Tetraspanin 7 promotes osteosarcoma cell invasion and metastasis by inducing EMT and activating the FAK-Src-Ras-ERK1/2 signaling pathway.

BACKGROUND: Tetraspanins are members of the 4-transmembrane protein superfamily (TM4SF) that function by recruiting many cell surface receptors and signaling proteins into tetraspanin-enriched microdomains (TEMs) that play vital roles in the regulation of key cellular processes including adhesion, motility, and proliferation. Tetraspanin7 (Tspan7) is a member of this superfamily that plays documented roles in hippocampal neurogenesis, synaptic transmission, and malignant transformation in certain tumor types. How Tspan7 influences the onset or progression of osteosarcoma (OS), however, remains to be defined. Herein, this study aimed to explore the relationship between Tspan7 and the malignant progression of OS, and its underlying mechanism of action. METHODS: In this study, the levels of Tspan7 expression in human OS cell lines were evaluated via qRT-PCR and western blotting. The effect of Tspan7 on proliferation was examined using CCK-8 and colony formation assays, while metastatic role of Tspan7 was assessed by functional assays both in vitro and in vivo. In addition, mass spectrometry and co-immunoprecipitation were performed to verify the interaction between Tspan7 and ß1 integrin, and western blotting was used to explore the mechanisms of Tspan7 in OS progresses. RESULTS: We found that Tspan7 is highly expressed in primary OS tumors and OS cell lines. Downregulation of Tspan7 significantly suppressed OS growth, metastasis, and attenuated epithelial-mesenchymal transition (EMT), while its overexpression had the opposite effects in vitro. Furthermore, it exhibited reduced OS pulmonary metastases in Tspan7-deleted mice comparing control mice in vivo. Additionally, we proved that Tspan7 interacted with ß1 integrin to facilitate OS metastasis through the activation of integrin-mediated downstream FAK-Src-Ras-ERK1/2 signaling pathway. CONCLUSION: In summary, this study demonstrates for the first time that Tspan7 promotes OS metastasis via interacting with ß1 integrin and activating the FAK-Src-Ras-ERK1/2 pathway, which could provide rationale for a new therapeutic strategy for OS.

Inhibition by O-desmethyltramadol of glutamatergic excitatory transmission in adult rat spinal substantia gelatinosa neurons.

To reveal cellular mechanisms for antinociception produced by clinically used tramadol, we investigated the effect of its metabolite O-desmethyltramadol (M1) on glutamatergic excitatory transmission in spinal dorsal horn lamina II (substantia gelatinosa; SG) neurons. The whole-cell patch-clamp technique was applied at a holding potential of -70 mV to SG neurons of an adult rat spinal cord slice with an attached dorsal root. Under the condition where a postsynaptic action of M1 was inhibited, M1 superfused for 2 min reduced the frequency of spontaneous excitatory postsynaptic current in a manner sensitive to a µ-opioid receptor antagonist CTAP; its amplitude and also a response of SG neurons to bath-applied AMPA were hardly affected. The presynaptic effect of M1 was different from that of noradrenaline or serotonin which was examined in the same neuron. M1 also reduced by almost the same extent the peak amplitudes of monosynaptic primary-afferent Aδ-fiber and C-fiber excitatory postsynaptic currents evoked by stimulating the dorsal root. These actions of M1 persisted for >10 min after its washout. These results indicate that M1 inhibits the quantal release of L-glutamate from nerve terminals by activating µ-opioid but not noradrenaline and serotonin receptors; this inhibition is comparable in extent between monosynaptic primary-afferent Aδ-fiber and C-fiber transmissions. Considering that the SG plays a pivotal role in regulating nociceptive transmission, the present findings could contribute to at least a part of the inhibitory action of tramadol on nociceptive transmission together with its hyperpolarizing effect as reported previously.

Knockdown of NSD2 Suppresses Renal Cell Carcinoma Metastasis by Inhibiting Epithelial-Mesenchymal Transition.

