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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 1,189 records · Page 66
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Down-regulation of MAP2K1 by miR-539 inhibits hepatocarcinoma progression

Liver cancer has been considered as one of the major leading causes of cancer-related mortality. The incidence of liver cancer tends to increase in less developed regions. Increasing evidences have demonstrated that mircoRNAs (miRNAs) play crucial roles in the modulation of tumor growth and progression. Whereas, the functional role of miR-539 in hepatocellular carcinoma (HCC) is not well established. In our present study, we sought to explore biological role of miR-539 in HCC progression. qRT-PCR was utilized to evaluate the expression level of miR-539. Immunoblotting analysis, qRT-PCR and luciferase reporter assays were used for the identification of the potential target of miR-539. Proliferation, migration and invasion assays and flow cytometric were performed to assess the biological functional role of miR-539. The molecular signaling pathways related to the integration of miR-539 were also evaluated. MiR-539 was reduced in human HCC. Mitogen-activated protein kinase 1, also known as MAP2K1 was verified as the target of miR-539. Overexpression of miR-539 inhibited migration, invasion and cell proliferation, while apoptosis rate was increased. Knockdown or overexpression of MAP2K1 in HCC cell transfected with ag-miR-539 or in-miR-539 indicated that miR-539 suppresses the progression of HCC by directly targeting and regulating MAP2K1. Our results reveal that miR-539 might be a tumor suppressor in HCC, supporting a potential target for advanced therapeutic strategy for this disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long noncoding RNA LINC00339 aggravates doxorubicin-induced cardiomyocyte apoptosis by targeting MiR-484

Highlights: • LncRNA LINC00339 was highly expressed in DOX stimulated primary rat cardiomyocytes and H9c2 cells. • Knockdown of LINC00339 significantly reduced primary rat cardiomyocytes and H9c2 cells proliferation and apoptosis. • LINC00339 acts as a critical pro-apoptosis lncRNA that aggravates DOX-induced cardiac remodeling by miR-484. Abnormally expressed long noncoding RNAs (lncRNAs) has been recognized as one of the key source in cardiac diseases. However, the role of lncRNA in doxorubicin (DOX)-induced cardiotoxicity remains largely unknown. In previous studies, we have screened some aberrantly expressed lncRNAs from an animal model for DOX-induced cardiotoxicity, and LINC00339 is one of the highly expressed lncRNA. In this study, we validated and further explored its regulatory mechanisms using in vitro model systems. Primary cultured myocardial cell (PC) and H9C2 cell line were treated with different concentrations of DOX and the expression of LINC00339 were markedly up-regulated. However, knockdown of endogenous LINC00339 by its siRNA improved cells proliferation activity and reduced cardiomyocyte apoptosis. Further experiments showed the opposite trend of expression between LINC00339 and miR-484. Bioinformatics analysis and luciferase reporter assay indicated that LINC00339 directly binds to miR-484. Moreover, miR-484 inhibitor abrogated the collagen synthesis inhibition induced by LINC00339. These findings reveal a novel function of the LINC00339/miR-484 axis in DOX-induced cardiotoxicity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CircRNA{sub 1}00290 promotes colorectal cancer progression through miR-516b-induced downregulation of FZD4 expression and Wnt/β-catenin signaling

Accumulating evidence indicates that circular RNAs (circRNA) exert crucial functions in the development and advance of cancers. CircRNA{sub 1}00290 has been reported to promote proliferation in oral cancer. However, whether it participates in colorectal cancer (CRC) remains unclear. Here, our report showed that circRNA{sub 1}00290 level was significantly increased in CRC tissues and cell lines. Besides, circRNA{sub 1}00290 expression was positively correlated with tumor metastasis while inversely correlated with prognosis. Silencing circRNA{sub 1}00290 markedly reduced cell proliferation rate, inhibited migration and invasion abilities, but promoted apoptosis in vitro. Mechanistically, our data revealed circRNA{sub 1}00290 was a competing endogenous RNA (ceRNA) of FZD4 by sponging miR-516b, leading to activation of Wnt/β-catenin pathway. Rescue assay indicated that FZD4-induced activation of β-catenin pathway is indispensable for the function of circRNA{sub 1}00290 in CRC. In summary, our study for the first time revealed a novel regulatory loop of circRNA{sub 1}00290/miR-516b/FZD4/Wnt/β-catenin implicated in CRC progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

