Correlation between tumor invasion and somatostatin receptor subtypes in acromegaly.

OBJECTIVE: The low expression of somatostatin receptor (SSTR) subtypes in somatotropinoma is associated with a poor response to somatostatin analogs (SSAs). However, the correlation between SSTRs and tumor invasion has not yet been clarified. Therefore, the authors aimed to investigate the relationship between SSTRs and tumor invasion, as well as the correlation between tumor invasiveness and pharmacological response to SSAs. METHODS: A total of 102 patients with acromegaly who underwent surgery between December 2016 and December 2021 at the largest pituitary tumor surgery center in southern China were included in this retrospective study. Patients were divided into the noninvasive tumor group (Knosp grades 0-2 and Hardy-Wilson grade I or II) and invasive group (either Knosp grade 3 or 4 or Hardy-Wilson grade III or IV). The positive response to SSAs was defined by the following criteria after at least 3 months of SSA treatment: 1) ≥ 50% reduction or age- and sex-adjusted normal range of insulin-like growth factor-1 (IGF-1) level; 2) ≥ 80% reduction in or normal range of growth hormone (GH) level; or 3) > 20% reduction in tumor volume. The reference for the normal range of age- and sex-adjusted serum IGF-1 levels was derived from a survey of 2791 healthy adults (1339 males and 1452 females) in China. Demographics and clinical characteristics including tumor size, biochemical assessment, expression levels of SSTRs, and response to preoperative SSAs were compared between the invasive group and noninvasive group. Receiver operating characteristic (ROC) curve analysis was performed to assess the association between SSTR2 and tumor invasion. RESULTS: Compared with the noninvasive group, the invasive group presented with a larger tumor size (9.99 ± 10.41 cm3 vs 3.50 ± 4.02 cm3, p < 0.001), relatively lower SSTR2 expression (p < 0.001), and poorer response to SSAs (36.4% vs 91.7%, p < 0.001). In addition, there was a significant negative correlation between SSTR2 mRNA level and tumor size (r = -0.214, p = 0.031). However, there were no statistically significant differences in the expression of SSTR1, SSTR3, and SSTR5 between the groups. ROC analysis revealed that the low SSTR2 mRNA level was closely associated with tumor invasion (area under the curve 0.805, p < 0.0001). CONCLUSIONS: Tumor invasion is negatively correlated with SSTR2 level but is not associated with other SSTR subtypes. Patients with invasive tumors have a poorer response to SSA therapy, which may be due to the low level of SSTR2 expression. Therefore, SSTR2 could be considered as a routine investigative marker for aiding management of postoperative residual tumors.

METTL3-mediated m6A modification of LINC00839 maintains glioma stem cells and radiation resistance by activating Wnt/ß-catenin signaling.

Long noncoding RNAs (lncRNAs) are involved in glioma initiation and progression. Glioma stem cells (GSCs) are essential for tumor initiation, maintenance, and therapeutic resistance. However, the biological functions and underlying mechanisms of lncRNAs in GSCs remain poorly understood. Here, we identified that LINC00839 was overexpressed in GSCs. A high level of LINC00839 was associated with GBM progression and radiation resistance. METTL3-mediated m6A modification on LINC00839 enhanced its expression in a YTHDF2-dependent manner. Mechanistically, LINC00839 functioned as a scaffold promoting c-Src-mediated phosphorylation of ß-catenin, thereby inducing Wnt/ß-catenin activation. Combinational use of celecoxib, an inhibitor of Wnt/ß-catenin signaling, greatly sensitized GSCs to radiation. Taken together, our results showed that LINC00839, modified by METTL3-mediated m6A, exerts tumor progression and radiation resistance by activating Wnt/ß-catenin signaling.

EZH2 interacts with HP1BP3 to epigenetically activate WNT7B that promotes temozolomide resistance in glioblastoma.

