistance. Methods One hundred thirty‐one ESCC patients who received neoadjuvant chemotherapy were enrolled. HOXA13 expression was examined by immunohistochemistry. RNA interference was used to knock down the HOXA13 expression in KYSE70 and transfected HOXA13 plasmid to overexpress HOXA13 in KYSE510 cells. We examined half‐maximal inhibitory concentration of cisplatin, apoptosis, and epithelial‐to‐mesenchymal transition (EMT) in ESCC cell lines with different HOXA13 expression levels by cell counting kit‐8, flow cytometry, and transwell analysis. Results The median survival of patients with high HOXA13 expression was significantly shorter than those with low expression ( P = 0.027). HOXA13 was associated with worse tumor regression grade ( P = 0.009). Low HOXA13 expressed cells decreased the half‐maximal inhibitory concentration of cisplatin ( P < 0.05), increased cisplatin‐induced apoptosis ( P < 0.05), and decreased EMT ( P < 0.05) compared with high HOXA13 expressed cells. In low HOXA13 expressed cells, cleaved caspase‐3 and cleaved PARP expression induced by cisplatin increased, while expression of E‐cadherin and Snail protein, markers of EMT, was upregulated and downregulated, respectively. EMT decreased in low HOXA13 expressed cells. Conclusion High HOXA13 expression was associated with inferior tumor regression grade and poor overall survival in ESCC patients treated with neoadjuvant chemotherapy. HOXA13 increased cisplatin‐resistance and promoted EMT in ESCC cells.

Shi, Qi↗

DOE OSTI2014

Amyloid precursor protein regulates migration and metalloproteinase gene expression in prostate cancer cells

Highlights: • APP knockdown reduced proliferation and migration of prostate cancer cells. • APP knockdown reduced expression of metalloproteinase and EMT-related genes. • APP overexpression promoted LNCaP cell migration. • APP overexpression increased expression of metalloproteinase and EMT-related genes. - Abstract: Amyloid precursor protein (APP) is a type I transmembrane protein, and one of its processed forms, β-amyloid, is considered to play a central role in the development of Alzheimer’s disease. We previously showed that APP is a primary androgen-responsive gene in prostate cancer and that its increased expression is correlated with poor prognosis for patients with prostate cancer. APP has also been implicated in several human malignancies. Nevertheless, the mechanism underlying the pro-proliferative effects of APP on cancers is still not well-understood. In the present study, we explored a pathophysiological role for APP in prostate cancer cells using siRNA targeting APP (siAPP). The proliferation and migration of LNCaP and DU145 prostate cancer cells were significantly suppressed by siAPP. Differentially expressed genes in siAPP-treated cells compared to control siRNA-treated cells were identified by microarray analysis. Notably, several metalloproteinase genes, such as ADAM10 and ADAM17, and epithelial–mesenchymal transition (EMT)-related genes, such as VIM, and SNAI2, were downregulated in siAPP-treated cells as compared to control cells. The expression of these genes was upregulated in LNCaP cells stably expressing APP when compared with control cells. APP-overexpressing LNCaP cells exhibited enhanced migration in comparison to control cells. These results suggest that APP may contribute to the proliferation and migration of prostate cancer cells by modulating the expression of metalloproteinase and EMT-related genes.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

DNAJC6 promotes hepatocellular carcinoma progression through induction of epithelial–mesenchymal transition

Highlights: • DNAJC6 is up-regulated in hepatocellular carcinoma tissues. • DNAJC6 promotes hepatocellular carcinoma cell proliferation and invasion. • DNAJC6 induces epithelial–mesenchymal transition by activating transforming growth factor β signaling. - Abstract: Epithelial–mesenchymal transition (EMT) is a developmental program, which is associated with hepatocellular carcinoma (HCC) development and progression. DNAJC6 (DNA/HSP40 homolog subfamily C member 6) encodes auxilin, which is responsible for juvenile Parkinsonism with phenotypic variability. However, the role of DNAJC6 in HCC development and progression is limited. Here, we report that DNAJC6 is up-regulated in HCC tissues and up-regulation of DNAJC6 expression predicts poor outcome in patients with HCC. Furthermore, overexpression of DNAJC6 enhances the ability for acquisition of mesenchymal traits, enhanced cell proliferation and invasion. DNAJC6 positively regulated expression of EMT-related transcription factor, also activating transforming growth factor β (TGF-β) pathway to contribute to EMT. Our findings demonstrated an important function of DNAJC6 in the progression of HCC by induction of EMT, and they implicate DNAJC6 as a marker of poor outcome in HCC.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Irradiated fibroblasts promote epithelial–mesenchymal transition and HDGF expression of esophageal squamous cell carcinoma

Recent evidence suggested that nonirradiated cancer-associated fibroblasts (CAFs) promoted aggressive phenotypes of cancer cells through epithelial–mesenchymal transition (EMT). Hepatoma-derived growth factor (HDGF) is a radiosensitive gene of esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the effect of irradiated fibroblasts on EMT and HDGF expression of ESCC. Our study demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of ESCC cells and the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. Scattering of ESCC cells was also accelerated by the supernatant from irradiated fibroblasts. Exposure of ESCC cells to supernatant from irradiated fibroblasts resulted in decreased E-cadherin, increased vimentin in vitro and β-catenin was demonstrated to localize to the nucleus in tumor cells with irradiated fibroblasts in vivo models. The expression of HDGF and β-catenin were increased in both fibroblasts and ESCC cells of irradiated group in vitro and in vivo models. Interestingly, the tumor cells adjoining the stromal fibroblasts displayed strong nuclear HDGF immunoreactivity, which suggested the occurrence of a paracrine effect of fibroblasts on HDGF expression. These data suggested that irradiated fibroblasts promoted invasion, growth, EMT and HDGF expression of ESCC. - Highlights: • Irradiated CAFs accelerated invasiveness and scattering of ESCC cell lines. • Irradiated CAFs promoted EMT of ESCC cells. • Irradiated fibroblasts induced nuclear β-catenin relocalization in ESCC cells. • Irradiated fibroblasts increased HDGF expression in vitro and in vivo.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

EML4-ALK induces epithelial–mesenchymal transition consistent with cancer stem cell properties in H1299 non-small cell lung cancer cells

The echinoderm microtubule-associated protein-like 4(EML4) – anaplastic lymphoma kinase (ALK) fusion gene has been identified as a driver mutation in non-small-cell lung cancer (NSCLC). However, the role of EML4-ALK in malignant transformation is not entirely clear. Here, for the first time, we showed that H1299 NSCLC cells stably expressing EML4-ALK acquire EMT phenotype, associated with enhanced invasive migration and increased expression of EMT-inducing transcription factors. H1299-EML4-ALK cells also displayed cancer stem cell-like properties with a concomitant up-regulation of CD133 and enhanced ability of mammospheres formation. Moreover, we found that inhibition of ERK1/2 reversed EMT induced by EML4-ALK in H1299 cells. Taken together, these results suggested that EML4-ALK induced ERK activation is mechanistically associated with EMT phenotype. Thus, inhibition of ERK signaling pathway could be a potential strategy in treatment of NSCLC patients with EML4-ALK translocation. - Highlights: • EML4-ALK induced epithelial–mesenchymal transition in H1299 cells. • Expression of EML4-ALK promotes invasion and migration in vitro. • EML4-ALK enhanced sphere formation and stem cell-like properties in H1299 cells. • Blockage of ERK1/2 reverse Epithelial–Mesenchymal transition induced by EML4-ALK.

60 APPLIED LIFE SCIENCES↗