High mobility group A2 (HMGA2) promotes EMT via MAPK pathway in prostate cancer

Highlights: • HMGA2 expression increases with prostate cancer progression. • Wild-type HMGA2 promotes EMT via MAPK. • Truncated HMGA2 increases cell viability and migration via non-EMT pathway. Studies have shown that High mobility group A2 (HMGA2), a non-histone protein, can promote epithelial-mesenchymal transition (EMT), which plays a critical role in prostate cancer progression and metastasis. Interestingly, full-length or wild-type HMGA2 and truncated (lacking the 3′UTR) HMGA2 isoforms are overexpressed in several cancers. However, there are no studies investigating the expression and differential roles of WT vs truncated HMGA2 isoforms in prostate cancer. Immunohistochemical staining of prostate tissue microarray revealed low membrane expression in normal epithelial prostate cells, and that expression increased with tumor grade as well as a switch from predominantly cytoplasmic HMGA2 in lower tumor grades, to mostly nuclear in high grade and bone metastatic tissue. LNCaP cells stably overexpressing wild-type HMGA2 displayed nuclear localization of HMGA2 and induction of EMT associated with increased Snail, Twist and vimentin expression compared to LNCaP Neo control cells, as shown by immunofluorescence and western blot analyses. This was associated with increased cell migration on collagen shown using boyden chamber assay. Conversely, LNCaP cells overexpressing truncated HMGA2 showed cytoplasmic HMGA2 expression that did not induce EMT yet displayed increased cell proliferation and migration compared to LNCaP Neo. Both wild-type and truncated HMGA2 increased levels of phospho-ERK, and interestingly, treatment with U0126, MAPK inhibitor, antagonized wild-type HMGA2-mediated EMT and cell migration, but did not affect truncated HMGA2-mediated cell proliferation or migration. Therefore, although both wild-type and truncated HMGA2 may promote prostate tumor progression, wild-type HMGA2 acts by inducing EMT via MAPK pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Platelet-derived growth factor receptor alpha (PDGFRα) is overexpressed in NK/T-cell lymphoma and mediates cell survival

Nasal-type natural killer/T-cell lymphoma (NKTCL) is a subtype of non-Hodgkin lymphoma (NHL) that is clinically aggressive and has a poor prognosis. Platelet-derived growth factor receptors (PDGFRs) and their ligands (PDGFs) play important roles in angiogenesis, cancer cell proliferation, survival, migration and poor prognosis in various tumours. However, the significance of PDGFRs in NKTCL remains unknown. Herein, the present study aimed to investigate the important role of PDGFRα in pathogenesis, progression and prognisis of NKTCL. Firstly, we performed immunohistochemical staining, qRT-PCR and western blotting to determine PDGFRα expression in formalin-fixed, paraffin-embedded tissue sections from 78 NKTCL cases and in cell lines. Secondly, correlations between PDGFRα expression and NKTCL clinical parameters and prognosis were analysed. Moreover, a biological assessment of PDGFRα blockade in two NKTCL cell lines was conducted through proliferation assay, cell-cycle evaluation and apoptosis detection by flow cytometry analyses. Furthermore, we detected in vivo activity of imatinib in mouse model of NKTCL. We found that the expression of PDGFRα was significantly higher in NKTCL tissues compared to the reactive lymphoid hyperplasia of the nasopharynx (P = 0.028). High PDGFRα expression was strongly associated with a high LDH level (P = 0.028) and III-IV stage (P = 0.013). NKTCL patients with high PDGFRα expression displayed a reduced median overall survival time and progression-free survival time when compared with those with low PDGFRα expression (P = 0.011, P = 0.005, respectively). Cox multivariate analysis showed that III-IV stage (P = 0.024) and high PDGFRα expression (P = 0.003) were independent prognostic factors in NKTCL patients. Biological assessment assays in two NKTCL cell lines revealed that a specific PDGFR antagonist, imatinib, inhibited cell viability, blocked cell cycle progression at G0/G1 stage and induced apoptosis. Similarly, the in vivo assay showed that imatinib delayed mouse model tumour growth. In conclusion, NKTCL tumour cells have prominent PDGFRα expression, which can serve as a candidate prognostic marker. PDGFR antagonists have significant biological effect on NKTCL and may be useful therapeutic agents for treatment of NKTCL.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Identification and characterization of a novel phosphoregulatory site on cyclin-dependent kinase 5

