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Human epidermal growth factor receptor 2 (HER2)+ breast cancer is characterized by high malignancy and poor prognosis. Long non-coding (lnc)RNAs are crucial in breast cancer progression and prognosis, especially in tumor-associated immune processes. The present study aimed to elucidate novel lncRNAs related to immune function that could serve as biomarkers for both diagnosis and prognosis of this cancer subtype. Using data from The Cancer Genome Atlas and The Immunology Database and Analysis Portal, correlation analysis was performed to identify differentially expressed lncRNAs and immune-related genes. Through receiver operating characteristic analysis, the diagnostic value of specific lncRNAs was identified and evaluated, with a focus on their capacity to distinguish between cancerous and non-cancerous states. The present research revealed 22 differentially expressed lncRNAs and 23 differentially expressed immune-related genes, with 19 immune-related lncRNAs. A total of 13 of these lncRNAs demonstrated diagnostic relevance. In particular, it was demonstrated that the expression of lncRNA CTC-537E7.2 was significantly correlated with patient survival, suggesting its potential as a prognostic marker. Additionally, the expression of lncRNA CTC-537E7.2 was significantly correlated with clinical parameters, such as hormone receptor status and patient demographics. Moreover, it exhibited associations with four distinct immune cell types and demonstrated involvement in the Janus kinase-signal transducer and activator of transcription pathway. Further assessment by in situ hybridization confirmed the increased expression of lncRNA CTC-537E7.2 in samples from HER2+ patients, reinforcing its significance. In summary, the present study uncovered a novel prognostic biomarker for HER2+ breast cancer, thereby laying the groundwork for investigating the underlying molecular mechanisms driving the development of this subtype of breast cancer. [ABSTRACT FROM AUTHOR]

Small ubiquitin-like modifier 4 (SUMO4) is the latest member of the sumoylation family, which enhances the stability of protein, regulates the distribution and localization of the protein, and affects the transcription activity of the protein. However, the role of SUMO4 in non-small cell lung cancer (NSCLC) has not yet been reported. The present study first demonstrated that SUMO4 was upregulated in a number of tissues from patients with NSCLC. Immunohistochemistry was performed to demonstrate the expression level of SUMO4 in lung cancer tumor tissues. Following the transfection, The EMT status and signaling pathway activation regulated by SUMO4-siRNA was assessed by western blotting. The Transwell and wound healing assays were performed to investigate the regulatory effect of SUMO4-siRNA on cell migration and invasion. Cell Counting Kit-8 assay was performed to investigate whether SUMO4-siRNA affected the chemosensitivity of the NSCLC cells to cisplatin. Statistical analysis of immunohistochemical results from the tissues showed that the overexpression of SUMO4 was significantly associated with sex, tumor type, history of smoking, T stage and poor prognosis. It was also identified that SUMO4 small interfering RNA attenuated invasion and migration in NSCLC cell lines, as well chemosensitivity to cisplatin via the inhibition of the JAK2/STAT3 pathway. In conclusion, SUMO4 may play an important role in the poor prognosis of patients with NSCLC. The present study indicates that SUMO4 may be a potential therapeutic target for NSCLC. [ABSTRACT FROM AUTHOR]

Osteosarcoma is a malignant tumor derived from the skeletal system, often occurring in bone tissues, and it is the most common malignant tumor in the skeletal system, with more than 90% of cases being highly malignant. The present study was designed to explore the regulatory effects of microRNA (miR)-19a on the proliferation and apoptosis of osteosarcoma cells, and its influence on the activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. The expression of miR-19a in adult SaOS-2 osteosarcoma cells was downregulated via lentiviral transfection, and the cells were divided into a control group, NC-inhibitor group and miR-19a-inhibitor group. The expression of miR-19a in each group was detected via quantitative polymerase Chain reaction (qPCR). Next, the cell proliferation and apoptosis levels in each group were detected via methyl thiazolyl tetrazolium (MTT) assay and flow cytometry, respectively, and the level of reactive oxygen species (ROS) in cells was further determined. Moreover, the expression levels of apoptosis-related proteins and JAK2/STAT3 signaling pathway-related proteins were detected through western blotting. The expression level of miR-19a in the miR-19a-inhibitor group was significantly lower than that in the control group and NC-inhibitor group (P<0.01). Downregulation of miR-19a significantly reduced the proliferation ability (P<0.01), increased the apoptosis level of SaOS-2 cells (P<0.01), and significantly increased the ROS level in cells (P<0.01). Downregulation of miR-19a also promote cleaved caspase-3/caspase-3 expression in the OS cells (P<0.01) and inhibited Bcl-2/Bax expression (P<0.01). Additionally, downregulation of miR-19a markedly lowered the protein expression levels of phosphorylated (p-)JAK2, p-STAT3 and myeloid cell leukemia-1 (Mcl-1) in the cells (P<0.01). To conclude, downregulation of miR-19a can inhibit the JAK2/STAT3 signaling pathway in SaOS-2 cells, promote the expression of apoptosis-related proteins, and increase the ROS level in cells, thereby promoting apoptosis and inhibiting cell proliferation. [ABSTRACT FROM AUTHOR]

Effect of CXCL8 gene silencing-mediated JAK-STAT signaling pathway on epithelial-mesenchymal transition (EMT) of human cutaneous melanoma cells was explored. Eighty patients with cutaneous melanoma were enrolled in the study. Cells were transfected accordingly and divided into five groups: The blank group (human cutaneous melanoma cells), NC group (human cutaneous melanoma cells + blank vector plasmid transfection), CXCL8 siRNA group (human cutaneous melanoma cells + CXCL8 silent expression vector plasmid transfection), AG490 group (human cutaneous melanoma cells + JAK-STAT signal pathway inhibitor transfection), CXCL8 siRNA + AG490 group (human cutaneous melanoma cells + JAK-STAT signaling pathway inhibitor + CXCL8 silent expression vector plasmid transfection). The expression levels of CXCL8, JAK2, STAT3, epithelial cadherin (E-cadherin), neurotrophic cadherin (N-cadherin) and vimentin in tissues and cells were detected by RT-qPCR and western blot analysis. CCK-8 and flow cytometry were used to detect cell proliferation and apoptosis. Compared with adjacent normal tissues, the expression of E-cadherin in human cutaneous melanoma tissues was significantly decreased, whereas the expression of CXCL8, JAK2, STAT3, vimentin and N-cadherin was significantly increased (P<0.05). Compared with the blank group, CXCL8 siRNA group and CXCL8 siRNA + AG490 group had significantly lower expression of CXCL8 (P<0.05). Compared with the blank group, the expression levels of JAK2, STAT3, vimentin and N-cadherin in CXCL8 siRNA group, AG490 group and CXCL8 siRNA + AG490 group were decreased, the expression of E-cadherin was increased, the cell proliferation ability was decreased and apoptosis was increased (P<0.05). Compared with CXCL8 siRNA group, the expression of JAK2, STAT3, vimentin and N-cadherin in CXCL8 siRNA + AG490 group were significantly decreased, the expression of E-cadherin was significantly increased, cell proliferation ability was decreased and apoptosis was increased (P<0.05). In conclusion, CXCL8 gene expression silencing may inhibit EMT and cell proliferation while promoting cell apoptosis of human cutaneous melanoma cells by inhibiting the activation of JAK-STAT signaling pathway. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive and lethal tumor of the central nervous system. The present study set out to identify reliable prognostic and predictive biomarkers for patients with GBM. RNA-sequencing data were obtained from The Cancer Genome Atlas database and DNA methylation data were downloaded using the University of California Santa Cruz-Xena database. The expression and methylation differences between patients with GBM, and survival times <1 and ≥1 year were investigated. A protein-protein interaction network was constructed and functional enrichment analyses of differentially expressed and methylated genes were performed. Hub genes were identified using the Cytoscape plug-in cytoHubba software. Survival analysis was performed using the survminer package, in order to determine the prognostic values of the hub genes. The present study identified 71 genes that were hypomethylated and expressed at high levels, and four genes that were hypermethylated and expressed at low levels in GBM. These genes were predominantly enriched in the 'JAK-STAT signaling pathway', 'transcriptional misregulation in cancer' and the 'ECM-receptor interaction', which are associated with GBM development. Among the 24 hub genes identified, 15 possessed potential prognostic value. An integrative analysis approach was implemented in order to analyze the association of DNA methylation with changes in gene expression and to assess the association of gene expression changes with GBM survival time. The results of the present study suggest that these 15 CpG-based genes may be useful and practical tools in predicting the prognosis of patients with GBM. However, future research on gene methylation and/or expression is required in order to develop personalized treatments for patients with GBM. [ABSTRACT FROM AUTHOR]