Glioblastoma (GBM) is the most lethal primary brain tumor in adults and harbors a subpopulation of glioma stem cells (GSCs). Enhancer of Zeste Homolog 2 (EZH2), a histone lysine methyltransferase, deeply involves in the stemness maintenance of GSC. However, the precise mechanism and therapeutic potential remain elusive. We postulated that the interactome of EZH2 in GSC is unique. Therefore, we performed proteomic and transcriptomic research to unveil the oncogenic mechanism of EZH2. Immunoprecipitation and mass spectrometry were used to identify proteins that co-precipitate with EZH2. We show that EZH2 binds to heterochromatin protein 1 binding protein 3 (HP1BP3) in GSCs and impairs the methylation of H3K9. Overexpression of HP1BP3 enhances the proliferation, self-renewal and temozolomide (TMZ) resistance of GBM cells. Furthermore, EZH2 and HP1BP3 co-activate WNT7B expression thereby increasing TMZ resistance and stemness of GBM cells. Importantly, inhibition of WNT7B autocrine via LGK974 effectively reverses the TMZ resistance. Our work clarifies a new oncogenic mechanism of EZH2 by which it interacts with HP1BP3 and epigenetically activates WNT7B thereby promoting TMZ resistance in GSCs. Our results provide a rationale for targeting WNT/ß-catenin pathway as a promising strategy to overcome TMZ resistance in GSCs.

Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond.

Glioblastoma multiforme (GBM), a highly invasive and incurable tumor, is the humans' foremost, commonest, and deadliest brain cancer. As in other cancers, distinct combinations of genetic alterations (GA) in GBM induce a diversity of metabolic phenotypes resulting in enhanced malignancy and altered sensitivity to current therapies. Furthermore, GA as a hallmark of cancer, dysregulated cell metabolism in GBM has been recently linked to the acquired GA. Indeed, Numerous point mutations and copy number variations have been shown to drive glioma cells' metabolic state, affecting tumor growth and patient outcomes. Among the most common, IDH mutations, EGFR amplification, mutation, PTEN loss, and MGMT promoter mutation have emerged as key patterns associated with upregulated glycolysis and OXPHOS glutamine addiction and altered lipid metabolism in GBM. Therefore, current Advances in cancer genetic and metabolic profiling have yielded mechanistic insights into the metabolism rewiring of GBM and provided potential avenues for improved therapeutic modalities. Accordingly, actionable metabolic dependencies are currently used to design new treatments for patients with glioblastoma. Herein, we capture the current knowledge of genetic alterations in GBM, provide a detailed understanding of the alterations in metabolic pathways, and discuss their relevance in GBM therapy.

Qki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency.

Defective cholesterol biosynthesis in eye lens cells is often associated with cataracts; however, how genes involved in cholesterol biosynthesis are regulated in lens cells remains unclear. Here, we show that Quaking (Qki) is required for the transcriptional activation of genes involved in cholesterol biosynthesis in the eye lens. At the transcriptome level, lens-specific Qki-deficient mice present downregulation of genes associated with the cholesterol biosynthesis pathway, resulting in a significant reduction of total cholesterol level in the eye lens. Mice with Qki depletion in lens epithelium display progressive accumulation of protein aggregates, eventually leading to cataracts. Notably, these defects are attenuated by topical sterol administration. Mechanistically, we demonstrate that Qki enhances cholesterol biosynthesis by recruiting Srebp2 and Pol II in the promoter regions of cholesterol biosynthesis genes. Supporting its function as a transcription co-activator, we show that Qki directly interacts with single-stranded DNA. In conclusion, we propose that Qki-Srebp2-mediated cholesterol biosynthesis is essential for maintaining the cholesterol level that protects lens from cataract development.

Exosomes derived from microRNA-512-5p-transfected bone mesenchymal stem cells inhibit glioblastoma progression by targeting JAG1.

In this study, we demonstrate that bone mesenchymal stem cell (BMSC)-derived exosomes alter tumor phenotypes by delivering miR-512-5p. miR-512-5p was downregulated in glioblastoma tissues and cells, and Jagged 1 (JAG1) was the target gene of miR-512-5p. We clarified the expression patterns of miR-512-5p and JAG1 along with their interactions in glioblastoma. Additionally, we observed that BMSC-derived exosomes could contain and transport miR-512-5p to glioblastoma cells in vitro. BMSC-derived exosomal miR-512-5p inhibited glioblastoma cell proliferation and induced cell cycle arrest by suppressing JAG1 expression. In vivo assays validated the in vitro findings, with BMSC-exosomal miR-512-5p inhibiting glioblastoma growth and prolonging survival in mice. These results suggest that BMSC-derived exosomes transport miR-512-5p into glioblastoma and slow its progression by targeting JAG1. This study reveals a new molecular mechanism for glioblastoma treatment and validates miRNA packaging into exosomes for glioblastoma cell communication.