Highlights: • Identification of a novel phosphosite on Cyclin-dependent kinase 5 (CDK5). • Elucidation of the mechanism by which the phosphosite negatively regulates CDK5 activity. • Potential role for this phosphoevent in regulating cellular proliferation-migration dichotomy. Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase essential for embryonic development whose overactivation has been implicated in several pathologies including neurodegeneration, cancer cell metastasis and type II diabetes. Therefore, it is important to investigate molecular mechanism(s) that mediate regulation of CDK5 activity. Here we identify and characterize a novel phosphoregulatory site on CDK5. Our mass spectrometry analysis identified seven putative phosphorylation sites on CDK5. Using phosphomimetic and non-phosphorylatable mutants, we determined that phosphorylation of S47, one of the identified sites, renders the kinase catalytically inactive. The inactivation of the kinase due to the phosphomimetic change at S47 results from inhibition of its interaction with its cognate activator, p35. We connect the effect of this regulatory event to a cellular phenotype by showing that the S47D CDK5 mutant inhibits cell migration and promotes cell proliferation. Together, these results have uncovered a potential physiological mechanism to regulate CDK5 activity. The evolutionary placement of a phosphorylatable residue (S/T) at this position not only in CDK5 but also in the majority of other CDK family members suggests that this phosphosite may represent a shared regulatory mechanism across the CDK family.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Toosendanin induces caspase-dependent apoptosis through the p38 MAPK pathway in human gastric cancer cells

Highlights: • Toosendanin suppresses viability of various gastric cancer cell lines. • Toosendanin induces G{sub 1}/S cell cycle arrest followed by inhibiting proliferation of AGS and HGC-27 cells. • Toosendanin induces caspase-dependent apoptosis via p38 MAPK signaling pathway in AGS and HGC-27 cells. • Toosendanin can be a promising therapeutic compound for gastric cancer therapy. Although many advances have been made in the treatment of gastric cancer (GC), numerous difficulties, such as the emergence of chemo-drug resistance, continue to lead to disappointing GC prognoses. Thus, novel alternative strategies are urgently needed. The use of natural products could be a viable option to treat GC. Toosendanin (TSN) is a triterpenoid derived from the bark of Melia toosendanin Sieb. et Zucc that has been shown to be highly cytotoxic to multiple cancer cells. As the underlying impact of TSN on GC and its molecular mechanism remain poorly understood, in this study, we performed a series of experiments involving the use of TSN to treat GC cells. In the present study, we showed that TSN suppressed cell viability, inhibited cell proliferation by causing G{sub 1}/S arrest and induced caspase-dependent apoptosis in AGS and HGC-27 cells. The possible mechanism of TSN-induced apoptosis may be associated with the activation of the p38 MAPK pathway. These results demonstrated the potential of TSN as a promising therapeutic compound to treat gastric cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Cell survival regulation during receptor-mediated endocytosis of chemically-modified lipoproteins associated to the formation of an Amphiphysin 2 (Bin1)/c-Myc complex