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is involved in cell immunity, division and death, as well as in tumor formation. The expression of key genes in the JAK-STAT signaling pathway in different types of cancer serves different roles. However, few reports are available on the prognostic value of the genes of the JAK-STAT signaling pathway in skin cutaneous melanoma (SKCM). The potential prognostic value of gene expression in the JAK-STAT signaling pathway in patients with SKCM was analyzed in the present study using data obtained from The Cancer Genome Atlas. To predict the potential functions and mechanisms of these genes in SKCM, gene set enrichment analysis (GSEA) and bioinformatics analysis were performed. A nomogram model including gene expression level and high risk factors was used to predict the risk level of prognostic. High expression levels of STAT1, STAT3, STAT4 and STAT5B, and low expression levels of STAT6 were associated with favorable prognosis [adjusted P<0.001; hazard ratio (HR), 0.595; 95% confidence interval (CI), 0.455–0.778; adjusted P=0.018; HR, 0.725; 95% CI, 0.555–0.947; adjusted P<0.001; HR, 0.590; 95% CI, 0.450–0.773; adjusted P=0.007; HR, 0.690; 95% CI, 0.526–0.940; and adjusted P=0.026; HR, 0.737, 95% CI, 0.563–0.964, respectively]. GSEA results demonstrated that these genes were involved in cell differentiation, invasion, adhesion, migration, cycle, colony formation and mitogen-activated protein kinase signaling. The combination of genes with favorable prognosis had a better effect on the overall survival (univariate survival analysis, P<0.05). The results of the present study suggest that STAT1, STAT3, STAT4, STAT5B and STAT6 gene expression may be used as a potential prognostic biomarker of SKCM, and the combined outcomes may exhibit a stronger interaction and higher survival time for SKCM. [ABSTRACT FROM AUTHOR]

Cytokines play an important role in the development of tumors. The purpose of the present study was to evaluate the mechanisms and cytokine level changes after transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). The Short Time-series Expression Miner (STEM) program was utilized to cluster cytokine expression profiles from the day before TACE to day 21 post-TACE. Based on the identified significant signatures, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed. Cytokines were serially monitored in 60 evaluable patients to identify the results of the STEM program. Examination of the significant signatures identified 6 significant time-varied expression patterns for 507 cytokines (profiles 16, 18, 28, 41, 42 and 43). GO analysis was enriched in 'cytokine receptor-binding' and 'cytokine receptor activity', and the identified signaling pathways included 'cytokine-cytokine receptor interaction' and the 'JAK-STAT signaling pathway'. Ciliary neurotrophic factor (CNTF) level was increased early after TACE, reaching a peak on day 7 before finally decreasing from day 14 onwards, and was significantly positively correlated with aminotransferase level. Serum levels of pre-TACE IL-10 predicted the local tumor response and overall survival (OS) of the patients, while serum levels of post-TACE IL-1β only indicated the local tumor response of the patient. Overall, the present study identified cytokine time-series expression profiles of patients with HCC undergoing TACE. Early phase increases in CNTF after TACE were associated with post-treatment hepatic injury. IL-1β may reflect an objective response after TACE, while IL-10 may represent a biomarker for OS and the objective response pre-TACE, which may help patients with HCC to benefit from TACE. [ABSTRACT FROM AUTHOR]

Accumulating evidence has demonstrated that thioredoxin interacting protein (TXNIP) is abnormally expressed in a variety of malignant tumors and functions as a tumor suppressor. However, the association between TXNIP and clear cell renal cell carcinoma (CCRCC) has not yet been fully elucidated. The aim of the present study was to evaluate the role of TXNIP in CCRCC using The Cancer Genome Atlas (TCGA) database. The RNA sequencing data and corresponding clinical data were collected from TCGA database. The association between TXNIP and patient clinicopathological characteristics was analyzed using analysis of variance and logistic regression. The Kaplan-Meier method and Cox proportional hazards model were used to assess the association between TXNIP and overall survival. Gene Set Enrichment Analysis (GSEA) was used to explore the associated signaling pathways. TXNIP expression was identified to be decreased in CCRCC tissues compared with normal tissues. The decreased expression of TXNIP in CCRCC was significantly associated with clinical stage [OR=0.509 for III vs. I (P=0.002); OR=0.527 for IV vs. I (P=0.012)], T stage [OR=0.552 for T3 vs. T1 (P=0.002)] and grade [OR=0.261 for G4 vs. G1 (P=0.027)]. Kaplan-Meier survival analysis indicated that cases of CCRCC with low TXNIP expression were associated with poorer prognoses compared with those with a high expression level (P=0.002). Univariate and multivariate Cox analyses indicated that TXNIP was an independent prognostic factor in CCRCC. GSEA revealed that 6 pathways exhibited significant differential enrichment in the TXNIP high-expression phenotype, including the WNT signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, the phosphatidylinositol signaling system, the transforming growth factor-β (TGF-β) signaling pathway, autophagy and the Janus kinase (JAK)-STAT signaling pathway. Taken together, the results of the present study indicate that TXNIP expression may be a potential prognostic marker for patients with CCRCC. In addition, the WNT signaling pathway, MAPK signaling pathway, phosphatidylinositol signaling system, TGF-β signaling pathway, autophagy and the JAK-STAT signaling pathway may be the crucial pathways regulated by TXNIP in CCRCC. [ABSTRACT FROM AUTHOR]

Human embryo lung cellular protein interacting with severe acute respiratory syndrome-coronavirus nonstructural protein-10 (HEPIS) is expressed at varying levels in multiple organs and breast cancer cell lines. However, its expression and function in breast cancer cells has yet to be studied. Therefore, RNA in situ hybridization was used to detect the expression of HEPIS in breast cancer and cancer-adjacent normal breast tissue. HEPIS was expressed at lower levels in breast cancer compared with that in adjacent normal tissue. Subcellular localization of HEPIS was mainly found in the cytoplasm of HeLa cells. Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine cell proliferation assays were used to investigate the role of HEPIS in cancer cell proliferation. Ectopic expression of HEPIS in MCF-7 cells was found to significantly inhibit cell proliferation. In contrast, knockdown of HEPIS by RNA interference exhibited the opposite effect. Furthermore, a dual-luciferase reporter assay was performed and HEPIS overexpression specifically inhibited the activity of the NF-κB reporter gene. Results of the gene chip assay revealed that 2,231 genes were differentially expressed in HEPIS-overexpressing cells. Results of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these genes were enriched in the 'mitogen-activated protein kinase signaling pathway', 'JAK-STAT signaling pathway' and 'focal adhesion'. Reverse transcription-quantitative PCR was used to confirm the expression levels of the differentially expressed genes interleukin 2 receptor subunit α (IL2RA), interferon α and β receptor subunit 2 (IFNAR2) and IFα8 (IFNA8). In conclusion, the results of the present study indicated that HEPIS may function as a potential repressor of breast cancer. [ABSTRACT FROM AUTHOR]

The Sonic hedgehog (Shh) signaling pathway may be interrelated with other signaling pathways, such as the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in gastrointestinal stromal tumor (GIST). The present study investigated the interaction among Shh, PI3K and MAPK signaling pathways in GIST cells. The expression of PI3K, MAPK and Shh signaling pathways in GIST-H1 cells were upregulated by endothelial growth factor (EGF) and recombinant Shh (N-shh) stimulation, and were downregulated by specific inhibitors of each signaling pathway. The proliferation rate of GIST-H1 cells were significantly increased under EGF or N-shh treatment (P<0.01). In addition, this effect was partially prevented by the pretreatment of the inhibitors of these signaling pathways. In summary, a cross regulation exists among the Shh, PI3K and MAPK signaling pathways in GIST-H-1 cells. The combined use of the inhibitors of these signaling pathways is a potentially novel option for GIST targeted therapy. [ABSTRACT FROM AUTHOR]

