LncRNA HOXB-AS3 binding to PTBP1 protein regulates lipid metabolism by targeting SREBP1 in endometrioid carcinoma.

Endometrial cancer (EC) is a malignant tumor with a high incidence in women, and the survival rate of high-risk patients decreases significantly after disease progression. The regulatory role of long non-coding RNAs (LncRNAs) in tumors has been widely appreciated, but there have been few studies in EC. To investigate the effect of HOXB-AS3 in EC, we used bioinformatics tools for prediction and collected clinical samples to detect the expression of HOXB-AS3. Colony formation assay, MTT assay, flow cytometry and apoptosis assay, and transwell assay were used to verify the role of HOXB-AS3 in EC. HOXB-AS3 was upregulated in EC, promoted the proliferation and invasive ability of EC cells, and inhibited apoptosis. In addition, the ROC curve illustrated its diagnostic value. We explored experiments via lentiviral transduction, FISH, Oil Red O staining, TC and FFA content detection, RNA-pulldown, RIP, and other mechanisms to reveal that HOXB-AS3 can bind to PTBP1 and co-regulate the expression of SREBP1, thereby regulating lipid metabolism in EC cells. To the best of our knowledge, this is the first study on HOXB-AS3 in disorders of lipid metabolism in EC. In addition, we believe HOXB-AS3 has the potential to be a neoplastic marker or a therapeutic target.

Does the economic growth target overweight induce more polluting activities? Evidence from China.

In China, official promotion evaluation based on economic performance motivates local governments to develop high economic growth targets, which has played an active role in boosting China's economic growth in the past decades, whereas its environmental consequences have not been fully exploited. This paper finds that the economic growth target overweight has a stronger positive impact on the output of high-polluting industries than on the output of low-polluting industries, thus inducing more polluting activities. To deal with the issues of reverse causality and omitted variables bias, we take an instrumental variable approach. Examining mechanisms, we show that economic growth target overweight promotes polluting activities through the deregulation of the polluting activities in high-polluting industries. We also find an increase in the impact of the economic growth target overweight after the 2008 global economic crisis. Our study provides new evidence for explaining the dual presence of rapid economic growth and heavy environmental pollution in China.

Recent Progress in Biosensors for Detection of Tumor Biomarkers.

Cancer is a leading cause of death worldwide, with an increasing mortality rate over the past years. The early detection of cancer contributes to early diagnosis and subsequent treatment. How to detect early cancer has become one of the hot research directions of cancer. Tumor biomarkers, biochemical parameters for reflecting cancer occurrence and progression have caused much attention in cancer early detection. Due to high sensitivity, convenience and low cost, biosensors have been largely developed to detect tumor biomarkers. This review describes the application of various biosensors in detecting tumor markers. Firstly, several typical tumor makers, such as neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), squamous cell carcinoma antigen (SCCA), carbohydrate, antigen19-9 (CA19-9) and tumor suppressor p53 (TP53), which may be helpful for early cancer detection in the clinic, are briefly described. Then, various biosensors, mainly focusing on electrochemical biosensors, optical biosensors, photoelectrochemical biosensors, piezoelectric biosensors and aptamer sensors, are discussed. Specifically, the operation principles of biosensors, nanomaterials used in biosensors and the application of biosensors in tumor marker detection have been comprehensively reviewed and provided. Lastly, the challenges and prospects for developing effective biosensors for early cancer diagnosis are discussed.

A Japanese Herbal Formula, Daikenchuto, Alleviates Experimental Colitis by Reshaping Microbial Profiles and Enhancing Group 3 Innate Lymphoid Cells.