Background: Renal cell carcinoma (RCC) accounts for around 85% of all primary kidney neoplasms, which is one of top 10 common cancers worldwide. Nuclear receptor suppressor of variegation, enhancer of zeste, and trithorax (SET) domain-containing 2 (NSD2), belonging to NSD protein family, functions as an oncogene in the pathogenesis of multiple cancers. Methods: GEO database was used to analyze the expression of NSD2 mRNA in renal cancer. Furthermore, NSD2 protein level in clear cell RCC (ccRCC) tissues was detected by immunohistochemistry (IHC). Knockdown efficiency of different siRNAs was evaluated by quantitative real-time PCR (qRT-PCR) and western blot analysis. The biological role and molecular mechanism of NSD2 in RCC metastasis were investigated via a series of functional experiments. Results: NSD2 mRNA was massively amplified in several types of renal cancer, especially in metastatic ccRCC. The expression level of NSD2 protein was elevated in ccRCC tissues, but not correlated with pathological grading. The migratory and invasive properties were significantly repressed in NSD2-silenced RCC cells, concurrent with an increase of E-cadherin expression and a decrease of N-cadherin and Vimentin expression. Conclusion: Down-regulation of NSD2 could potently suppress cell migration and invasion through inhibiting epithelial-mesenchymal transition (EMT), indicating that NSD2 may be a potential therapeutic target for metastatic RCC.

Molecular Dynamics Simulations of Wild Type and Mutants of SAPAP in Complexed with Shank3.

Specific interactions between scaffold protein SH3 and multiple ankyrin repeat domains protein 3 (Shank3) and synapse-associated protein 90/postsynaptic density-95⁻associated protein (SAPAP) are essential for excitatory synapse development and plasticity. In a bunch of human neurological diseases, mutations on Shank3 or SAPAP are detected. To investigate the dynamical and thermodynamic properties of the specific binding between the N-terminal extended PDZ (Post-synaptic density-95/Discs large/Zonaoccludens-1) domain (N-PDZ) of Shank3 and the extended PDZ binding motif (E-PBM) of SAPAP, molecular dynamics simulation approaches were used to study the complex of N-PDZ with wild type and mutated E-PBM peptides. To compare with the experimental data, 974QTRL977 and 966IEIYI970 of E-PBM peptide were mutated to prolines to obtain the M4P and M5P system, respectively. Conformational analysis shows that the canonical PDZ domain is stable while the ßN extension presents high flexibility in all systems, especially for M5P. The high flexibility of ßN extension seems to set up a barrier for the non-specific binding in this area and provide the basis for specific molecular recognition between Shank3 and SAPAP. The wild type E-PBM tightly binds to N-PDZ during the simulation while loss of binding is observed in different segments of the mutated E-PBM peptides. Energy decomposition and hydrogen bonds analysis show that M4P mutations only disrupt the interactions with canonical PDZ domain, but the interactions with ßN1' remain. In M5P system, although the interactions with ßN1' are abolished, the binding between peptide and the canonical PDZ domain is not affected. The results indicate that the interactions in the two-binding site, the canonical PDZ domain and the ßN1' extension, contribute to the binding between E-PBM and N-PDZ independently. The binding free energies calculated by MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) are in agreement with the experimental binding affinities. Most of the residues on E-PBM contribute considerably favorable energies to the binding except A963 and D964 in the N-terminal. The study provides information to understand the molecular basis of specific binding between Shank3 and SAPAP, as well as clues for design of peptide inhibitors.

Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs.

Nuclear receptor binding SET domain (NSD) proteins are a class of histone lysine methyltransferases and implicated in multiple cancer types with aberrant expression and involvement of cancer related signaling pathways. In this study, a series of small-molecule compounds including compound 2 and 3 are identified against the SET domain of NSDs through structure-based virtual screening. Our lead compound 3 exhibits potent inhibitory activities in vitro towards the NSD2-SET and NSD3-SET with an IC50 of 0.81 µM and 0.84 µM, respectively, and efficiently inhibits histone H3 lysine 36 dimethylation and decreases the expression of NSDs-targeted genes in non-small cell lung cancer cells at 100 nM. Compound 3 suppresses cell proliferation and reduces the clonogenicity in H460 and H1299 non-small cell lung cancer cells, and induces s-phase cell cycle arrest and apoptosis. These data establish our compounds as a valuable tool-kit for the study of the biological roles of NSDs in cancer.