Sigma-1 receptor (sigma-1R), a 25-kDa integral membrane protein, is expressed at a high density in various tumor cell lines and its ligands mediate tumor cell proliferation. However, the effect of this receptor on proliferation and the associated intracellular molecules in tumors remains unclear. The present study aimed to investigate the effect of sigma-1R overexpression on MCF-7 cell proliferation and the associated intracellular molecules that serve a key role in this process. The sigma-1R proliferative function was examined by comparing the proliferation rates of a sigma-1R-overexpressing line, MCF-41 with a sigma-1R-defective line, MCF-7, in culture media with various serum concentrations. The results demonstrated that MCF-41 cells grew significantly faster compared with MCF-7 cells, indicating a proliferation-enhancing receptor function. This proliferation-enhancing effect was completely eliminated by adding a PKC inhibitor to the culture media for MCF-41 cells. To identify which PKC subtype affects the proliferative function of sigma-1R, five inhibitors of PKC subtypes or enzymes involved in the PKC signaling cascade were introduced to MCF-7 and MCF-41 cell culture media and their effects on cell proliferation were compared. It was revealed that only the classic PKC subtype inhibitor, GF109203×, significantly inhibited MCF-41 cell proliferation compared with the MCF-7 line. In conclusion, among PKC iso-enzymes only classic PKC subtype enzymes serve an important role in sigma-1R overexpression enhancing MCF-7 cell proliferation. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most common malignancies in men globally. The aim of the present study was to identify the key genes and pathways involved in the occurrence of PCa. Gene expression profile (GSE55945) was downloaded from Gene Expression Omnibus, and the differentially expressed genes (DEGs) were identified. Subsequently, Gene ontology analysis, KEGG pathway analysis and protein-protein interaction (PPI) analysis of DEGs were performed. Finally, the identified key genes were confirmed by immunohistochemistry. The GO analysis results showed that the DEGs were mainly participated in cell cycle, cell division, cell development and cell junction. The KEGG pathway analysis showed that the DEGs were mainly enriched in proteoglycans in cancer, endocytosis, focal adhesion and hippo signaling pathway. The PPI analysis results showed that RPS21, FOXO1, BIRC5, POLR2H, RPL22L1 and NPM1 were the key genes involved in the occurrence of PCa, and the Module analysis indicated that the occurrence of PCa was associated with cell cycle, oocyte meiosis and ribosome biogenesis. IHC result showed that the expression of RPS21, BIRC5, POLR2H, RPL22L1 and NPM1 were significantly upregulated in PCa, while the expression of FOXO1 was significantly downregulated in PCa, matching with the bioinformatics analysis. Taken together, several key genes and pathways were identified involved in PCa, which might provide the potential biomarker for prognosis, diagnosis and drug targets. [ABSTRACT FROM AUTHOR]

Stromal cell-derived factor-1 (SDF-1) regulates multiple cell signal pathways in a variety of cellular functions, including cell migration, proliferation, survival and angiogenesis. SDF-1-induced chemotaxis is an important step of lymphocyte migration. However, the molecular mechanisms that modulate SDF-1-mediated lymphocyte migration are not well identified. Nitric oxide (NO) has been found to function as a signaling molecule in a number of signaling pathways, including migration. In the present study, the potential role of NO in SDF-1-induced migration and the association between NO and the cytoskeletal changes of Jurkat cells was investigated. The present study demonstrated that Jurkat cells induced the production of NO by SDF-1 stimulation, using Griess reaction method and western blot analysis, and that NO was involved in SDF-1-induced rearrangement and polymerization of the cytoskeleton, using NOS inhibitor L-NMMA. Furthermore, NO was required for the migration of Jurkat cells. The research suggested that NO signaling pathways exerted a critical role in SDF-1-induced cytoskeleton changes and the migration of Jurkat cells. This work provides insight into the migration mechanism of acute lymphoblastic leukemia and provides an effective theoretical basis for therapy strategies for acute lymphoblastic leukemia. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematological malignancy that lacks a cure. However, novel combination therapy is a current anti-MM strategy. Doxorubicin (DOX) is a type of anthracycline which is a first-line chemotherapeutic for treating MM and induces senescence in many types of cancer. Dinaciclib is a potent, small molecule CDK inhibitor with promise for treating several types of cancer in I/II phase clinical trials. In the present study the anticancer effects and underlying mechanisms of dinaciclib combined with DOX in MM RPMI-8226 cells were investigated. Results indicated that DOX induced cell viability inhibition, cell cycle arrest and senescence. Furthermore, DOX resulted in increased alterations in DNA damage-related proteins such as p-ATM, p-Chk2, p-p53, p21 and γH2AX, but not p16. Notably, the combination of dinaciclib and DOX inhibited cell growth and promoted senescence by transforming the suppressive effects of the ATM/Chk2/p53/p21 signaling pathway and enhancing the p16 signaling pathway. Thus, low-dose dinaciclib enhanced anti-MM effects mediated by DOX via transformation of p21-p16 signaling pathways, leading to accelerated senescence, but not apoptosis. The present findings suggest this approach may be a promising therapeutic strategy for the treatment of MM. [ABSTRACT FROM AUTHOR]

Wentilactone A (WA), a marine-derived compound, inhibits proliferation of NCI-H446, as demonstrated by previous research; however, the anti-SCLC mechanism underlying WA was not fully investigated. The present study aimed to investigate the anti-SCLC mechanism underlying WA in vitro and in vivo. Cell Counting Kit-8 was used to assay cell growth, flow cytometry was conducted to analyze cell apoptosis and nude mice xenografts were used to examine SCLC growth following WA treatment. Bioinformatics was used for verification of the target gene of WA. Reverse transcription-quantitative polymerase chain reaction and western blot were used to examine aldo-keto reductase family 1 member C1 (AKR1C1) mRNA and protein levels, and AKR1C1-associated proteins prior to and following WA treatment. Cell growth, apoptosis and growth of nude mice xenografts were assayed prior to and following transfection with AKR1C1 knockdown or overexpression carriers, respectively. It was determined that AKR1C1 was a target gene of WA. Decreased AKR1C1 expression and WA treatment promoted apoptosis in SCLC via the insulin like growth factor-1 receptor/insulin receptor substrate 1/phosphoinositide 3-kinase/AKT/nuclear factor-erythroid 2-associated factor 2/Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein/Caspase-3 pathway. WA attenuated the proliferation and induced the apoptosis of SCLC cells in vitro and in vivo by targeting the AKR1C1 gene. WA may be a novel AKR1C1-targeted drug candidate for the treatment of SCLC in the future. [ABSTRACT FROM AUTHOR]

Aclidinium, a muscarinic antagonist, is generally used to treat the respiratory system diseases whereas it is not clear whether aclidinium has therapeutic effect in ovarian cancer (OC). The aim of this study was to investigate the impact of aclidinium on OC and its potential mechanism. CCK-8 was employed to test the potential effect of aclidinium on SKOV3 cell proliferation. Transwell migration and invasion assay was performed to assess the influence of aclidinium on SKOV3 cell metastasis and invasion. Furthermore, flow cytometry apoptotic analysis was used to evaluate the effect of aclidinium on cell apoptosis. Finally, western blotting was applied to determine the changes of key proteins in apoptosis and PI3K/AKT/mTOR signaling pathway induced by aclidinium. The study showed that aclidinium had antiproliferative activity on SKOV3 cells. Simultaneously, aclidinium could significantly inhibit the number of migrated and invaded SKOV3 cells and markedly increased the SKOV3 cell apoptosis rate. Mechanistically, the expression of PI3K/AKT/mTOR signaling pathway related proteins were significantly inhibited in aclidinium treated SKOV3 cells. Our findings proposed a clue for further OC studies in preclinical and clinical treatment and aclidinium may be useful for the treatment of OC in the future. [ABSTRACT FROM AUTHOR]

The leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) has been reported to serve an important role in a number of human malignancies and is correlated with poor prognosis. However, little is known about the role of LETM1 in renal cell carcinoma (RCC). In the present study, the expression levels of LETM1 were investigated in RCC cell lines (Caki-1, 786-O, OS-RC-2, A498 and ACHN) and the HK-2 normal human renal tubular epithelial cell line. Short interfering RNA (siRNA) was used to knock down the expression of LETM1 in 786-O and A498 cells. The results indicated that the constitutive expression of LETM1 was notably upregulated in RCC cell lines. Knockdown of LETM1 significantly decreased cell proliferation, migration and invasion. Mechanistically, it was revealed that the knockdown of LETM1 expression sharply downregulated the protein expression of β-Catenin, Cyclin D1 and c-Myc in 786-O and A498 cells. In conclusion, these results suggest that knockdown of LETM1 exhibits tumor suppressive effects, at least in part by controlling the downstream Wnt/β-Catenin signaling pathway. Therefore, LETM1 may act as a novel therapeutic target for the treatment of RCC. [ABSTRACT FROM AUTHOR]