Predictors of postoperative biochemical remission in acromegaly.

PURPOSE: Acromegaly is a rare neuroendocrine condition that can lead to significant morbidity. Despite China's vast population size, studies on acromegaly remain sparse. This study aimed to investigate the clinical characteristics and predictors of biochemical remission after surgery for acromegaly using the China Acromegaly Patient Association (CAPA) database. METHODS: A retrospective nationwide study was conducted using patient-reported data from CAPA database between 1998 and 2018. The principal component analysis (PCA) and logistic regression analysis were employed to determine independent predictors of biochemical remission at 3 months in patients after surgery. RESULTS: Of the 546 surgical cases (mean age: 36.8 years; 59.5% females), macroadenomas and invasive tumors (Knosp score 3-4) were 83.9% and 64.1%, respectively. Ninety-five percent of patients were treated with endonasal surgery and 36.8% exhibited biochemical remission at 3-months postoperatively. The following independent predictors of biochemical remission were identified: preoperative growth hormone (GH) levels between 12 and 28 µg/L [odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.37-0.92; p = 0.021], preoperative GH levels > 28 µg/L (OR = 0.55; 95% CI, 0.34-0.88; p = 0.013), macroadenoma (OR = 0.56; 95% CI, 0.32-0.96; p = 0.034), giant adenomas (OR = 0.14; 95% CI, 0.05-0.38; p < 0.001), Knosp score 3-4 (OR = 0.37; 95% CI, 0.24-0.57; p < 0.001), and preoperative medication usage (OR = 2.32; 95% CI, 1.46-3.70; p < 0.001). CONCLUSIONS: In this nationwide study spanning over two decades, we highlight that higher preoperative GH levels, large tumor size, and greater extent of tumor invasiveness are associated with a lower likelihood of biochemical remission at 3-months after surgery, while preoperative medical therapy increases the chance of remission.

Extracellular vesicles derived from hypoxic glioma stem-like cells confer temozolomide resistance on glioblastoma by delivering miR-30b-3p.

Rationale: Glioma stem-like cells (GSCs) contribute to temozolomide (TMZ) resistance in gliomas, although the mechanisms have not been delineated. Methods:In vitro functional experiments (colony formation assay, flow cytometric analysis, TUNEL assay) were used to assess the ability of extracellular vesicles (EVs) from hypoxic GSCs to promote TMZ resistance in glioblastoma (GBM) cells. RNA sequencing and quantitative Reverse Transcription-PCR were employed to identify the functional miRNA in hypoxic EVs. Chromatin immunoprecipitation assays were performed to analyze the transcriptional regulation of miRNAs by HIF1α and STAT3. RIP and RNA pull-down assays were used to validate the hnRNPA2B1-mediated packaging of miRNA into EVs. The function of EV miR-30b-3p from hypoxic GSCs was verified by in vivo experiments and analysis of clinical samples. Results: Hypoxic GSC-derived EVs exerted a greater effect on GBM chemoresistance than those from normoxic GSCs. The miRNA profiling revealed that miR-30b-3p was significantly upregulated in the EVs from hypoxic GSCs. Further, HIF1α and STAT3 transcriptionally induced miR-30b-3p expression. RNA immunoprecipitation and RNA-pull down assays revealed that binding of miR-30b-3p with hnRNPA2B1 facilitated its transfer into EVs. EV-packaged miR-30b-3p (EV-miR-30b-3p) directly targeted RHOB, resulting in decreased apoptosis and increased proliferation in vitro and in vivo. Our results provided evidence that miR-30b-3p in CSF could be a potential biomarker predicting resistance to TMZ. Conclusion: Our findings indicated that targeting EV-miR-30b-3p could provide a potential treatment strategy for GBM.

Glioblastoma-Derived Extracellular Vesicles Facilitate Transformation of Astrocytes via Reprogramming Oncogenic Metabolism.