Daikenchuto (DKT) is one of the most widely used Japanese herbal formulae for various gastrointestinal disorders. It consists of Zanthoxylum Fructus (Japanese pepper), Zingiberis Siccatum Rhizoma (processed ginger), Ginseng radix, and maltose powder. However, the use of DKT in clinical settings is still controversial due to the limited molecular evidence and largely unknown therapeutic effects. Here, we investigated the anti-inflammatory actions of DKT in the dextran sodium sulfate (DSS)-induced colitis model in mice. We observed that DKT remarkably attenuated the severity of experimental colitis while maintaining the members of the symbiotic microbiota such as family Lactobacillaceae and increasing levels of propionate, an immunomodulatory microbial metabolite, in the colon. DKT also protected colonic epithelial integrity by upregulating the fucosyltransferase gene Fut2 and the antimicrobial peptide gene Reg3g. More remarkably, DKT restored the reduced colonic group 3 innate lymphoid cells (ILC3s), mainly RORγthigh-ILC3s, in DSS-induced colitis. We further demonstrated that ILC3-deficient mice showed increased mortality during experimental colitis, suggesting that ILC3s play a protective function on colonic inflammation. These findings demonstrate that DKT possesses anti-inflammatory activity, partly via ILC3 function, to maintain the colonic microenvironment. Our study also provides insights into the molecular basis of herbal medicine effects, promotes more profound mechanistic studies towards herbal formulae and contributes to future drug development.

Dietary Derived Micronutrients Modulate Immune Responses Through Innate Lymphoid Cells.

Innate lymphoid cells (ILCs) are a group of innate immune cells that possess overlapping features with T cells, although they lack antigen-specific receptors. ILCs consist of five subsets-ILC1, ILC2, ILC3, lymphoid tissue inducer (LTi-like) cells, and natural killer (NK) cells. They have significant functions in mediating various immune responses, protecting mucosal barrier integrity and maintaining tissue homeostasis in the lung, skin, intestines, and liver. ILCs react immediately to signals from internal and external sources. Emerging evidence has revealed that dietary micronutrients, such as various vitamins and minerals can significantly modulate immune responses through ILCs and subsequently affect human health. It has been demonstrated that micronutrients control the development and proliferation of different types of ILCs. They are also potent immunoregulators in several autoimmune diseases and play vital roles in resolving local inflammation. Here, we summarize the interplay between several essential micronutrients and ILCs to maintain epithelial barrier functions in various mucosal tissues and discuss their limitations and potentials for promoting human health.

CNOT7 modulates biological functions of ovarian cancer cells via AKT signaling pathway.

AIMS: CNOT7 plays an important role in many biological processes, providing attractive opportunities for the treatment of malignant tumors. However, the functions and mechanism of CNOT7 in ovarian cancer (OC) have not been elucidated. The purpose of this study was to assess the role of CNOT7 in OC. MATERIALS AND METHODS: SKOV3 and A2780 cells were chosen as the cell lines for the experiments of this manuscript via the analysis of the expression of CNOT7 protein and the mRNA level in ovarian surface epithelium (OSE) cells, SKOV3, HO8910 and A2780 cells. The expression of CNOT7 was detected by western blot assays and RT-PCR in A2780 and SKOV3 cells. The MTT assays, colony formation assays and EdU assays were used to measure cell proliferation when CNOT7 was knocked down or overexpressed in A2780 and SKOV3 cells. Furthermore, cell migration and invasion ability were achieved from transwell assays. Cell cycle and apoptosis rate after small interference RNA-CNOT7 (siRNA-CNOT7) were detected by flow cytometry assays. Finally, the cell proliferation, migration and invasion ability were detected when A2780 and SKOV3 cells with CNOT7 overexpression were treated with LY294002. KEY FINDINGS: The expression of CNOT7 protein in OC cells, including SKOV3, HO8910 and A2780 cells were significantly higher than that in OSE cells (P < 0.05). The mRNA level of CNOT7 in HO8910 and A2780 cells were significantly higher than that in OSE cells (P < 0.01). However, the mRNA level of CNOT7 in SKOV3 cells was no significant difference compared with OSE cells (P > 0.05). The results suggested that knockdown of CNOT7 could inhibit the cell proliferation, migration and invasion ability in A2780 and SKOV3 cells, and increase cell apoptosis and autophagy. The expression of apoptosis-related molecules (PARP, Caspase3 and Caspase9) and autophagy-related protein (LC3B) were up-regulated after CNOT7 knockdown, while the expression of cycle-related protein (CDK6) and the anti-apoptotic gene (Bcl2) were downregulated. Meanwhile, the opposite results were observed when CNOT7 was overexpressed in A2780 and SKOV3 cells. It is worth noting that the effect of CNOT7 overexpression in A2780 and SKOV3 cells could be partially or completely eliminated by treatment with AKT inhibitor LY294002. SIGNIFICANCE: CNOT7 has a carcinogenic effect in OC, and the carcinogenic effect may be achieved via the AKT signaling pathway.