MicroRNAs have been suggested as potential regulators in gastric cancer (GC) development through affecting the expression of their target genes. Previous studies have demonstrated that miR-140-5p is downregulated in GC. However, the underlying functional role of miR-140-5p in GC remains largely unknown. The present study revealed that miR-140-5p expression was significantly decreased in 60 GC tissues, compared with corresponding adjacent non-tumor tissues. A lower miR-140-5p expression was significantly associated with lymph node metastasis and an advanced Tumor-Node-Metastasis stage in patients with GC. Furthermore, patients with a lower miR-140-5p expression exhibited shorter disease-free survival and overall survival times. Gain- and loss-of-function assays revealed that increased miR-140-5p expression significantly inhibited GC cell proliferation and invasion ability, as well as the Wnt/β-catenin signaling pathway by decreasing WNT1 and β-catenin expression. However, decreasing miR-140-5p expression had the opposite effects. Bioinformatics methods and dual-luciferase reporter assays revealed that WNT1 was a direct target of miR-140-5p. miR-140-5p suppressed cell proliferation and invasion by regulating WNT1 expression. Therefore, the results of the present study demonstrated that miR-140-5p may serve as a potential prognostic marker and therapeutic target in patients with GC. [ABSTRACT FROM AUTHOR]

To investigate the effects of hypoxia on the features of cancer stem cells in the glioma cancer U87 cell line and underlying mechanism, stem cell markers and features in U87 were studied under the hypoxic and normoxic culture conditions by reverse transcription-quantitative polymerase chain reaction, western blot analysis, MTT, a colony formation test and flow cytometry. Compared to the normoxic group, the cluster of differentiation 133+ phenotype, clone formation rate and cell vitality were significantly elevated in U87 cells cultured in a hypoxic microenvironment. Also, the mRNA and protein expression of neurogenic locus notch homolog protein 1 (Notch1) and Oct3/4 were significantly elevated in U87 cells cultured in a hypoxic microenvironment, however, transcription factor SOX-2 expression was not significantly changed. These results indicate that hypoxia can promote the proliferation of glioma stem cells and maintain the characteristics of stem cells through the activation of Notch1 and Oct3/4 or Notch1 activation, affecting the biological characteristics of glioma cells. [ABSTRACT FROM AUTHOR]

Polypeptide-N-acetyl-galactosaminlytransferase 7 (GALNT7), a member of the GalNAc-transferase family, has not been previously evaluated as a prognostic factor of glioblastoma (GBM) or low-grade glioma (LGG). Based on The Cancer Genome Atlas database and bioinformatics analyses, the expression of GALNT7 was demosntrated to be higher in GBM and LGG tissues than in normal brain tissue. The expression levels of GANLT7 were associated with age, tumor grade, survival rate, disease-free survival time and overall survival time. Gene correlation and gene-set enrichment analyses suggested that GALNT7 may affect the proliferative and invasive abilities of glioma cells through multiple signaling pathways, including regulation of the actin cytoskeleton, natural killer cell-mediated cytotoxicity, the janus kinase-signal transducer and activator of transcription (STAT) signaling pathway, cell adhesion molecules and extracellular matrix receptor interaction pathways. Furthermore, 5 target genes of GALNT7 involved in these signaling pathways were identified, including Crk, Rac family small GTPase 1, STAT3, poliovirus receptor and Tenascin C. In summary, high expression of GALNT7 was associated with poor prognosis of glioma, and may be used as an effective biomarker of glioma. [ABSTRACT FROM AUTHOR]

Lymphoma is a type of cancer that develops from certain immune system cells. Arsenic trioxide (ATO) has attracted wide attention owing to its antitumor activities. However, the role of ATO in tumorigenesis and progression remains to be investigated. In the present study, the antitumor function of ATO was investigated in in lymphoma Raji and Jurkat cell lines and the effect of ATO on nuclear factor (NF)-κB expression levels. A Cell Counting kit-8 assay was used to assess cellular proliferation and the degree of cell apoptosis was measured by flow cytometric analysis; these assays demonstrated that ATO inhibited proliferation and promoted the apoptosis of Raji and Jurkat cells in a dose- and time-dependent manner. Western blot analysis revealed that ATO treatment affected the expression of apoptosis-associated proteins by downregulating the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and upregulating the pro-apoptotic protein Bcl-2-associatedX and the degree of caspase-3 cleavage. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis showed that the mRNA and protein expression levels of NF-κB were downregulated significantly following treatment with 2 µM ATO for 24, 48 and 72 h in the two cell lines. Additionally, immunofluorescence staining indicated that NF-κB expression diminished following ATO treatment in a time-dependent manner. These data indicated that ATO inhibited the proliferation of lymphoma cells by inducing cell apoptosis, which may be associated with the inhibition of the NF-κB signaling pathway. The findings of the present study may lay the foundation for developing a personalized medicine strategy using ATO via targeting of the NF-κB signaling pathway in lymphoma. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a commonly observed malignant cancer. However, the limited therapies for colorectal cancer do not bring much benefit for patients. Chondroitin synthase-1 (CHSY1) is an enzyme responsible for the biosynthesis of chondroitin sulfate and has been implicated in the tumorigenesis of several cancer types; however, there is limited information regarding the role of CHSY1 in colorectal cancer. In the present study, CHSY1 was demonstrated to be highly expressed in colorectal cancer tissues and in cell lines, and the CHSY1 expression level was associated with the 5-year survival rate of patients with colorectal cancer. Following CHSY1 knockdown, the proliferation of colorectal cancer cells was significantly decreased. The number of RKO cells decreased by 50% following CHSY1 knockdown compared with that in the control after culture for 5 days. However, the apoptosis rate of RKO cells increased to 14.15% after CHSY1 knockdown. In addition, the activity of caspase-3/7 was also enhanced. Furthermore, the expression of B-cell lymphoma 2 (Bcl-2) was reduced, whereas the levels of Bcl-2-associated X protein (Bax) and truncated caspase-3/7 were increased following CHSY1 knockdown. Additionally, the phosphorylation level of IκB and the expression of nuclear factor (NF)κB also decreased. In contrast, forced expression of CHSY1 increased the level of Bcl-2, NFκB, and phosphorylated IκB, whereas the level of bax and truncated caspase-3/7 decreased. Therefore, the data of the present study suggest that CHSY1 promoted cell proliferation by regulating NFκB signaling and suppressed cell apoptosis by regulating/caspase-3/7 signaling in colorectal cancer. The present study also suggests that CHSY1 may be a potential target for colorectal cancer therapy. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the molecular mechanisms of inhibition of Isoliquiritigenin (ISL) on the proliferation and migration of A549 cells. A549 cells were cultured in vitro, and the effects of ISL inhibition were examined using cell counting kit-8, Transwell invasion and flow cytometric assays. Western blot analysis was also performed to detect cell apoptosis and the expression of phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway-associated proteins. The results demonstrated a significant inhibition of proliferation and migration of A549 cells when treated with ISL (P<0.05). Furthermore, ISL treatment significantly downregulated the expression of E-cadherin, and upregulated the expression of N-cadherin and vimentin. Flow cytometric analysis revealed a significant increase in cell apoptosis in the ISL group as well as the expression of pro-apoptotic proteins Bcl-2-associated X protein and active caspase-3. Conversely, the expression of anti-apoptotic protein B-cell lymphoma 2 was decreased. There was a significant decrease in the phosphorylation of AKT and mammalian target of rapamycin, and in the expression of cell proliferation proteins P70 and cyclin D1 in ISL-treated cells. In conclusion, ISL has significant inhibitory effects on the proliferation and migration of A549 cells by promoting cell apoptosis. The mechanism may involve of PI3K/AKT signaling pathways in A549 cells, which may a potential therapeutic target for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) may serve important roles in the regulation of human non-small cell lung cancer (NSCLC) cell growth and apoptosis. To the best of our knowledge, the present study was the first to explore the role of miRNA-133a/epidermal growth factor receptor (EGFR) in regulating NSCLC cell growth and apoptosis via the AKT/extracellular signal-regulated kinase (ERK) signaling pathway. It was determined that miRNA-133a expression was lower in NSCLC tissue than in the adjacent mucosae. Additionally, EGFR expression in the NSCLC tissue was higher compared with in the adjacent mucosae. Furthermore, the upregulation of miRNA-133a in NSCLC cells suppressed cell growth and induced apoptosis. Upregulating miRNA-133a also increased caspase-3 protein expression, while suppressing that of EGFR, phosphorylated (p)-AKT and p-ERK in NSCLC cells. Therefore, the results of the current study demonstrated that miRNA-133a downregulates EGFR expression in NSCLC via the AKT/ERK signaling pathway. These findings provide insights into the function of miRNA-133a in NSCLC, as well as into the molecular mechanisms underlying the miRNA-133a-mediated downregulation of the EGFR/AKT/ERK signaling pathway in NSCLC. [ABSTRACT FROM AUTHOR]