Highlights: • Cells under oxidative stress form a complex between amphiphysin 2(Bin1) and c-Myc. • The complex provides cells with a novel survival state established between proliferation and cell death. • Novel clones of amphiphysin 2 are described. Amphiphysin 2 and members of the BAR-domain family of proteins participate in a wide array of cellular processes including cell cycle and endocytosis. Given that amphiphysin 2 is related to diverse cell responses as a result of metabolic stress, we investigated in macrophages whether oxidative stress originated by the internalization of oxidized low density lipoproteins (oxLDL) affect both, the expression of amphiphysin 2 and its binding partner c-Myc. Here we report that under oxidative stress, a complex formation between amphiphysin 2(Bin1) and c-Myc allows the cell to develop a novel survival equilibrium state established between cell proliferation and cell death. We propose that under conditions of oxidative stress given by the internalization of oxLDL, macrophages employ the formation of the amphiphysin 2(Bin1)/c-Myc complex as a control mechanism to initially avoid the process of cell death in an attempt to prolong cell survival.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice

Highlights: • Aniti-IL-11 antibody blocks IL-11-, but not IL-6-induced cell proliferation. • Anti-IL-11 antibody detects IL-11-poducing cells of colon cancer in wild-type mice. • We established two lines of Il11−/− mice by the CRISPR-Cas9 method. • These tools might be valuable to elucidate the functions of IL-11 in vivo. Interleukin (IL)-11 belongs to the members of the IL-6 family of cytokines and is involved in a variety of biological responses, including hematopoiesis, bone development, and carcinogenesis. However, the cellular sources of IL-11 and regulation of IL-11 expression under physiological and pathological conditions are not fully understood. One of the causes to prevent characterization of IL-11 in vivo is due to the lack of reliable antibodies that detect IL-11 by immunohistochemistry. Moreover, although mice lacking Il11ra have been generated and extensively characterized, Il11-deficient mice have not been characterized yet. Here we generated two anti-IL-11 antibodies that blocked biological activities of IL-11 and detected IL-11 by immunohistochemistry, respectively. One clone of anti-IL-11 antibodies blocked IL-11-, but not IL-6-induced cell proliferation and IL-11-induced phosphorylation of STAT3 of an IL-11-dependent cell line. Moreover, we used recently established Il11-deficient mice to test the specificity of anti-IL-11 antibodies for immunohistochemistry. Another clone of anti-IL-11 antibodies stained stromal cells surrounding tumors of the colon of wild-type, but not Il11-deficient mice following treatment with Azoxymethane plus dextran sulfate sodium. Together, these newly developed anti-IL-11 antibodies provide a better understanding of the functions of IL-11 in vivo under various physiological and pathological conditions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Long non-coding RNA OGFRP1 regulates LYPD3 expression by sponging miR-124-3p and promotes non-small cell lung cancer progression

Highlights: • The expression levels of lncRNA OGFRP1 was up-regulated in NSCLC tissues and cell lines. • Overexpression of lncRNA OGFRP1 was associated with advanced clinical features and poor prognosis in NSCLC patients. • LncRNA OGFRP1 promoted NSCLC cells proliferation, migration and invasion by regulation of miR-124-3p-LYPD3 pathway. Long noncoding RNA (OGFRP1) has been reported to be involved in the progression of non-small cell lung cancer (NSCLC). However, the expression pattern, functions and molecular mechanisms of OGFRP1 in NSCLC remains unclear. In the present study, we found that OGFRP1 expression was significantly up-regulated in both NSCLC tissues and cell lines, and the upregulation of OGFRP1 expression is a powerful predictor of advanced clinical stage, lymph nodes metastasis and poor prognosis for NSCLC patients. Loss-of-function assay indicated that knockdown of OGFRP1 inhibited proliferation, migration and invasion, and induced apoptosis in vitro. Mechanistically, OGFRP1 could directly bind to miR-124-3p and effectively act as a competing endogenous RNA (ceRNA) for miR-124-3p to promote the expression of the target gene LYPD3. Taken together, OGFRP1 contributed to progression of NSCLC at least partly through upregulating LYPD3 expression by sponging miR-124-3p, indicating that OGFRP1 may be a novel prognostic biomarker and therapeutic target in NSCLC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