Silencing PARP-1 binding protein Inhibits Cell Migration and Invasion via Suppressing UBE2C in Nasopharyngeal Cancer Cells.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignancy with a 2 per 100 000 incidence rate in the world. Overall survival (OS) of patients in stage I-II disease is around 80%, whereas OS of patients in stage III-IVB disease drops to 60%, implying the importance of diagnosis to reduce NPC mortality. However, more than 70% patients of NPC were diagnosed at advanced stages (stage III and IV) in clinics, and it definitely contributes to little substantial improvement in the 5-year survival rates although NPC is sensitive to radio-and chemotherapy. Hence, development of novel biomarkers and targetable genes in NPC is eagerly awaited. METHODS: We had analyzed the dataset GSE12452 and found hundreds of genes trans-activated in NPC. Among them, this study focused on PARP-1 binding protein (PARPBP) whose overexpression was also validated in GSE13597 and GSE53819 datasets. RESULTS: Knockdown of PARPBP significantly reduced cell viability in NPC and also identified hundreds of differentially expressed genes including 377 downregulated and 518 upregulated genes in HONE-1 cells with stably knockdown PARPBP. Furthermore, PARPBP might promote cell migration and invasion in NPC through positive regulation of ubiquitin-conjugating enzyme 2C (UBE2C). CONCLUSION: The results demonstrate the aberrant expression of PARPBP in NPC, and imply its importance in nasopharyngeal carcinogenesis which further opens up the possibility of PARPBP as a novel diagnostic biomarker for NPC therapy.

BDNF gene hydroxymethylation in hippocampus related to neuroinflammation-induced depression-like behaviors in mice.

BACKGROUND: Neuroinflammation is a multifactorial condition related to glial cells and neurons activation, and it is implicated in CNS disorders including depression. BDNF is a crucial molecule that related to the pathology of depression, and it is the target of DNA methylation. DNA hydroxymethylation, an active demethylation process can convert 5-mC to 5-hmC by Tets catalyzation to regulate gene transcription. The regulatory function for BDNF gene in response to neuroinflammation remains poorly understood. METHODS: Neuroinflammation and depressive-like behaviors were induced by lipopolysaccharide (LPS) administration in mice. The microglial activation and cellular 5-hmC localization in the hippocampus were confirmed by immunostaining. The transcripts of Tets and BDNF were examined by qPCR method. The global 5-hmC levels and enrichment of 5-hmC in BDNF gene in the hippocampus were analyzed using dot bolt and hMeDIP-sequencing analysis. RESULTS: LPS administration induced a spectrum of depression-like behaviors (including behavioral despair and anhedonia) and increased expression of Iba-1, a marker for microglia activation, in hippocampus, demonstrating that LPS treatment cloud provide stable model of neuroinflammation with depressive-like behaviors as expected. Our results showed that Tet1, Tet2 and Tet3 mRNA expressions and consequent global 5-hmC levels were significantly decreased in the hippocampus of LPS group compared to saline group. We also demonstrated that 5-hmC fluorescence in the hippocampus located in excitatory neurons identified by CaMK II immunostaining. Furthermore, we demonstrated that the enrichment of 5-hmC in BDNF gene was decreased and corresponding BDNF mRNA was down-regulated in the hippocampus in LPS group compared to saline group. CONCLUSION: Neuroinflammation-triggered aberrant BDNF gene hydroxymethylation in the hippocampus is an important epigenetic element that relates with depression-like behaviors.

Carboxypeptidase Vitellogenic-Like Promotes the Proliferation and Metastasis of Osteosarcoma through the TGF-ß/Smad Signaling Pathway.

OBJECTIVE: This research explored the biological role and underlying mechanisms of carboxypeptidase vitellogenic-like (CPVL) in the progression of osteosarcoma. METHODS: Through mining of microarray data from the GEO database and utilization of qRT-PCR and Western blot analyses, CPVL expression in osteosarcoma tissues and cells was evaluated. RNA interference and lentiviral transduction techniques were applied to edit the CPVL gene. RNA-seq was used to screen for the downstream target genes of CPVL. RESULTS: In both osteosarcoma biopsy samples and cell lines, the expression of CPVL was abnormally higher than that in normal cells or osteoblasts. CPVL silencing notably inhibited the proliferative activity of osteosarcoma cells, whereas CPVL overexpression had the opposite effect. CPVL silencing had potent tumor-suppressive ability in a xenograft osteosarcoma model in nude mice. CPVL silencing significantly suppressed osteosarcoma cell migration, invasion and EMT, whereas CPVL overexpression accelerated these events. Downstream genes related to the occurrence and development of osteosarcoma, including TGF-ß/Smad signaling pathway molecules (TGF-ß2, TGF-ßR1, Smad2/3, and Smad5), were suppressed by CPVL silencing. CONCLUSIONS: High CPVL expression in osteosarcoma not only promoted tumor growth but also induced the EMT process through the TGF-ß/Smad signaling pathway. CPVL may be a new antitumor therapeutic target for osteosarcoma.