Melanoma is highly malignant, particularly prone to metastasizing to the skin. The incidence of melanoma varies markedly between countries, and is relatively low in China. The aim of the present study was to investigate the antitumorigenic effect of damnacanthal on melanoma cells, and its molecular mechanism. MUM-2B cells were treated with 0–20 µM damnacanthal for 12, 24 and 48 h. In vitro, it was demonstrated that damnacanthal inhibited proliferation and promoted apoptosis of melanoma cells in a dose- and time-dependent manner. Damnacanthal treatment increased caspase-3/8 and 9 activity, and promoted B-cell lymphoma 2-associated X protein, tumor protein p53 (p53) and p21 protein expression levels in melanoma cells. Damnacanthal treatment also resulted in downregulated nuclear factor-κB (NF-κB), cyclin D and cyclin E protein expression in melanoma cells. In conclusion, the results of the present study demonstrated that the antitumorigenic activity of damnacanthal on melanoma cells is executed via the p53/p21 and NF-κB/cyclin/ caspase-3 signaling pathways. [ABSTRACT FROM AUTHOR]

Human bladder cancer is one of the most aggressive tumours known and has shown resistance to traditional chemotherapy, which depends heavily on DNA-damaging drugs. β-elemene is one of the least cytotoxic antitumor agents that are extracted from Curcuma aromatica salisb and it exhibits antitumor effects in many carcinomas. β-elemene has attracted the attention of clinicians and scientists worldwide due to its few side effects and limited effect on the bone marrow. However, the antitumor mechanism of β-elemene remains largely unstudied. In the present study, the expression of the AKT serine/threonine kinase (AKT) signaling pathway in bladder cancer and normal bladder tissue was investigated, and the influence of β-elemene on bladder cancer cells and the mechanisms involved were assessed. The results showed that phosphatase and tensin homolog deleted on chromosome ten (PTEN) was downregulated and phosphorylated-AKT (pAKT) was overexpressed in human bladder cancer. β-elemene significantly suppressed the viability of bladder cancer cells, while leaving normal bladder cells unaffected. In addition, there was an increased number of apoptotic bladder cancer cells following β-elemene treatment, and a significant reduction in cell invasion and migration. Subsequent western blot analyses revealed that bladder cancer cells treated with β-elemene had increased PTEN expression and decreased expression of pAKT. Taken together, these results suggest that β-elemene has an antitumor effect in bladder cancer cells through the upregulation of PTEN and suppression of AKT phosphorylation. [ABSTRACT FROM AUTHOR]

Effect of crizotinib on apoptosis of lung cancer cells was investigated. Human non-small cell lung adenocarcinoma H2228 cells were cultured in the presence of 0, 20, 40, 80, 160 and 320 nmol/l of crizotinib for 3 days, respectively. The inhibition rate of cell proliferation was measured by MTT assay, and half maximal inhibitory concentration (IC50) was calculated. Cell apoptosis was detected by flow cytometry. Transwell assay was performed to detect cell migration. Expression of Janus protein tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) proteins was detected by western blot analysis. Crizotinib significantly inhibited the proliferation of human lung cancer H2228 cells, and the inhibitory effect was enhanced with the increase of the concentration of crizotinib (p<0.01). The IC50 value was 311.26 nnol/l. According to IC50 value, concentration of crizotinib at 300 nmol/l was selected for the study. It was found that crizotinib at 300 nmol/l significantly promoted cell apoptosis (p<0.01) and inhibited cell migration (p<0.01). Compared with pretreatment levels, crizotinib downregulated the expression of JAK and STAT (p<0.01) on the 1st day of treatment, but with the prolongation of time, no further significant difference was observed on the 1st, 2nd or 3rd day in the level of JAK protein (p=0.47); there were no statistically significant differences in the level of STAT protein (p=0.91). Crizotinib can inhibit the migration and promote cell apoptosis of human lung cancer cell line H2228 by regulating the expression of JAK and STAT proteins in JAK-STAT signaling pathway. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs), a type of non-coding RNAs derived from back-splicing, have been reported to function as gene expression regulators involved in tumor development of multiple human tumors. However, the clinical significance and underlying molecular mechanisms of circ_001569 in osteosarcoma still be unknown. In the study, we found that circ_001569 expression was significantly overexpressed in osteosarcoma tissues compared with adjacent noncancerous bone tissues. Higher circ_001569 expression significantly correlated with distant metastasis and advanced tumor stage of osteosarcoma patients. Gain-function and loss-function assays showed that circ_001569 knockdown significantly inhibited osteosarcoma cell proliferation and cell colon formation capacities. Moreover, upregulation of circ_001569 significantly promoted osteosarcoma cell resistance to cisplatin by activating Wnt/β-catenin signaling pathway. Thus, these results indicated that circ_001569 represented a novel potentially therapeutic target of osteosarcoma. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is the most common renal carcinoma in the human kidney. To date, to the best of our knowledge, there are no biomarkers for the early monitoring and diagnosis of RCC patients. The present study aimed to develop deeper insight into the molecular mechanisms of microRNAs (miRNAs/miRs) in the regulation of RCC development and to reveal candidate miRNA biomarkers in human RCC. A meta-analysis was used to integrate the published and independent RCC miRNA expression profiling investigations that compared the miRNA expression profiles in RCC samples with control samples. The meta-signature miRNA target genes were then predicted in TargetScan. The predicted targets were further analyzed using Gene Ontology and pathway enrichment analysis with the Database for Annotation, Visualization and Integrated Discovery online tool, and then the transcription factors of meta-signature miRNA target genes were identified in Tfacts. A total of 7 publicly available and independent RCC miRNA expression profiling datasets were collected, and 2 upregulated (hsa-miR-155-5p and hsa-miR-210-5p) and 6 downregulated (hsa-miR-138-5p, hsa-miR-141-5p, hsa-miR-200c-5p, hsa-miR-362-5p, hsa-miR-363-5p and hsa-miR-429) meta-signature miRNAs in renal carcinoma were identified. The targeted gene enrichment analysis indicated that the meta-signature miRNAs may influence several pathways that participate in cancerogenesis, including the 'rap1 signaling pathway', 'renal cell carcinoma' and 'microRNAs in cancer'. Overall, the present meta-analysis identified 2 upregulated and 6 downregulated meta-signature miRNAs from 7 renal carcinoma datasets, the dysregulated miRNAs that may contribute to kidney carcinoma development. This research may reveal candidate miRNA biomarkers in human RCC. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) has the highest fatality rates of all gynecological malignancies worldwide. The epithelial-to-mesenchymal transition (EMT) serves an essential role in the progression of OC. An improved understanding of the molecular mechanism underlying EMT in OC may increase the survival rate. ATP-binding cassette transporter A7 (ABCA7) is a candidate regulator of OC progression. However, the role of ABCA7 in OC is unclear. Using the PROGgeneV2 platform, the present study revealed that increased expression of ABCA7 is associated with poor outcomes in OC. The expression of ABCA7 was higher in OC tissues than in adjacent noncancerous tissues. ABCA7-knockdown decreased the migration of OC cells and the activation of mothers against decapentaplegic homolog 4 (SMAD4). Notably, downregulation of ABCA7 also increased the expression of an epithelial marker (E-cadherin) and decreased that of a mesenchymal marker (N-cadherin). In addition, the decreased expression of SMAD4 and EMT markers induced by ABCA7 depletion could be rescued by transforming growth factor β1 (TGF-β1) stimulation. Overall, these findings suggested that ABCA7 accelerates EMT in OC by upregulating the TGF-β signaling pathway. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer; however, the specific genes and signaling pathways involved in this cancer remain largely unclear. The present study analyzed three profile datasets, GSE6004, GSE29265 and GSE60542, which were comprised of 47 PTC and 41 normal thyroid tissue samples, to identify key genes and pathways associated with PTC. Initially, differentially-expressed genes (DEGs) between PTC and normal thyroid tissue were screened using R 3.4.0 (2017-04-21, R Foundation, Vienna, Austria, http://www.R-project.org/). These DEGs were then clustered by gene ontology functional terms and representative signaling pathways. Additionally, specific key gene nodes were filtered out from a constructed protein-protein interaction (PPI) network. The results identified a total of 423 shared DEGs associated with PTC, including 211 upregulated and 212 downregulated genes. These 423 genes were primarily enriched in glycosaminoglycan binding, sulfur compound binding, heparin binding, enzyme activator activity, peptidase activator activity and hsa04512: Extracellular matrix (ECM)-receptor interaction. A total of 21 central node genes were identified as key genes in the PTC disease process including complement factor D (CFD), Collagen Type I α 1 Chain (COL1A1), Extracellular Matrix Protein 1 (ECM1) and Fibronectin 1 (FN1). These genes are involved in protease binding, G-protein coupled receptor binding, extracellular matrix structural constituent and peptidase regulator activity. To conclude, using bioinformatics analysis, the present study identified candidate DEGs and critical pathways in PTC that may improve the current understanding regarding the underlying mechanisms of PTC. These genes and pathways may be used as potential therapeutic targets of PTC in the future. [ABSTRACT FROM AUTHOR]