NFAT5 promotes in vivo development of murine melanoma metastasis

Highlights: • First time to demonstrate a role of NFAT5 in the development of melanoma. • Depletion of NFAT5 suppresses cell proliferation and migration in vitro. • Depletion of NFAT5 suppresses tumor growth and metastasis in vivo. • NFAT5 as a novel therapeutic target in melanoma. Malignant melanoma is one of the most fatal and aggressive skin cancers, originating from pigment-containing melanocytes. Despite progress in clinical research, treatment options for malignant melanoma have been limited. The nuclear factor of activated T-cell 5 (NFAT5), originally identified as tonicity regulated transcription factor Ton/EBP, is now known as a carcinogenic gene in several types of cancer pathology. In this study, we knocked down NFAT5 to investigate its role in melanoma cancer. shRNA-mediated knockdown of NFAT5 led to a significant decrease in cell proliferation in vitro. Additionally, depletion of NFAT5 inhibited the cell migratory ability of B16BL6 melanoma cells and led to more accumulation at the G2/M phase of the cell cycle. Furthermore, NFAT5 was essential for the development of melanoma cancer pathophysiology in an in vivo mouse model. NFAT5 knockdown-induced tumor growth was slow and tumor volume was significantly reduced compared to mock controls. Moreover, NFAT5 knockdown was associated with a low number of metastatic nodules on the lung and liver. To our knowledge, our data demonstrate for the first time a role of NFAT5 in the development of melanoma. We provide evidence for NFAT5 as a marker of cell migration and metastasis, indicating that NFAT5 represents a novel therapeutic target in melanoma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LINC00662 promotes gastric cancer cell growth by modulating the Hippo-YAP1 pathway

Highlights: • High expression of LINC00662 predicted poor prognosis of gastric cancer patients. • LINC00662 activated Hippo-YAP1 pathway via sponging miR-497-5p. • The LINC00662-miR-497-5p-YAP1 signal axis may be a target of gastric cancer. Long non-coding RNAs (lncRNAs) function as vital regulators of the progression of various diseases, particularly cancers. In the present study, utilizing the Cancer Genome Atlas (TCGA) data set and a series of cell experiments and clinical tissue samples assays, we found that LINC00662 expression was significantly up-regulated in gastric cancer (GC) tissues and cell lines. High expression of LINC00662 predicted poor prognosis compared to in patients showing low expression. Knockdown of LINC00662 expression decreased GC cell proliferation and increased the chemo-sensitivity of GC cells. Further, we demonstrated that knockdown of LINC00662 suppressed the Hippo-YAP1 signaling pathway in GC cells. Mechanistically, LINC00662 regulated YAP1-mediated GC cell proliferation by sponging miR-497-5p. Overall, our results revealed a critical role for the LINC00662-miR-497-5p–YAP1 axis in GC cell growth, providing a new target for GC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Lnc-SNHG1 may promote the progression of non-small cell lung cancer by acting as a sponge of miR-497

Highlights: • lnc-SNHG1 promotes the progression of non-small cell lung cancer(NSCLC). • lnc-SNHG1 might modulate cell proliferation, migration and invasion by sponging miR-497. • The effect of lnc-SNHG1 on NSCLC could be rescued by miR-497. • lnc-SNHG1 promotes cancer cell motility in a miR-497-dependent manner via IGF1-R. Lnc-SNHG1 (small nucleolar RNA host gene 1) is considered an important regulating factor in several types of cancers. However, the biological functions and underlying molecular mechanisms in which lnc-SNHG1 is involved in non-small cell lung cancer (NSCLC) still need to be explored. In this study, we investigated the detailed effects and possible molecular mechanisms. The transcript level of lnc-SNHG1 was higher in lung adenocarcinoma specimens and NSCLC cell lines than in noncancer tissue and cells. The level of expression was positively correlated with invasiveness and was negatively correlated with the level of miR-497 in vivo and in vitro. In exploring the regulatory mechanism, we found that lnc-SNHG1 might modulate tumor growth by sponging miR-497. The inhibitory effect of si-lnc-SNHG1 on NSCLC cell proliferation, migration and invasion could be rescued by miR-497 inhibition, while the overexpression of miR-497 could reverse the effect of lnc-SNHG1 overexpression. Furthermore, our study demonstrated that the lnc-SNHG1 regulated the expression of the insulin-like growth factor 1 receptor (IGF1-R) by acting as a sponge of miR-497 in NSCLC. lnc-SNHG1 could be a novel biomarker as well as a curative target.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibition of PD1:PD-L1 interaction by an E. coli-derived optimized PD1 variant