C12orf48, termed PARP-1 binding protein, enhances poly(ADP-ribose) polymerase-1 (PARP-1) activity and protects pancreatic cancer cells from DNA damage.

To identify novel therapeutic targets for aggressive and therapy-resistant pancreatic cancer, we had previously performed expression profile analysis of pancreatic cancers using microarrays and found dozens of genes trans-activated in pancreatic ductal adenocarcinoma (PDAC) cells. Among them, this study focused on the characterization of a novel gene C12orf48 whose overexpression in PDAC cells was validated by Northern blot and immunohistochemical analysis. Its overexpression was observed in other aggressive and therapy-resistant malignancies as well. Knockdown of C12orf48 by siRNA in PDAC cells significantly suppressed their growth. Importantly, we demonstrated that C12orf48 protein could directly interact with Poly(ADP-ribose) Polymerase-1 (PARP-1), one of the essential proteins in the repair of DNA damage, and positively regulate the poly(ADP-ribosyl)ation activity of PARP-1. Depletion of C12orf48 sensitized PDAC cells to agents causing DNA damage and also enhanced DNA damage-induced G2/M arrest through reduction of PARP-1 enzymatic activities. Hence, our findings implicate C12orf48, termed PARP-1 binding protein (PARPBP), or its interaction with PARP-1 to be a potential molecular target for development of selective therapy for pancreatic cancer.

Cellular functions and molecular mechanisms of ubiquitination in osteosarcoma.

Although some advances have been made in the treatment of osteosarcoma in recent years, surgical resection remains the mainstream treatment. Initial and early diagnosis of osteosarcoma could be very difficult to achieve due to the insufficient sensitivity for the means of examination. The distal metastasis of osteosarcoma also predicts the poor prognosis of osteosarcoma. In order to solve this series of problems, people begin to discover a new method of diagnosing and treating osteosarcoma. Ubiquitination, as an emerging posttranslational modification, has been shown to be closely related to osteosarcoma in studies over the past decades. In general, this review describes the cellular functions and molecular mechanisms of ubiquitination during the development of osteosarcoma.

Tspan9 Induces EMT and Promotes Osteosarcoma Metastasis via Activating FAK-Ras-ERK1/2 Pathway.

Object: At present, there are few effective treatment options available to patients suffering from osteosarcoma (OS). Clarifying the signaling pathways that govern OS oncogenesis may highlight novel approaches to treating this deadly form of cancer. Recent experimental evidence suggests that the transmembrane protein tetraspanin-9 (Tspan9) plays a role in tumor development. This study was thus formulated to assess the molecular role of Tspan9 as a regulator of OS cell metastasis. Methods: Gene expression in OS cell lines was evaluated via qRT-PCR, while CCK-8, colony formation, Transwell, and wound healing assays were used to explore the in vitro proliferative, invasive, and migratory activities of OS cells. The relationship between Tspan9 and in vivo OS cell metastasis was assessed by injecting these cells into the tail vein of nude mice. Interactions between the Tspan9 and integrin ß1 proteins were explored through mass spectrometric and co-immunoprecipitation, and Western blotting to assess the functional mechanisms whereby Tspan9 shapes OS pathogenesis. Results: Both primary OS tumors and OS cell lines commonly exhibited Tspan9 upregulation, and the knockdown of this tetraspanin suppressed the migration, invasion, and epithelial-mesenchymal transition (EMT) activity in OS cells, whereas Tspan9 overexpression resulted in opposite phenotypes. Tumor lung metastasis were significantly impaired in mice implanted with HOS cells in which Tspan9 was downregulated as compared to mice implanted with control HOS cells. Tspan9 was also found to interact with ß1 integrin and to contribute to OS metastasis via the amplification of integrin-mediated downstream FAK/Ras/ERK1/2 signaling pathway. Conclusion: These data suggest that Tspan9 can serve as a promising therapeutic target in OS.