Discovery and optimization of a potent and selective indazolamine series of IRAK4 inhibitors.

IRAK4 is a key mediator of innate immunity. There is a high interest in identifying novel IRAK4 inhibitors for the treatment of inflammatory autoimmune diseases. We describe here a highly potent and selective IRAK4 inhibitor (HS271) that exhibited superior enzymatic and cellular activities, as well as excellent pharmacokinetic properties. HS271 displayed robust in vivo anti-inflammatory efficacy as evaluated in rat models of LPS induced TNFα production and collagen-induced arthritis.

Clinicalpathologic and Prognostic Significance of CGI-58 in Endometrial Cancer.

Recent studies have reported that CGI-58 played an important role in carcinogenesis and tumoral progression in several cancers. In this study, we investigated the expression and prognostic value of CGI-58 in patients with endometrail cancer. Initially, the expression of CGI-58 was analyzed in 552 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Then, the mRNA level of CGI-58 from 32 normal endometrium and 40 endometrial cancer tissues was determined using real-time PCR. In addition, immunohistochemical staining of CGI-58 was performed in 140 endometrial specimens including 35 normal endometrial tissues, 25 atypical endometrial hyperplasia and 80 endometrial cancers. The expression of CGI-58 was significantly up-regulated in endometrial cancer tissues compared with normal endometrial tissue both in TCGA database and clinical cohorts. Over-expression of CGI-58 was significantly correlated with poor histological differentiation. Furthermore, high levels of CGI-58 expression were significantly associated with shorter overall survival for all analyzed cases. Our findings demonstrate that CGI-58 is up-regulated in endometrial cancer and high CGI-58 expression is a poor prognostic marker for endometrial cancer. CGI-58 may be a potential contributor to endometrial cancer oncogenesis and progression.

Identification and prognostic value of DLGAP5 in endometrial cancer.

BACKGROUND: Endometrial cancer poses a serious threat to women's health worldwide, and its pathogenesis, although actively explored, is not fully understood. DLGAP5 is a recently identified cell cycle-regulation gene not reported in endometrial cancer. This study was aiming to analyze the role of DLGAP5 in tumorigenesis and development and to investigate its prognostic significance of patients with endometrial cancer. METHODOLOGY: Microarray datasets (GSE17025, GSE39099 and GSE63678) from the GEO database were used for comparative analysis, and their intersection was obtained by applying the Venn diagram, and DLGAP5 was selected as the target gene. Next, transcriptome data (n = 578) was downloaded from TCGA-UCEC to analyze the mRNA expression profile of DLGAP5. Then, immunohistochemical data provided by HPA were used to identify the different protein expression levels of DLGAP5 in tumor tissues and normal tissues. Subsequently, the prognostic meaning of DLGAP5 in patients with endometrial cancer was explored based on survival data from TCGA-UCEC (n = 541). Finally, the reliability of DLGAP5 expression was verified by RT-qPCR. RESULTS: Transcriptome data from TCGA-UCEC, immunohistochemical data from HPA, and RT-qPCR results from clinical samples were used for triple validation to confirm that the expression of DLGAP5 in endometrial cancer tissues was significantly higher than that in normal endometrial tissues. Kaplan-Meier survival analysis announced that the expression level of DLGAP5 was negatively correlated with the overall survival of patients with endometrial cancer. CONCLUSIONS: DLGAP5 is a potential oncogene with cell cycle regulation, and its overexpression can predict the poor prognosis of patients with endometrial cancer. As a candidate target for the diagnosis and treatment of endometrial cancer, it is worthwhile to make further study to reveal the carcinogenicity of DLGAP5 and the mechanism of its resistance of organisms.

Human papillomavirus type 16 E7 oncoprotein-induced upregulation of lysine-specific demethylase 5A promotes cervical cancer progression by regulating the microRNA-424-5p/suppressor of zeste 12 pathway.