Glioblastoma (GBM) may arise from astrocytes through a multistep process involving a progressive accumulation of mutations. We explored whether GBM-derived extracellular vesicles (EVs) may facilitate neoplastic transformation and malignant growth of astrocytes. We utilized conditioned media (CM) of cultured glioma cells, its sequential filtration, diverse cell-based assays, RNA sequencing, and metabolic assays to compare the effects of EV-containing and EV-depleted CM. GBM EVs facilitated the neoplastic growth of pre-transformed astrocytes but not normal human or mouse astrocytes. They induced proliferation, self-renewal, and colony formation of pre-transformed astrocytes and enhanced astrocytoma growth in a mouse allograft model. GBM EVs appear to reprogram astrocyte metabolism by inducing a shift in gene expression that may be partly associated with EV-mediated transfer of full-length mRNAs encoding ribosomal proteins, oxidative phosphorylation, and glycolytic factors. Our study suggests an EV/extracellular RNA (exRNA)-mediated mechanism that contributes to astrocyte transformation via metabolic reprograming and implicates horizontal mRNA transfer.

Establishing a novel prediction model for improving the positive rate of prostate biopsy.

BACKGROUND: At present, prostate-specific antigen (PSA) is the primary evaluation index for judging the necessity of prostate cancer (PCa) biopsy. However, there is a high false-positive rate and a low predictive value due to many interference factors. In this study, we tried to find a novel prediction model that could improve the positive rate of prostate biopsy and reduce unnecessary biopsy. METHODS: We retrospectively studied 237 patients, including their age, body mass index (BMI), PSA, prostate volume (PV), prostate imaging-reporting and data system (PI-RADS) v2 score, neutrophil-lymphocyte ratio (NLR), biopsy Gleason score (BGS), and other information. The univariate and multivariate logistic analyses were used to screen out indicators related to PCa. After establishing a prediction formula model, we used receiver operating characteristic (ROC) curves to assess its prediction performance. RESULTS: Our study found that age, PSA, PI-RADS v2 score, and diabetes significantly correlated with PCa. Based on multivariate logistic regression analysis results, we created the following prediction formula: Y = 2.599 × PI-RADS v2 score + 1.766 × diabetes + 0.052 × age + 1.005 × PSAD - 9.119. ROC curves showed the formula's threshold was 0.3543. The composite formula had an excellent capacity to detect PCa with the area under the curve (AUC) of 0.91. In addition, the composite formula also achieved significantly better sensitivity, specificity, and diagnostic accuracy than PSA, PSA density (PSAD), and PI-RADS v2 score alone. CONCLUSIONS: Our predictive formula predicted performance better than PSA, PSAD, and PI-RADS v2 score. It can thus contribute to the diagnosis of PCa and be used as an indicator for prostate biopsy, thereby reducing unnecessary biopsy.

CircRNACCDC66 regulates cisplatin resistance in gastric cancer via the miR-618/BCL2 axis.

Gastric cancer (GC) remains a serious threat to human health with a high cancer-related death rate and unsatisfactory treatment effects after curative resection, especially with advanced GC. Thus, exploration of the molecular mechanism of cisplatin (CDDP) resistance in GC is crucial. circCCDC66 (hsa_circ_0001313) expression was detected by quantitative reverse-transcription PCR in GC cell lines and tissues. The characteristics of circCCDC66 in CDDP resistance in GC were evaluated in vivo and vitro. We performed luciferin reporter assays, biotin-coupled RNA pull-downs and fluorescence in situ hybridization (FISH) to assess the relationship of miR-618 to circCCDC66. Function was determined by cytotoxicity assay, western immunoblotting and TUNEL. CircCCDC66 was overexpressed in CDDP-resistant cells and tissues. The circCCDC66 expression was significantly associated with malignancy and was an independent risk factor for disease-free survival (DFS) in GC patients treated by CDDP based chemotherapy. Data from in vitro and vivo experiments demonstrated that circCCDC66 inhibited apoptosis by targeting miR-618 and release of B-cell lymphoma-2 (BCL2). CircCCDC66 is an essential regulator in the development of CDDP resistance and may serve as a promising therapeutic target for GC patients. Otherwise, our study adds more evidence of circRNA functioning as a sequestering agent for miRNA.