Kangfuxin (KFX) is an oral liquid derived from Periplaneta americana, with complex components. KFX has been demonstrated to exhibit anticancer activity in a variety of different types of tumor, including gastric cancer; however, its underlying molecular mechanism remains unclear. The present study was designed to investigate the pro-apoptotic effects of KFX on SGC-7901 cells, in order to provide a theoretical basis for clinical application. In order to clarify the pro-apoptotic effects of KFX on SGC-7901 cells, MTT analysis was conducted. To evaluate the anticancer effect of KFX, peroxisome proliferator-activated receptor (PPAR)-γ was analyzed by reverse transcription-polymerase chain reaction. Western blot analysis was used to determine the effects of KFX on the expression of cleaved caspase-3, phosphorylated extracellular signal-regulated kinase (p-ERK), ERK, tumor protein p53 (p53), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X, interleukin (IL)-6 and IL-1β. In addition, terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL) analysis was used to detect apoptosis in SGC-7901 cells. It was revealed that PPAR-γ was increased in SGC-7901 cells following treatment with KFX, shown by an increase in mRNA expression. Furthermore, western blot analysis identified that KFX treatment groups exhibited markedly inhibited levels of Bcl-2, IL-6, IL-1β and p-ERK, and induced p53 protein expression. Additionally, TUNEL and MTT assays demonstrated that treatment with KFX may induce SGC-7901 cell apoptosis and inhibit proliferation. In conclusion, to the best of our knowledge, the results of the present study demonstrated for the first time that KFX may induce SGC-7901 cell apoptosis and inhibit its proliferation, and this may be primarily attributed to its role in mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase/ERK signaling pathway inhibition. [ABSTRACT FROM AUTHOR]

In the present study, the anti-tumor effects of combination treatment with an siRNA targeting B-Raf proto-oncogene serine/threonine kinase (BRAF)V600E and phosphoinositide 3-kinase (PI3K) signaling pathway inhibitors was investigated in melanoma cell lines harboring BRAFV600E. Human melanoma A375 and WM115 cells were treated with siRNA targeting to BRAF or BRAFV600E, combined with treatment with PI3K signaling pathway inhibitors. CCK-8 and EdU proliferation assays were performed to assess cell viability and proliferation, respectively, following treatment. In addition, flow cytometry analysis was performed to determine cell cycle distribution, and western blot analysis was performed to analyze the activity of the extracellular signal-regulated kinase (ERK) and PI3Ksignaling pathways following treatment. Targeting BRAFV600E using small interfering (si)RNA significantly decreased cell viability and DNA replication in tumor cell lines that harbor oncogenic BRAFV600E. Inhibition of BRAFV600E by siRNA combined with treatment with PI3K or mammalian target of rapamycin signaling pathway inhibitors significantly decreased cell viability and proliferation compared with siRNA or inhibitor treatment alone. Concomitant BRAFV600E and PI3K inhibition led to G1/S phase arrest in melanoma cells. However, melanoma cells in which oncogenic BRAFV600E is not highly expressed (WM115 cells) were not sensitive to BRAFV600E targeted therapy. The PI3K signaling pathway inhibitors were more effective in this cell line. The results from the present study provide an insight into the potential effectiveness of combination therapy and personalized cancer treatments. [ABSTRACT FROM AUTHOR]

Jumonji AT-rich interactive domain 1B (JARID1B) has been revealed to remove methyl residues from methylated lysine 4 on histone H3 (H3K4) and has also been reported to be associated with the progression of numerous types of tumor. However, its roles and mechanisms in pancreatic cancer (PC) remain unknown. The present study demonstrated that JARID1B is elevated in PC and is associated with the growth of pancreatic tumors. Overexpression of JARID1B significantly promoted the proliferation in vitro and tumor formation in vivo of PC cells. Furthermore, silencing the expression of JARID1B in other PC cells revealed opposite effects. Further research revealed that JARID1B exerted its function through modulation of H3K4me3 at the phosphatase and tensin homolog (PTEN) gene promoter which was associated with inactive PTEN transcription. To the best of our knowledge, the present study was the first to demonstrate that JARID1B promotes the growth of PC and that targeting JARID1B may be a useful strategy to suppress the progression of PC. [ABSTRACT FROM AUTHOR]

Breast cancer progression results from the acquisition of genetic and epigenetic alterations that promote tumor cell proliferation and survival. Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a proteinase that regulates the proteolytic activity of various precursor proteins as well as protein maturation. PCSK6 also influences cancer cell proliferation, invasion and migration. Therefore, to investigate the effects of PCSK6 in breast cancer, human breast cancer MDA-MB-231 cells were treated with recombinant human PCSK6 in vitro. Treatment with recombinant PCSK6 significantly increased the proliferation, invasion and migration abilities of MDA-MB-231 cells. In addition, PCSK6 treatment reduced cell cycle arrest and prevented apoptosis of MDA-MB-231 cells. This provides further support for the hypothesis that PCSK6 serves a role in promoting tumor cell proliferation. PCSK6 treatment also increased the expression of phosphorylated extracellular signal-regulated kinase 1/2 and Wnt family member 3A, suggesting that these pathways are activated by PCSK6. The results of the present study suggested that PCSK6 may promote the proliferation of breast cancer MDA-MB-231 cells by disturbing cell cycle arrest via the mitogen-activated protein kinase pathway. Therefore, PCSK6 may be a potential therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]

Ovarian endometrioid borderline tumors (EBTs) are extremely rare, and are thought to be precursors of endometrioid carcinoma, beginning as adenofibroma or endometriosis and progressing in a slow, stepwise manner. In endometrioid carcinomas, a high frequency of activating mutations in phosphatase and tensin homolog (PTEN), β-catenin or AT-rich interaction domain 1A (ARID1A) genes, and the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway have been observed. However, the frequency of these alterations in EBTs and how they contribute to tumor progression remain unclear. To the best of our knowledge, this is the first study to assess the status of the PI3K/AKT signaling pathway in EBTs, in association with PTEN and ARID1A mutations. PTEN mutations were observed in EBTs and also in the area of endometriosis without atypia. However, the PI3K/AKT signaling pathway was revealed to be activated only in EBTs. The observations of the present study suggest that the PTEN mutation represents an early event in EBT tumorigenesis, while additional genetic alterations may be necessary to activate the PI3K/AKT signaling pathway and induce the development of the invasive carcinoma. [ABSTRACT FROM AUTHOR]