Human papillomavirus (HPV) infection and viral protein expression cause several epigenetic alterations that lead to cervical carcinogenesis. Our previous study identified that upregulated lysine-specific demethylase (KDM) 2 A promotes cervical cancer progression by inhibiting mircoRNA (miR)-132 function. However, the roles of histone methylation modifiers in HPV-related cervical cancer remain unclear. In the present study, changes in the expression of 48 histone methylation modifiers were assessed following knockdown of HPV16 E6/E7 in CaSki cells. The dysregulated expression of KDM5A was identified, and its function in cervical cancer was investigated in vitro and in vivo. E7 oncoprotein-induced upregulation of KDM5A promoted cervical cancer cell proliferation and invasiveness in vitro and in vivo, which was correlated with poor prognosis in patients with cervical cancer. KDM5A was found to physically interact with the promoter region of miR-424-5p, and to suppress its expression by removing the tri- and di-methyl groups from H3K4 at the miR-424-5p locus. Furthermore, miR-424-5p repressed cancer cell proliferation and invasiveness by targeting suppressor of zeste 12 (Suz12). KDM5A upregulation promoted cervical cancer progression by repressing miR-424-5p, which resulted in a decrease in Suz12. Therefore, KDM5A functions as a tumor activator in cervical cancer pathogenesis by binding to the miR-424-5p promoter and inhibiting its tumor-suppressive function. These results indicate a function for KDM5A in cervical cancer progression and suggest its candidacy as a novel prognostic biomarker and target for the clinical management of this malignancy.

An Adjustable pH-Responsive Drug Delivery System Based on Self-Assembly Polypeptide-Modified Mesoporous Silica.

In this study, an adjustable pH-responsive drug delivery system using mesoporous silica nanoparticles (MSNs) as the host materials and the modified polypeptides as the nanovalves is reported. Since the polypeptide can self-assemble via electrostatic interaction at pH 7.4 and be disassembled by pH changes, the modified poly(l-lysine) and poly(l-glutamate) are utilized for pore blocking and opening in the study. Poly(l-lysine)-MSN (PLL-MSN) and poly(l-glutamate)-MSN (PLG-MSN) are synthesized via the ring opening polymerization of N-carboxyanhydrides onto the surface of mesoporous silica nanoparticles. The successful modification of the polypeptide on MSN is proved by Zeta potential change, X-ray photoelectron spectroscopy (XPS), solid state NMR, and MALDI-TOF MS. In vitro simulated dye release studies show that PLL-MSN and PLG-MSN can successfully load the dye molecules. The release study shows that the controlled release can be constructed at different pH by adjusting the ratio of PLL-MSN to PLG-MSN. Cellular uptake study indicates that the drug is detected in both cytoplasm and nucleus, especially in the nucleus. In vitro cytotoxicity assay indicates that DOX loaded mixture nanoparticles (ratio of PLL-MSN to PLG-MSN is 1:1) can be triggered for drug release in HeLa cells, resulting in 88% of cell killing.

Decreased OLA1 (Obg-Like ATPase-1) Expression Drives Ubiquitin-Proteasome Pathways to Downregulate Mitochondrial SOD2 (Superoxide Dismutase) in Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is a failure of pulmonary vascular resistance to decline at birth rapidly. One principal mechanism implicated in PPHN development is mitochondrial oxidative stress. Expression and activity of mitochondrial SOD2 (superoxide dismutase) are decreased in PPHN; however, the mechanism remains unknown. Recently, OLA1 (Obg-like ATPase-1) was shown to act as a critical regulator of proteins controlling cell response to stress including Hsp70, an obligate chaperone for SOD2. Here, we investigated whether OLA1 is causally linked to PPHN. Compared with controls, SOD2 expression is reduced in distal-pulmonary arteries (PAs) from patients with PPHN and fetal-lamb models. Disruptions of the SOD2 gene reproduced PPHN phenotypes, manifested by elevated right ventricular systolic pressure, PA-endothelial cells apoptosis, and PA-smooth muscle cells proliferation. Analyses of SOD2 protein dynamics revealed higher ubiquitinated-SOD2 protein levels in PPHN-lambs, suggesting dysregulated protein ubiquitination. OLA1 controls multiple proteostatic mechanisms and is overexpressed in response to stress. We demonstrated that OLA1 acts as a molecular chaperone, and its activity is induced by stress. Strikingly, OLA1 expression is decreased in distal-PAs from PPHN-patients and fetal-lambs. OLA1 deficiency enhanced CHIP affinity for Hsp70-SOD2 complexes, facilitating SOD2 degradation. Consequently, mitochondrial H2O2 formation is impaired, leading to XIAP (X-linked inhibitor of apoptosis) overexpression that suppresses caspase activity in PA-smooth muscle cells, allowing them to survive and proliferate, contributing to PA remodeling. In-vivo, ola1-/- downregulated SOD2 expression, induced distal-PA remodeling, and right ventricular hypertrophy. We conclude that decreased OLA1 expression accounts for SOD2 downregulation and, therefore, a therapeutic target in PPHN treatments.