Hormone levels are related to functional compensation in prolactinomas: A resting-state fMRI study.

Prolactinomas are tumors of the pituitary gland, which overproduces prolactin leading to dramatic fluctuations of endogenous hormone levels throughout the body. While it is not fully understood how endogenous hormone disorders affect a patient's brain, it is well known that fluctuating hormone levels can have negative neuropsychological effects. Using resting-state functional magnetic resonance imaging (rs-fMRI), we investigated whole-brain functional connectivity (FC) and its relationship with hormone levels in prolactinomas. By performing seed-based FC analyses, we compared FC metrics between 33 prolactinoma patients and 31 healthy controls matched for age, sex, and hand dominance. We then carried out a partial correlation analysis to examine the relationship between FC metrics and hormone levels. Compared to healthy controls, prolactinoma patients showed significantly increased thalamocortical and cerebellar-cerebral FC. Endogenous hormone levels were also positively correlated with increased FC metrics, and these hormone-FC relationships exhibited sex differences in prolactinoma patients. Our study is the first to reveal altered FC patterns in prolactinomas and to quantify the hormone-FC relationships. These results indicate the importance of endogenous hormones on functional compensation of the brain in patients with prolactinomas.

A novel circular RNA circFN1 enhances cisplatin resistance in gastric cancer via sponging miR-182-5p.

Cisplatin (CDDP) is commonly used for gastric cancer (GC) chemotherapy. However, after several CDDP-based treatment cycles, patients always acquire chemotherapy resistance, which limits the overall clinical efficacy of the treatment. Clarification of the mechanisms responsible for CDDP resistance is required to improve therapeutic outcomes for patients. Circular RNAs (circRNAs) are noncoding RNAs involved in the pathogenesis of cancer, although their role in the mechanism underlying CDDP resistance in GC remains unknown. In the present study, we explored the underlying roles of circRNAs in the modulation of CDDP resistance in CDDP-sensitive and CDDP-resistant human GC cells. Using RNA sequencing and quantitative reverse transcription polymerase chain reaction, expression of circFN1 (originating from exons 10, 11, and 12 of the FN1 gene hsa_circ_0058147) was higher in CDDP-resistant GC cells and tissues. CircFN1 upregulation in GC patients treated by CDDP was significantly correlated with aggressive biological behavior. CircFN1 promoted viability and inhibited apoptosis of GC cells exposed to CDDP in vivo and in vitro. Furthermore, circFN1 suppressed GC cell apoptosis by "sponging" miR-182-5p. These findings demonstrate the involvement of circFN1 in CDDP resistance of GC and implicate circFN1 as a therapeutic target for GC patients treated with CDDP. It provides novel evidence of the function of circRNAs as microRNA sponges and highlight a potential therapeutic target for extinguishing CDDP resistance in patients with GC.

The long noncoding RNA ZFAS1 promotes the progression of glioma by regulating the miR-150-5p/PLP2 axis.

Numerous studies have reported that long noncoding RNA (lncRNA) dysregulation is involved in the progression of many malignant tumors, including glioma. The lncRNA ZNFX1 antisense RNA 1 (ZFAS1) plays an oncogenic role in various malignant tumors, such as gastric cancer and hepatocellular carcinoma. However, the underlying molecular mechanism of ZFAS1 in glioma has not been fully clarified. In this study, we found that the expression of ZFAS1 was upregulated in both glioma tissues and cell lines. Functional experiments revealed that ZFAS1 promoted glioma proliferation, migration and invasion, and increased resistance to temozolomide in vitro. By using online databases, RNA pull-down assays and luciferase reporter assays, ZFAS1 was demonstrated to act as a sponge of miR-150-5p. Furthermore, proteolipid protein 2 (PLP2) was shown to be the functional target of miR-150-5p. Rescue experiments revealed that ZFAS1 regulated the expression of PLP2 by sponging miR-150-5p. Finally, a xenograft tumor assay demonstrated that ZFAS1 promoted glioma growth in vivo. Our results showed that ZFAS1 promoted glioma malignant progression by regulating the miR-150-5p/PLP2 axis, which may provide a potential therapeutic target for the treatment of glioma.