In the present study, the anti-tumor effects of combination treatment with an siRNA targeting B-Raf proto-oncogene serine/threonine kinase (BRAF)V600E and phosphoinositide 3-kinase (PI3K) signaling pathway inhibitors was investigated in melanoma cell lines harboring BRAFV600E. Human melanoma A375 and WM115 cells were treated with siRNA targeting to BRAF or BRAFV600E, combined with treatment with PI3K signaling pathway inhibitors. CCK-8 and EdU proliferation assays were performed to assess cell viability and proliferation, respectively, following treatment. In addition, flow cytometry analysis was performed to determine cell cycle distribution, and western blot analysis was performed to analyze the activity of the extracellular signal-regulated kinase (ERK) and PI3Ksignaling pathways following treatment. Targeting BRAFV600E using small interfering (si)RNA significantly decreased cell viability and DNA replication in tumor cell lines that harbor oncogenic BRAFV600E. Inhibition of BRAFV600E by siRNA combined with treatment with PI3K or mammalian target of rapamycin signaling pathway inhibitors significantly decreased cell viability and proliferation compared with siRNA or inhibitor treatment alone. Concomitant BRAFV600E and PI3K inhibition led to G1/S phase arrest in melanoma cells. However, melanoma cells in which oncogenic BRAFV600E is not highly expressed (WM115 cells) were not sensitive to BRAFV600E targeted therapy. The PI3K signaling pathway inhibitors were more effective in this cell line. The results from the present study provide an insight into the potential effectiveness of combination therapy and personalized cancer treatments. [ABSTRACT FROM AUTHOR]

The angiopoietin 1 (Ang1)/angiopoietin receptor (Tie2) signaling pathway may have a notable role in the pathogenesis of inflammatory diseases. The abnormal expression of angiopoietin 1 and Tie2 has also been reported in various malignant tumors, including papillary thyroid carcinoma (PTC). However, the role and mechanism of the Ang1/Tie2 pathway in the progression of PTC remains unclear. Therefore, the aims of the present study were to clarify this. Significantly high expression levels of Ang1 and Tie2 were observed in PTC tissues and cell lines. Furthermore, MTT and wound-healing assays revealed that the Ang1-mediated stimulation of human PTC cells resulted in increased proliferation and migration. Conversely, the downregulation of Tie2 levels using short hairpin RNA targeted at Tie2 abrogated the Ang1-mediated effect on cell proliferation and migration. In studying the expression of phosphoinositide-3 kinase (PI3K)/RAC serine/threonine-protein kinase (Akt) pathway, the upregulation of Ang1/Tie2 was found to be associated with the activation of the PI3K/Akt pathway in PTC. In conclusion, the data from the present study indicated that the Ang1/Tie2 induces PTC oncogenesis via the PI3K/Akt pathway, providing novel insights into human PTC therapy. [ABSTRACT FROM AUTHOR]

S100A11, a member of S100 calcium-binding protein family, is associated with the numerous processes of tumorigenesis and metastasis. In the present study, the role of S100A11, and its possible underlying mechanisms in cell proliferation, apoptosis and cell cycle distribution in human pancreatic cancer were explored. Immunohistochemical analyses of S100A11 and phosphorylated (p)-AKT serine/threonine kinase (AKT) were performed in 30 resected specimens from patients with pancreatic cancer. PANC-1 cells were transfected with pcDNA3.1-S100A11 or treated with 50 µmol/l LY294002 for 48 h. Cell proliferation was determined using a cell counting kit-8 assay, whereas apoptosis and cell cycle distribution were determined by flow cytometry analysis. The mRNA and protein levels of S100A11, and AKT were determined using semi quantitative reverse transcription-polymerase chain reaction and western blot analyses, respectively. Pearson correlation analysis revealed that the expression levels of S100A11 and p-AKT were positively correlated (r, 0.802; P<0.05). Compared with the control group, S100A11 overexpression significantly promoted PANC-1 cell proliferation and reduced the percentage of early apoptotic cells. Flow cytometric analysis indicated that the proportion of PANC-1 cells in the S phase was significantly elevated and cell percentage in the G0/G1 phase declined in response to S100A11 overexpression (all P<0.05). S100A11 overexpression also significantly increased AKT mRNA and p-AKT protein expression levels (both P<0.05). The phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, significantly inhibited PANC-1 cell proliferation, promoted apoptosis and caused G1/S phase arrest in PANC-1 cells (all P<0.05). These findings together suggest that S100A11 promotes the viability and proliferation of human pancreatic cancer PANC-1 cells through the upregulation of the PI3K/AKT signaling pathway. Thus, S100A11 may be considered as a novel drug target for targeted therapy of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Cluster of differentiation (CD)133 has been reported to be involved in the activation of the extracellular signal‑regulated kinase (ERK) signaling pathway in different types of cancer cells. CD133 has been reported to be involved in the activation of the ERK signaling pathway in various cancer cells. Transforming growth factor (TGF)‑β1 has also been reported to mediate the activation of the ERK signaling pathway. In addition, TGF‑β1 has been previously shown to mediate the activation of the ERK signaling pathway. Hence, the present study investigated the function of CD133 in the TGF‑β1‑induced activation of the ERK/P70S6K signaling pathway in human gastric cancer (GC) cells. To this end, GC cell lines SGC7901 and MKN45 were treated with TGF‑β1. The expression of CD133, phospho‑ERK (p‑ERK) and phospho‑P70S6 kinase (p‑P70S6K) was upregulated in the cells treated with TGF‑β1, while the expression of ERK and P70S6K was not altered. To investigate whether CD133 is involved in the TGF‑β1‑induced activation of the ERK/P70S6K signaling pathway in GC cells, immunomagnetic cell sorting was employed to isolate CD133+ GC cells, and a CD133‑expression construct or CD133‑targeting small interfering ribonucleic acids were transfected into cells to modulate the expression of CD133. Subsequently, the expression of CD133, ERK, p‑ERK, P70S6K, and p‑P70S6K was analyzed by western blotting. The CD133+ cells displayed a high expression of p‑ERK and p‑P70S6K. Furthermore, SGC7901 GC cells were treated with U0126, an inhibitor of the ERK signaling pathway, to assess whether CD133 is upstream of ERK/P70S6K. The results showed that the expression of p‑ERK and p‑P70S6K was downregulated in the cells treated with U0126, while the expression of CD133 remained unaltered. The above preliminary results showed that CD133 likely mediates the TGF‑β1‑induced activation of the ERK/P70S6K signaling pathway in human GC cells. To further understand the mechanism of regulation of the ERK/P70S6K signaling pathway by CD133, the expression of CD133 was modulated by transfecting cells with CD133‑expression constructs or CD133‑targeting small interfering ribonucleic acids. Results indicated that overexpression and silencing of CD133 directly increased and decreased the expression of p‑ERK and p‑P70S6K, respectively. Therefore, we hypothesized that CD133 mediates the TGF‑β1‑induced activation of the PI3K/ERK/P70S6K signaling pathway in human GC cells. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most common types of tumors and the leading cause of cancer‑associated mortality in the world. Additionally, non‑small cell lung cancer (NSCLC) accounts for ~80% of all lung cancer cases. Epithelial-mesenchymal transition (EMT) is an important cell biological process, which is associated with cancer migration, metastasis, asthma and fibrosis in the lung. In the present study, it was revealed that miR‑145‑5p was able to suppress EMT by inactivating the c‑Jun N‑terminal kinase (JNK) signaling pathway in NSCLC cells. Mitogen‑activated protein kinase kinase kinase 1 (MAP3K1) was predicted and confirmed to be a novel target of miR‑145‑5p. Overexpression of MAP3K1 was able to reverse the inhibition of EMT induced by miR‑145‑5p via the JNK signaling pathway. Overall, the results revealed that miR‑145‑5p inhibits EMT via the JNK signaling pathway by targeting MAP3K1 in NSCLC cells. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate whether autophagy was triggered by curcumol and to explore the association between autophagy and apoptosis of MG‑63 cells and the underlying mechanism. MG‑63 cells were cultured in vitro. An MTT assay was performed to evaluate the proliferation inhibition of the MG‑63 osteosarcoma cell line by curcumol. Fluorescein isothiocyanate‑Annexin V/propidium iodide staining flow cytometry was performed to analyze the apoptotic rate of cells. The morphological alterations of cell nuclei were evaluated by Hoechst 33258 viable cell staining. The effects of autophagy in cells was investigated by green fluorescent protein (GFP)‑light chain 3 (LC3) transfection and using a fluorescence microscope. The expression levels of LC3II, LC3I and cleaved caspase‑3 and Janus kinase (JNK) signaling pathway activation were determined by western blot analysis. Cell proliferation was inhibited by curcumol in a dose‑ and time‑dependent manner. Curcumol induced apoptosis by the caspase‑dependent signaling pathway in MG‑63 cells. The present study demonstrated that curcumol could induce autophagy of MG‑63 cells, which was evaluated by transmission electron microscopy. Compared with the curcumol treatment alone group, the GFP‑LC3‑transfected green fluorescence plasmids and the LC3II/LC3I levels in cells of the curcumol and chloroquine (CQ) treatment group were upregulated, and the apoptotic ratio was downregulated following pretreatment with autophagy inhibitor CQ for 1 h. Furthermore, curcumol treatment induced phosphorylation of the JNK signaling pathway. Of note, pretreatment with the JNK inhibitor, SP600125, decreased the rates of autophagy and apoptosis, suggesting a crucial role served by the JNK signaling pathway in the activation of autophagy by curcumol. Taken together, the results of the present study suggested that activation of the JNK signaling pathway was involved in curcumol‑induced autophagy. Curcumol is a novel drug for chemotherapeutic combination therapy. Curcumol demonstratedm potential antitumor activities in MG‑63 cells and may be used as a novel effective reagent in the treatment of osteosarcoma. [ABSTRACT FROM AUTHOR]