Effect of monoacylglycerol lipase on the tumor growth in endometrial cancer.

AIM: Abnormal lipid metabolism plays a dual role in tumorigenesis, specifically in the occurrence and development of cancers. Monoacylglycerol lipase (MAGL), a hydrolase that is important for lipid metabolism, plays a vital role in different aspects of tumorigenesis. Many studies have shown that MAGL is highly elevated in a variety of cancers and plays an active role. However, its potential role in supporting endometrial cancer (EC) growth and progression has not yet been explored in depth. METHODS: Immunohistochemistry and quantitative real-time reverse transcription polymerase chain reaction were performed to estimate the protein and messenger RNA (mRNA) levels of MAGL in tumor tissues. Then, JZL184 and small interfering RNA (siRNA) were used to decrease the expression of MAGL in EC cells. The gene and protein expression levels of MAGL were measured using quantitative real-time PCR and western blotting, respectively. Additionally, the effect of MAGL on tumor growth in EC was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide , cell cycle and western blotting assay in vitro. RESULTS: We found that MAGL was overexpressed in EC and was significantly correlated with surgical-pathological stage, myometrial invasion, number of pregnancies and body mass index. The growth and cell cycle progression of tumor cells were significantly impaired in vitro by the pharmacological and siRNA-mediated MAGL inhibition. In addition, MAGL inhibition seemed to repress two target genes, Cyclin D1 and Bcl-2. CONCLUSION: In summary, we have demonstrated that MAGL is involved in EC growth and progression. Our results suggest that targeting MAGL may be a novel and valid treatment for EC.

DACH1 suppresses epithelial to mesenchymal transition (EMT) through Notch1 pathway and reverses progestin resistance in endometrial carcinoma.

Progestin resistance limits the effectiveness of progestin therapy in endometrial carcinoma for patients who desire to preserve fertility. To investigate the molecular mechanism of progestin resistance in endometrial carcinoma, we performed microarray analysis among Ishikawa and progestin resistant cell IshikawaPR cells. We found that epithelial to mesenchymal transition (EMT) was involved in progestin resistance and dachshund family transcription factor 1 (DACH1) is positively correlated with progesterone receptor (PGR). Knockdown of DACH1 in Ishikawa cell promoted proliferation, metastasis ability, and resistance to progestin. Conversely, overexpression of DACH1 in IshikawaPR cell rendered more sensitive to progestin treatment. Xenograft model assay also had similar results. In addition, our data showed that DACH1 overexpression inhibited EMT and decreased c-Jun, Notch1 and Hes1expression. Our study demonstrated for the first time that EMT is involved in progestin resistance of EC. The response to progestin could be reserved by DACH1 suppressed EMT through Notch1 pathway via c-Jun.

Oncogenic role of ABHD5 in endometrial cancer.