Association of a novel long non-coding RNA in 8q24 with prostate cancer susceptibility.

Recent genome-wide association studies reported strong and reproducible associations of multiple genetic variants in a large "gene-desert" region of chromosome 8q24 with susceptibility to prostate cancer (PC). However, the causative or functional variants of these 8q24 loci and their biological mechanisms associated with PC susceptibility remain unclear and should be investigated. Here, focusing on its most centromeric region (so-called Region 2: Chr8: 128.14-128.28 Mb) among the multiple PC loci on 8q24, we performed fine mapping and re-sequencing of this critical region and identified SNPs (single nucleotide polymorphisms) between rs1456315 and rs7463708 (chr8: 128,173,119-128,173,237 bp) to be most significantly associated with PC susceptibility (P = 2.00 × 10(-24) , OR = 1.74, 95% confidence interval = 1.56-1.93). Importantly, we show that this region was transcribed as a ∼13 kb intron-less long non-coding RNA (ncRNA), termed PRNCR1 (prostate cancer non-coding RNA 1), and PRNCR1 expression was upregulated in some of the PC cells as well as precursor lesion prostatic intraepithelial neoplasia. Knockdown of PRNCR1 by siRNA attenuated the viability of PC cells and the transactivation activity of androgen receptor, which indicates that PRNCR1 could be involved in prostate carcinogenesis possibly through androgen receptor activity. These findings could provide a new insight in understanding the pathogenesis of genetic factors for PC susceptibility and prostate carcinogenesis.

TRPV1 agonist piperine but not olvanil enhances glutamatergic spontaneous excitatory transmission in rat spinal substantia gelatinosa neurons.

We examined the effects of TRPV1 agonists olvanil and piperine on glutamatergic spontaneous excitatory transmission in the substantia gelatinosa (SG) neurons of adult rat spinal cord slices with the whole-cell patch-clamp technique. Bath-applied olvanil did not affect the frequency and amplitude of spontaneous excitatory postsynaptic current (sEPSC), and unchanged holding currents at -70 mV. On the other hand, superfusing piperine reversibly and concentration-dependently increased sEPSC frequency (half-maximal effective concentration: 52.3 µM) with a minimal increase in its amplitude. This sEPSC frequency increase was almost repetitive at an interval of more than 20 min. Piperine at a high concentration produced an inward current in some neurons. The facilitatory effect of piperine was blocked by TRPV1 antagonist capsazepine. It is concluded that piperine but not olvanil activates TRPV1 channels in the central terminals of primary-afferent neurons, resulting in an increase in the spontaneous release of l-glutamate onto SG neurons.

Involvement of Astrocytes and microRNA Dysregulation in Neurodegenerative Diseases: From Pathogenesis to Therapeutic Potential.

Astrocytes are the most widely distributed and abundant glial cells in the central nervous system (CNS). Neurodegenerative diseases (NDDs) are a class of diseases with a slow onset, progressive progression, and poor prognosis. Common clinical NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Although these diseases have different etiologies, they are all associated with neuronal loss and pathological dysfunction. Accumulating evidence indicates that neurotransmitters, neurotrophic factors, and toxic metabolites that are produced and released by activated astrocytes affect and regulate the function of neurons at the receptor, ion channel, antigen transfer, and gene transcription levels in the pathogenesis of NDDs. MicroRNAs (miRNAs) are a group of small non-coding RNAs that play a wide range of biological roles by regulating the transcription and post-transcriptional translation of target mRNAs to induce target gene expression and silencing. Recent studies have shown that miRNAs participate in the pathogenesis of NDDs by regulating astrocyte function through different mechanisms and may be potential targets for the treatment of NDDs. Here, we review studies of the role of astrocytes in the pathogenesis of NDDs and discuss possible mechanisms of miRNAs in the regulation of astrocyte function, suggesting that miRNAs may be targeted as a novel approach for the treatment of NDDs.