Highlights: • Cancer cells interact with immune checkpoints to shut down T cell response. • An optimization system for the selection of modified immune checkpoint proteins. • Using the described system improved PD1 variants were identified. • The improved variants are active in a cellular assay that mimics T cell:cancer interaction. Immune-checkpoint receptors are a set of signal transduction proteins that can stimulate or inhibit specific anti-tumor responses. It is well established that cancer cells interact with different immune checkpoints to shut down T-cell response, thereby enabling cancer proliferation. Given the importance of immune checkpoint receptors, a structure-function analysis of these systems is imperative. However, recombinant expression and purification of these membrane originated proteins is still a challenge. Therefore, many attempts are being made to improve their expression and solubility while preserving their biological relevance. For this purpose, we designed an E. coli-based optimization system that enables the acquisition of mutations that increases protein solubility and affinity towards its native ligand, while maintaining biological activity. Here we focused on the well-characterized extracellular domain of the 'programmed cell death protein 1' (PD1), an immune checkpoint receptor known to inhibit T-cell proliferation by interacting with its ligands PD-L1 and PD-L2. The simple ELISA-based screening system shown here enabled the identification of high-affinity, highly soluble, functional variants derived from the extracellular domain of human PD1. The system was based on the expression of a GST-tagged variants library in E. coli, which enabled the selection of improved PD1 variants after a single optimization round. Within only two screening rounds, the most active variant showed a 5-fold higher affinity and 2.4-fold enhanced cellular activity as compared to the wild type protein. This scheme can be translated toward other types of challenging receptors toward development of research tools or alternative therapeutics.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Planar compression of extracellular substrates induces S phase arrest via ATM-independent CHK2 activation

Highlights: • Planar compression of the extracellular substrate induces S phase arrest. • Cancer cells do not exhibit compression-induced S phase arrest. • The CHK2-p53 pathway mediates compression-induced S phase arrest. • Compression-induced activation of CHK2 is independent of ATM. • Actin disassembly upon substrate compression is required for S phase arrest. Cell proliferation is regulated not only by soluble chemical factors but also by mechanical cues surrounding cells. Mechanical stretch of extracellular substrates is known to promote cell proliferation by driving exit from the G{sub 0} phase and entry into the S phase. Here, we report that planer compression of extracellular substrates induces cell cycle arrest in the S phase. The compression-induced S phase arrest is mediated by the checkpoint kinase 2 (CHK2)-p53 pathway. In contrast to the canonical S phase checkpoint pathway activated by DNA damage, CHK2 activation by the substrate compression is independent of ataxia telangiectasia mutated (ATM). We further find that disassembly of the actin cytoskeleton is required for the compression-induced S phase arrest. Notably, cancer cells do not exhibit S phase arrest upon the substrate compression. Our results suggest a novel mechanism for homeostatic control of cell growth under mechanical perturbations.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CircNUP214 sponges miR-145 to promote the expression of ZEB2 in thyroid cancer cells