BACKGROUND: Abhydrolase domain containing 5 (ABHD5) functions as a tumor suppressor in colorectal and prostate cancers. The aim of this study was to investigate the roles of ABHD5 in endometrial cancer. MATERIALS AND METHODS: ABHD5 expression was detected in clinical samples by immunohistochemical staining. Cell proliferation and invasion were evaluated with the Cell Counting Kit-8 and Transwell assay, respectively. Western blotting was performed to analyze protein expression. Glucose uptake was assessed by 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose. Lactate production was detected by a lactate assay kit. RESULTS: In the present study, ABHD5 was overexpressed in endometrial cancer tissues, and its expression was closely correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. In addition, we observed that the knockdown of ABHD5 inhibited cell proliferation, invasion, glucose uptake and lactate production in HEC-1A cells, which expressed high levels of ABHD5. Conversely, the opposite effects were observed when ABHD5 was ectopically expressed in Ishikawa cells, which had low levels of ABHD5. Furthermore, the changes in glycolysis regulators (enolase 1 [ENO1], glucose transporter 1 [GLUT1] and lactate dehydrogenase A [LDHA]) and epithelial-to-mesenchymal transition-related proteins (E-cadherin and Snail) in HEC-1A cells with ABHD5 knockdown were consistent with the effects of ABHD5 on glycolysis and cell invasion. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was increased, while the phosphorylated AKT (p-AKT) was decreased when ABHD5 was downregulated. Notably, treatment with the allosteric AKT inhibitor MK-2206 completely abolished the effects caused by ABHD5 overexpression in Ishikawa cells. Finally, ABHD5 knockdown potently suppressed tumor growth in vivo. CONCLUSION: Overall, these results suggest that ABHD5 may play an oncogenic role in endometrial cancer via the AKT pathway.

Silibinin inhibits endometrial carcinoma via blocking pathways of STAT3 activation and SREBP1-mediated lipid accumulation.

AIMS: To seek new conservative treatments for young women with early-stage endometrial carcinoma (EC) who desire to retain fertility, we investigated the effects and the underlying mechanism of silibinin in EC, which exhibits promising anti-cancer and tumour-suppressing properties in many malignant tumours. MAIN METHODS: Through relevant experiments such as MTT assay, cell colony formation assay and subcutaneous xenograft experiment, we showed that silibinin inhibited the proliferation of EC cells and tumours. Silibinin significantly induced cell cycle arrest and promoted apoptosis in vitro. In vivo TUNEL assay confirmed the apoptotic effect caused by silibinin. STAT3 is activated in the development of tumours. Silibinin notably inhibited the expression of STAT3 phosphorylation and regulated the expression of downstream genes involved in cell cycle and apoptosis at protein and mRNA levels in EC cells. Furthermore, silibinin decreased the expression of intranuclear SREBP1, which is a key regulator of lipid metabolism in the nucleus, and reduced the lipid accumulation in EC cells. Downregulation of the expression levels of SREBP1 and its downstream genes associated with lipid metabolism was also observed in silibinin-treated EC cells. KEY FINDINGS: The results revealed that a novel anticancer drug, silibinin, markedly suppressed cell proliferation, cell cycle progression, apoptosis inhibition and lipid accumulation by blocking STAT3 and SERBP1 signalling pathways in EC cells. SIGNIFICANCE: Silibinin has anti-tumour characteristics and inhibits abnormal lipid metabolism in EC. This compound is expected to contribute to the conservative and adjuvant treatment of EC and should therefore be investigated further.

Fatostatin suppresses growth and enhances apoptosis by blocking SREBP-regulated metabolic pathways in endometrial carcinoma.

Fatostatin, a chemical inhibitor of the sterol regulatory element­binding protein (SREBP) pathway, has been reported to possess high antitumor activity against prostate and pancreatic cancer. The main aim of the present study was to investigate the effects and mechanism of fatostatin in endometrial carcinoma (EC). In the present study, we determined that fatostatin inhibited EC cell viability and colony formation capacity, decreased the invasive and migratory capacities of EC cells, induced EC cell cycle arrest at the G2/M phase and stimulated caspase­mediated apoptosis of EC cells. In addition, fatostatin significantly decreased the protein expression levels of nuclear SREBPs and their downstream genes and increased the protein expression levels of cleaved caspase­9, caspase­3 and PARP in EC cells. In addition, the mRNA expression levels of SREBP­controlled downstream genes were also significantly downregulated. The quantification assays of fatty acids and total cholesterol revealed that the levels of free fatty acids and total cholesterol in EC cells were decreased. The present study indicated that fatostatin exhibited antitumor effects by blocking SREBP­regulated metabolic pathways and inducing caspase­mediated apoptosis in EC and may be a potent therapeutic strategy for the treatment of EC.

Long non-coding RNA expression profile in cervical cancer tissues.