Dual functional nanoparticles efficiently across the blood-brain barrier to combat glioblastoma via simultaneously inhibit the PI3K pathway and NKG2A axis.

The blood-brain barrier (BBB) and complex tumour immunosuppressive micro-environment posed austere challenges for combatting brain tumours such as the glioblastoma. In this study, we have developed a novel dual functional dendrimer drug delivery system (DDS) by the PAMAM and loaded with siLSINCT5 (NP- siRNA) for efficiently across the BBB to inhibit glioblastoma. To achieve the goal of BBB crossing, on the surface of NP-siRNA was decorated with the cell penetrating peptides tLyp-1 (tLypNP-siRNA). Moreover, to overcome the immunosuppressive microenvironment within the glioblastoma (GBM) tissues, a checkpoint inhibitor named as anti-NKG2A monoclonal antibody (aNKG2A), which was able of promoting anti-tumour immunity by unleashing both T and NK Cells, was further conjugated on the surface of siLSINCT5-loaded nanoparticles via the pH-sensitive linkage. Therefore, the developed dual functional and siLSINCT5-loaded dendrimer nanoparticles (tLyp/aNKNP-siRNA) was supposed to have the ability to efficiently cross the BBB and inhibit GBM by simultaneously inhibit the LSINCT5-activated signalling pathways and activate the anti-tumour immunity. The hypothesis was thoroughly confirmed by in vitro cellular and in vivo animal experiments, and provided a novel strategy for combating glioblastoma.

Identify old drugs as selective bacterial ß-GUS inhibitors by structural-based virtual screening and bio-evaluations.

Irinotecan (CPT-11) is a cytotoxic drug that has wide applicability and usage in cancer treatment. Despite its success, patients suffer dose-dependent diarrhea, limiting the drug's efficacy. No effective therapy is available for this unmet medical need. The bacterial ß-glucuronidase (ß-GUS) plays pivotal role in CPT-11-induced diarrhea (CID) via activating the non-toxic SN-38G to toxic SN-38 inside intestine. By using structural-based virtual screening, three old drugs (N-Desmethylclozapine, Aspartame, and Gemifloxacin) were firstly identified as selective bacterial ß-GUS inhibitors. The IC50 values of the compounds in the enzyme-based and cell-based assays range from 0.0389 to 3.6040 and 0.0105 to 5.3730 µM, respectively. The compounds also showed good selectivity against mammalian ß-GUS and no significant cytotoxicity in bacteria. Molecular docking and molecular dynamics simulations were performed to further investigate the binding modes of compounds with bacterial ß-GUS. Binding free energy decomposition revealed that the compounds formed strong interactions with E413 in catalytic trail from primary monomer and F365' on the bacterial loop from the other monomer of bacterial ß-GUS, explaining the selectivity against mammalian ß-GUS. The old drugs identified here may be used as bacterial ß-GUS inhibitors for CID or other bacterial ß-GUS-related disorders.

NSD2 Promotes Renal Cancer Progression Through Stimulating Akt/Erk Signaling.

BACKGROUND: Nuclear receptor suppressor of variegation, enhancer of zeste, and trithorax (SET) domain-containing 2 (NSD2), is a well-known histone lysine methyltransferase (HMTase). The aim of this study was to investigate the biological role of NSD2 in clear cell renal cell carcinoma (ccRCC). METHODS: GEO and OncoLnc databases were used to identify NSD2 expression and estimate its clinical value in ccRCC. Immunohistochemistry (IHC) was applied to further evaluate NSD2 protein level in ccRCC tissues. The expression of NSD2 in different cell lines and the transfection efficiency were determined by quantitative real-time PCR and Western blot analysis. The effect of NSD2 and the underlying mechanism in ccRCC progression were investigated via MTT, flow cytometry, Western blotting and xenograft tumor assays. RESULTS: NSD2 was over-expressed in both ccRCC tissues and cell lines. NSD2 expression could discriminate ccRCC samples from normal samples, and moreover, high NSD2 expression was characterized with a short overall survival (OS) time. Additionally, knockdown of NSD2 suppressed proliferation and induced apoptosis of cancer cells by inhibiting Akt/Erk signaling and regulating Bcl-2 and Bax expression. Meanwhile, up-regulation of NSD2 contributed to the opposite effects. Silencing of NSD2 reduced xenograft tumor growth in vivo. CONCLUSION: NSD2 serves as an oncogenic factor in the progression of ccRCC via activation of Akt/Erk signaling.