Environmental enrichment prevents Aß oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways.

As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble Aß oligomers impairs LTP, but EE can fully prevent this. Mechanistically, the key molecular features of the EE benefit are an upregulation of miRNA-132 and an inhibition of histone deacetylase (HDAC) signaling. Specifically, soluble Aß oligomers decreased miR-132 expression and increased HDAC3 levels in cultured primary neurons. Further, we provide evidence that HDAC3 is a direct target of miR-132. Overexpressing miR-132 or injecting an HDAC3 inhibitor into mice in standard housing mimics the benefits of EE in enhancing hippocampal LTP and preventing hippocampal impairment by Aß oligomers in vivo. We conclude that EE enhances hippocampal synaptic plasticity by upregulating miRNA-132 and reducing HDAC3 signaling in a way that counteracts the synaptotoxicity of human Aß oligomers. Our findings provide a rationale for prolonged exposure to cognitive novelty and/or epigenetic modulation to lessen the progressive effects of Aß accumulation during human brain aging.

The lncRNA-DLEU2/miR-186-5p/PDK3 axis promotes the progress of glioma cells.

Long non-coding RNAs (lncRNAs) have great value in research on tumour targeted therapy, including for glioma. In the present study, we investigated the role of the lncRNA deleted in lymphocytic leukaemia 2 (lncRNA-DLEU2) in glioma. First, we found that lncRNA-DLEU2 is highly expressed in glioma tissues and cell lines. Next, experiments in cells showed that lncRNA-DLEU2 knockdown inhibited, whereas lncRNA-DLEU2 overexpression promoted, the clone formation, migration and invasion of glioma cells. A luciferase reporter assay and an RNA immunoprecipitation assay demonstrated that lncRNA-DLEU2 acts as a sponge for miR-186-5p in glioma cells. Further, studies suggested that miR-186-5p inhibits the expression of PDK3, which is an oncogene in glioma. Moreover, with rescue experiments, we demonstrated that lncRNA-DLEU2 regulates the expression of PDK3 and the progression of glioma in a miR-186-5p-dependent manner. Finally, we also showed that lncRNA-DLEU2 promotes glioma growth in a manner that is related to miR-186-5p and PDK3 in vivo. In conclusion, our study reported for the first time that lncRNA-DLEU2 promotes glioma progression by targeting the miR-186-5p/PDK3 axis. These findings provide novel strategies for the gene therapy treatment of glioma.

S100A11 functions as novel oncogene in glioblastoma via S100A11/ANXA2/NF-κB positive feedback loop.

Glioblastoma (GBM) is the most universal type of primary brain malignant tumour, and the prognosis of patients with GBM is poor. S100A11 plays an essential role in tumour. However, the role and molecular mechanism of S100A11 in GBM are not clear. Here, we found that S100A11 was up-regulated in GBM tissues and higher S100A11 expression indicated poor prognosis of GBM patients. Overexpression of S100A11 promoted GBM cell growth, epithelial-mesenchymal transition (EMT), migration, invasion and generation of glioma stem cells (GSCs), whereas its knockdown inhibited these activities. More importantly, S100A11 interacted with ANXA2 and regulated NF-κB signalling pathway through decreasing ubiquitination and degradation of ANXA2. Additionally, NF-κB regulated S100A11 at transcriptional level as a positive feedback. We also demonstrated the S100A11 on tumour growth in GBM using an orthotopic tumour xenografting. These data demonstrate that S100A11/ANXA2/NF-κB positive feedback loop in GBM cells that promote the progression of GBM.

Long non-coding RNA SNHG5 promotes glioma progression via miR-205/E2F3 axis.

In recent years, many studies have reported on the abnormal expression and correlation of long non-coding RNAs (lncRNAs) in tumours. However, the accurate molecular mechanism of lncRNAs in glioma is still in its infancy. In the present study, we aimed to explore the molecular mechanism of small nucleolar RNA host gene 5 (SNHG5) in glioma progression. First, we found that SNHG5 expression was higher in glioma and was related to glioma glucose uptake, migration and invasion. Second, through a series of assays, we concluded that SNHG5 acts as a sponge for miR-205, which inhibits tumour growth in glioma by targeting E2F transcription factor 3 (E2F3). Third, using a xenograft mouse model, we demonstrated that SNHG5 regulates tumourigenesis in vivo Taken together, our results show that the SNHG5/miR-205/E2F3 axis is involved in glioma progression and may provide a new therapeutic target for the diagnosis and therapy of glioma.

Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression.

BACKGROUND: Cisplatin (CDDP) treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic efficacy in patients with GC. Circular RNAs (circRNAs) are a class of noncoding RNAs whose functions are related to the pathogenesis of cancer, but, in CDDP resistance of GC remains unknown. METHODS: circAKT3 (hsa_circ_0000199, a circRNA originating from exons 8, 9, 10, and 11 of the AKT3 gene) was identified by RNA sequencing and verified by quantitative reverse transcription PCR. The role of circAKT3 in CDDP resistance in GC was assessed both in vitro and in vivo. Luciferase reporter assay, biotin-coupled RNA pull-down and fluorescence in situ hybridization (FISH) were conducted to evaluate the interaction between circAKT3 and miR-198. Functional experiments were measured by western blotting, a cytotoxicity assay, clonogenic assay and flow cytometry. RESULTS: The expression of circAKT3 was higher in CDDP-resistant GC tissues and cells than in CDDP-sensitive samples. The upregulation of circAKT3 in GC patients receiving CDDP therapy was significantly associated with aggressive characteristics and was an independent risk factor for disease-free survival (DFS). Our data indicated that circAKT3 promotes DNA damage repair and inhibits the apoptosis of GC cells in vivo and in vitro. Mechanistically, we verified that circAKT3 could promote PIK3R1 expression by sponging miR-198. CONCLUSIONS: circAKT3 plays an important role in the resistance of GC to CDDP. Thus, our results highlight the potential of circAKT3 as a therapeutic target for GC patients receiving CDDP therapy.

Exosomal transfer of long non-coding RNA SBF2-AS1 enhances chemoresistance to temozolomide in glioblastoma.

BACKGROUND: Acquired drug resistance is a constraining factor in clinical treatment of glioblastoma (GBM). However, the mechanisms of chemoresponsive tumors acquire therapeutic resistance remain poorly understood. Here, we aim to investigate whether temozolomide (TMZ) resistance of chemoresponsive GBM was enhanced by long non-coding RNA SBF2 antisense RNA 1 (lncRNA SBF2-AS1) enriched exosomes. METHOD: LncSBF2-AS1 level in TMZ-resistance or TMZ-sensitive GBM tissues and cells were analyzed by qRT-PCR and FISH assays. A series of in vitro assay and xenograft tumor models were performed to observe the effect of lncSBF2-AS1 on TMZ-resistance in GBM. CHIP assay were used to investigate the correlation of SBF2-AS1 and transcription factor zinc finger E-box binding homeobox 1 (ZEB1). Dual-luciferase reporter, RNA immunoprecipitation (RIP), immunofluorescence and western blotting were performed to verify the relation between lncSBF2-AS1, miR-151a-3p and XRCC4. Comet assay and immunoblotting were performed to expound the effect of lncSBF2-AS1 on DNA double-stand break (DSB) repair. A series of in vitro assay and intracranial xenografts tumor model were used to determined the function of exosomal lncSBF2-AS1. RESULT: It was found that SBF2-AS1 was upregulated in TMZ-resistant GBM cells and tissues, and overexpression of SBF2-AS1 led to the promotion of TMZ resistance, whereas its inhibition sensitized resistant GBM cells to TMZ. Transcription factor ZEB1 was found to directly bind to the SBF2-AS1 promoter region to regulate SBF2-AS1 level and affected TMZ resistance in GBM cells. SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells. Clinically, high levels of lncSBF2-AS1 in serum exosomes were associated with poor response to TMZ treatment in GBM patients. CONCLUSION: We can conclude that GBM cells remodel the tumor microenvironment to promote tumor chemotherapy-resistance by secreting the oncogenic lncSBF2-AS1-enriched exosomes. Thus, exosomal lncSBF2-AS1 in human serum may serve as a possible diagnostic marker for therapy-refractory GBM.