Cervical cancer (CC), one of the most common types of cancer of the female population, presents an enormous challenge in diagnosis and treatment. Long non-coding (lnc)RNAs, non-coding (nc)RNAs with length >200 nucleotides, have been identified to be associated with multiple types of cancer, including CC. This class of nc transcripts serves an important role in tumor suppression and oncogenic signaling pathways. In the present study, the microarray method was used to obtain the expression profile of lncRNAs and protein-coding mRNAs and to compare the expression of lncRNAs between CC tissues and corresponding adjacent non-cancerous tissues in order to screen potential lncRNAs for associations with CC. Overall, 3356 lncRNAs with significantly different expression pattern in CC tissues compared with adjacent non-cancerous tissues were identified, while 1,857 of them were upregulated. These differentially expressed lncRNAs were additionally classified into 5 subgroups. Reverse transcription quantitative polymerase chain reactions were performed to validate the expression pattern of 5 random selected lncRNAs, and 2lncRNAs were identified to have significantly different expression in CC samples compared with adjacent non-cancerous tissues. This finding suggests that those lncRNAs with different expression may serve important roles in the development of CC, and the expression data may provide information for additional study on the involvement of lncRNAs in CC.

LncRNA-TCONS_00026907 is involved in the progression and prognosis of cervical cancer through inhibiting miR-143-5p.

Our previous long noncoding RNA (lncRNA) microarray revealed that lncRNA-TCONS_00026907 is aberrantly expressed between cervical cancer tissues and adjacent tissues. This study aims to explore the potential role of TCONS_00026907 in the development of cervical cancer. The expression levels of TCONS_00026907 in cervical cancer tissues and adjacent tissues from 83 patients of cervical cancer were detected by quantitative real-time polymerase chain reaction and the survival rate was analyzed. In vitro, HeLa and SiHa cells were transfected with small hairpin RNA (shRNA)-TCONS_00026907, then cell proliferation, cycle distribution, apoptosis, migration and invasion were measured. To confirm TCONS_00026907 regulates expression of ELK1 through inhibiting miR-143-5p, overexpression of miR-143-5p and silencing of ELK1 were, respectively, performed in HeLa and SiHa cells. Results showed that TCONS_00026907 level was significantly higher in cervical cancer tissues compared to noncancerous tissues and the survival rate was lower in the high expression group. Silencing of TCONS_00026907, overexpression of miR-143-5p and silencing of ELK1 inhibited cervical cell cycle, proliferation, migration, and invasion, but promoted apoptosis, respectively. Furthermore, silencing of TCONS_00026907 suppressed the growth of cervical tumors and altered the expression of ELK1, p-ELK1, C-fos, Cyclin D1 and Bcl-2 in vivo. Our study identifies TCONS_00026907 as a potent proto-oncogene and indicates that TCONS_00026907/miR143-5p/ELK1 regulatory pathway plays an important role in cervical cancer.

OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression.

OLA1, an Obg-family GTPase, has been implicated in eukaryotic initiation factor 2 (eIF2)-mediated translational control, but its physiological functions remain obscure. Here we report that mouse embryos lacking OLA1 have stunted growth, delayed development leading to immature organs-especially lungs-at birth, and frequent perinatal lethality. Proliferation of primary Ola1(-/-) mouse embryonic fibroblasts (MEFs) is impaired due to defective cell cycle progression, associated with reduced cyclins D1 and E1, attenuated Rb phosphorylation, and increased p21(Cip1/Waf1) Accumulation of p21 in Ola1(-/-) MEFs is due to enhanced mRNA translation and can be prevented by either reconstitution of OLA1 expression or treatment with an eIF2α dephosphorylation inhibitor, suggesting that OLA1 regulates p21 through a translational mechanism involving eIF2. With immunohistochemistry, overexpression of p21 protein was detected in Ola1-null embryos with reduced cell proliferation. Moreover, we have generated p21(-/-) Ola1(-/-) mice and found that knockout of p21 can partially rescue the growth retardation defect of Ola1(-/-) embryos but fails to rescue them from developmental delay and the lethality. These data demonstrate, for the first time, that OLA1 is required for normal progression of mammalian development. OLA1 plays an important role in promoting cell proliferation at least in part through suppression of p21 and organogenesis via factors yet to be discovered.