Long Non-Coding RNA PART1 Exerts Tumor Suppressive Functions in Glioma via Sponging miR-190a-3p and Inactivation of PTEN/AKT Pathway.

BACKGROUND: Glioma is the most commonly diagnosed primary brain tumor. Dysregulation of long non-coding RNA (lncRNA) is associated with initiation and development of various cancer types including glioma. METHODS: The relative expression of lncRNA was analyzed by real time-quantitative polymerase chain reaction (RT-qPCR). Cell counting kit (CCK-8) and flow cytometry analysis were applied to explore the role of prostate androgen-regulated transcript 1 (PART1) in glioma cell lines. Luciferase reporter assay, Western blotting and RT-qPCR were used to investigate the association between PART1, miR-190a-3p and phosphatase and tensin homolog deleted on chromosome ten (PTEN) in glioma cell lines. RESULTS: In the present study, we elucidated a pivotal role and molecular mechanism of lncRNA PART1 in glioma cell lines. It was found that PART1 was significantly downregulated in glioma tissues compared to normal tissues according to TCGA data and our RT-qPCR results. The cell-based assays showed that PART1 suppressed cell proliferation and triggered cell apoptosis in glioma cell lines. PART1 inactivated PI3K/AKT cascade in glioma cell lines. Transfection of constitutively activated AKT (Myr-AKT) reversed PART1 induced cell apoptosis and cell growth arrest. The bioinformatic analysis suggested that miR-190a-3p might bind to PART1. In the dual luciferase reporter assay, we validated that PART1 directly bound to miR-190a-3p in glioma cell lines. Furthermore, there was a reciprocal repression between PART1 and miR-190-3p. In addition, PART1 upregulated PTEN and inactivated PI3K/AKT pathway in glioma cell lines. Moreover, silencing of PTEN reversed PART1 overexpression induced cell growth arrest and apoptosis. In glioma tissues, the Pearson Correlation analysis showed that there was a strong-positive correlation between PART1 level and PTEN mRNA level. CONCLUSION: Taken together, the current study revealed a PART1/miR-190a-3p/PTEN/PI3K/AKT axis in glioma and provided novel insights for understanding the complex lncRNA-miRNA network in glioma.

[Corrigendum] Pivotal roles of protein 4.1B/DAL­1, a FERM­domain containing protein, in tumor progression (Review).

Following the publication of this article, the authors have realized that the grant number published in the 'Funding' section associated with the support that they received from the Changzhou Sci&Tech Program ('20180170') was incorrect: This was the application number, not the formal grant number. The official project grant number should have been written as 'CJ20180064'. The authors apologize to the funders of their research project, and to the readership of the Journal for any inconvenience caused. [the original article was published in International Journal of Oncology 55: 979­987, 2019; DOI: 10.3892/ijo.2019.4877].

Erythrocyte membrane protein band 4.1-like 3 inhibits osteosarcoma cell invasion through regulation of Snai1-induced epithelial-to-mesenchymal transition.

Erythrocyte membrane protein band 4.1-like 3 (EPB41L3) is an important membrane skeletal protein that may interact with numerous membrane proteins. Loss of EPB41L3 is reported in multiple cancer types, and it is originally identified as a tumor suppressor. In this study, through analyzing expression profiling retrieved from the Gene Expression Omnibus (GEO) dataset, we find that EPB41L3 is upregulated in primary osteosarcoma (OS) and osteosarcoma cell lines. Importantly, EPB41L3 may promote osteosarcoma cell proliferation and suppress osteosarcoma cell migration and invasion. Reduced EPB41L3 leads to a decrease of E-cadherin as well as an increase of N-cadherin and Vimentin, implying a prominent epithelial-to-mesenchymal transition. Furthermore, we demonstrate that EPB41L3 inhibits the epithelial-to-mesenchymal transition through destabilizing the Snai1 protein, one of the most important transcription factors of the epithelial-to-mesenchymal transition process. Collectively, our study has first established the complex and vital roles of EPB41L3 and implicated EPB41L3 as a potential biomarker in osteosarcoma.