Highlights: • CircNUP214 plays oncogenic role in papillary thyroid cancer cells. • Inhibition of circNUP214 impairs the proliferation, migration, invasion and tumorgenesis of papillary thyroid cancer cells. • CircNUP214 acted as a sponge of miR-145 and ZEB2 was a functional target of miR-145. • CircNUP214/miR-145/ZEB2 axis plays critical roles in papillary thyroid cancer pathogenesis. Circular (circ)RNAs have been implicated in cancer development. However, few studies have examined the role of circRNAs in papillary thyroid cancer (PTC). In this study we found that circNUP214 was upregulated in clinical PTC specimens relative to adjacent normal tissue. In vitro analyses showed that circNUP214 knockdown suppressed PTC cell proliferation, invasion, migration, and tumorigenesis. A luciferase reporter assay confirmed that circNUP214 binds to miR-145, which directly targets zinc finger E-box binding homeobox (ZEB)2. Thus, circNUP214 may play an oncogenic role in PTC by acting as a sponge for miR-145, leading to upregulation of ZEB2. These results provide evidence for a new regulatory mechanism in PTC development involving circNUP214, which can serve as a potential therapeutic target in PTC treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The LINC01138 interacts with PRMT5 to promote SREBP1-mediated lipid desaturation and cell growth in clear cell renal cell carcinoma

Highlights: • LINC01138 is highly expressed in ccRCC and correlated with poor patient survival. • LINC01138 regulates growth and lipid desaturation in ccRCC. • LINC01138 promotes ccRCC cell proliferation through SREBP1-mediated lipid desaturation. • LINC01138 interacts with PRMT5 to regulate SREBP1 protein stability. Clear cell renal cell carcinoma (ccRCC), the most common type of kidney malignancy, is an incurable disease characterized by multiple metabolic abnormalities, especially lipid accumulation and desaturation. Though great progresses have been made in understanding the mechanisms of ccRCC, metabolic abnormalities remain largely unclear. Here, we found lncRNA LINC01138 is highly expressed in ccRCC and is associated with poor patient survival. LINC01138 regulates ccRCC growth through sterol regulatory element-binding protein 1 (SREBP1)-mediated lipid desaturation. Mechanistically, we demonstrated that LINC01138 interacts with PRMT5 to increase arginine methylation and protein stability of SREBP1, promoting lipid desaturation and cell proliferation in ccRCC. Our study identified LINC01138 as a novel regulator of metabolic abnormalities in ccRCC, providing a potential therapeutic target for metabolic therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LncRNA ZEB1-AS1/miR-409–3p/ZEB1 feedback loop is involved in the progression of non-small cell lung cancer

Highlights: • ZEB1-AS1 was increase in NSCLC cells and ZEB1-AS1 silencing inhibited cell proliferation and induced apoptosis. • ZEB1-AS1 positively regulates ZEB1 through sponging miR-409–3p. • ZEB1 could bind to the promoter region of ZEB1-AS1 to activate its expression. • The positive feedback loop of ZEB1-AS1/miR-409–3p/ZEB1 could facilitate the NSCLC oncogenesis. Emerging evidence has illustrated that long noncoding RNA (LncRNA) ZEB1 antisense RNA 1 (ZEB1-AS1) involved in the development of various type of human cancers. However, the role of ZEB1-AS1 in non-small cell lung cancer (NSCLC) is still elusive and poorly understood. The present study aimed to provide functional evidence and elucidate the molecular mechanisms by which the ZEB1-AS1 promotes oncogenesis of NSCLC. Our study found that ZEB1-AS1 was upregulated in NSCLC cells and knockdown of ZEB1-AS1 significantly inhibited cell growth and induced cell apoptosis. Mechanically, miR-409–3p was confirmed as a direct target of ZEB1-AS1 and negatively regulated by ZEB1-AS1 via competing endogenous RNA (ceRNA) mechanism; miR-409–3p inhibited ZEB1 expression by directly binding to the 3′UTR. Importantly, as predicted by JASPAR and further confirmed by luciferase reporter gene and ChIP assays, we found ZEB1 could bind to the promoter region of ZEB1-AS1 to activate its expression. Restoration of ZEB1 could partially abolished the action of ZEB1-AS1 silencing on cell proliferation and apoptosis. Collectively, the results suggested that ZEB1-AS1/miR-409–3p/ZEB1 constitutes a positive feedback loop to promote the tumorigenesis of NSCLC, highlighting the possibility of improving NSCLC treatment by targeting the ZEB1-AS1 signaling pathway.

60 APPLIED LIFE SCIENCES↗