Luteolin (3',4',5,7-tetrahydroxyflavone) is a common dietary flavonoid, which has been demonstrated to exert anticancer effects in multiple cancer models. However, the detailed mechanisms underlying the inhibitory effect of luteolin on glioblastoma cell metastasis remain poorly understood. The present study assessed the effects of luteolin in the U251MG and U87MG human glioblastoma cell lines. Luteolin treatment significantly inhibited glioblastoma cell migration, and this effect was associated with downregulated matrix metalloproteinase (MMP)-2, MMP-9 and upregulated tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. In addition, luteolin also inhibited the epithelial-mesenchymal transition-associated phenotype. Furthermore, the phosphorylated insulin-like growth factor-1 receptor/phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (p-IGF-1R/PI3K/AKT/mTOR) signaling pathway was demonstrated to participate in these processes. The results of the present study demonstrated that the flavonoid luteolin reduced the migration of glioblastoma cells by altering p-IGF-1R/PI3K/AKT/mTOR activation, and may have potential applications for chemoprevention in a clinical setting. [ABSTRACT FROM AUTHOR]

Breast cancer is the second leading cause of cancer-associated mortality in females in the USA. Hsa-miR-599 was demonstrated to function as a tumour suppressor during cancer progression. However, the function and mechanism of the hsa-miR-599 in human breast cancer remain elusive. Thus, the aim of the present study was to investigate the potential role of hsa-miR-599 in breast cancer biology. The expression levels of hsa-miR-599 in 40 pairs of surgical specimens and human breast cancer cell lines were detected using quantitative polymerase chain reaction analysis. The overexpression of hsa-miR-599 was established by transfecting mimics into the MCF-7 and MDA-MB-231 cell lines. Cell counting kit-8, colony formation and transwell assays were used to investigate the potential function of hsa-miR-599 in MCF-7 and MDA-MB-231 cell lines. Luciferase assays combined with western blot analysis was performed to validate the regulation of a putative target of hsa-miR-599. The results demonstrated that hsa-miR-599 was downregulated in the breast cancer tissues and breast cancer cell lines. Overexpression of hsa-miR-599 was revealed to inhibit the viability and proliferation of cell in vitro and tumour growth in vivo. The results of the luciferase assay indicate that bromodomain containing 4 (BRD4) is a direct target of hsa-miR-599. Furthermore, the xenograft mouse model demonstrated that overexpressed hsa-miR-599 reduced BRD4 expression. These results suggest that hsa-miR-599 serves as an oncosuppressive microRNA that impairs breast cancer tumorigenesis and progression by directly targeting BRD4. Furthermore, increased BRD4 expression partially reversed the suppressive effect of hsa-miR-599. In conclusion, the results of the present study demonstrated that hsa-miR-599 suppressed breast cancer progression by downregulating BRD4. The overexpression of hsa-miR-599 may be considered as a novel therapeutic target for the treatment of patients with breast cancer. [ABSTRACT FROM AUTHOR]

The present study evaluated the retinoic acid (RA) enhancement of temozolomide (TMZ) effects on the human glioma cells U251 and explored its underlying molecular mechanism. The cell growth was detected using the MTT assay and the cell cycle was assessed by flow cytometry. Cell apoptosis was analyzed by Annexin V/propidium iodide staining, and the cell morphology was evaluated using transmission electron microscopy (TEM). Additionally, reverse transcription-PCR and western blot analysis were applied to detect the mRNA and protein levels. The RA treatment in combination with TMZ in the human U251 cells further inhibited cells growth, arresting cell cycle progression at the G0/G1 phase, and significantly induced apoptosis of U251 cells. After the RA+TMZ treatment of U251 cells, autophagy associated proteins Beclin 1 and LC3B were significantly increased, and the TEM analysis were consistent with autophagy protein levels. Moreover, Keap1/Nrf2/ARE expression was downregulated significantly, indicating the involvement in the mechanisms that RA treatment could enhance the TMZ effects on U251 cells. RA treatment in combination with TMZ may provide some experimental evidence for the possible effect of RA+TMZ against the growth and the proliferation of glioma cells. Therefore, the RA+TMZ administration may have potential utility for glioblastoma treatment. [ABSTRACT FROM AUTHOR]

Several studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) is associated with initiation, progression and metastasis of numerous types of malignancy. However, the role of the Janus kinase-interleukin 6-STAT3 signaling pathway in the pathogenesis and recurrence of meningiomas is unknown. The present study evaluated STAT3 activation by western blotting and immunohistochemistry and assessed its association with Ki-67 labeling in 13 cases of meningioma in which frozen tissue and =5.5-year follow-up information were available, and in formalin-fixed meningioma tissues from 14 cases with an 8.4-year follow-up. The results of the western blot analysis indicated that STAT3 phosphorylation was markedly higher in grade II meningiomas compared with that in grade I, with mean densitometric values of 8.6 and 1.7 following normalization to actin, respectively. High STAT3 phosphorylation/activation was identified in 2 of 3 recurrent World Health Organization (WHO) grade I meningiomas and 0 of 3 non-recurrent meningiomas. Strong STAT3 phosphorylation/activation signal was also found in 2 of 4 recurrent grade II meningiomas and 1 of 3 non-recurrent cases. According to the immunohistochemistry results, phospho-STAT3 was not increased in WHO grade II tumors compared with that in grade I tumors, and was not significantly different between recurrent and non-recurrent cases. Ki-67 labeling was significantly increased in grade II vs. grade I tumors, and was also significantly increased in recurrent compared with non-recurrent grade I meningiomas. The results of the current study suggest that, while detection of phosphorylated/activated STAT3 may be useful in isolated cases, identifying activation may be of little value in predicting recurrence. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the reversal effect of resveratrol on the phenomenon of multidrug resistance in U2OS/adriamycin (ADR) cells and to clarify the molecular mechanisms. To examine the cell survival and half-inhibitory concentration (IC50) of ADR in U2OS and U2OS/ADR cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used. The accumulation of ADR in U2OS and U2OS/ADR cells was investigated by flow cytometry. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the expression of multidrug resistance protein 1 (MDR1), P-glycoprotein (P-gp), p65 and p38. Compared with U2OS cells, the IC50 value of ADR was significantly increased in U2OS/ADR cells, which exhibited high levels of MDR1/P-gp. However, resveratrol could drastically reduce the IC50 value of ADR and the expression of MDR1/P-gp, and increased the accumulation of ADR in U2OS/ADR cells. In addition, the expression levels of p38 (phosphorylated) and p65 (acetylated and total) in U2OS/ADR cells were also significantly suppressed by resveratrol. These results suggested that the nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) signaling pathways are correlated with ADR-induced drug resistance in U2OS/ADR cells. Furthermore, resveratrol could downregulate the expression of MDR1/P-gp and reverse the drug resistance phenomenon in U2OS/ADR cells partly at least by suppressing the activation of the NF-κB and p38 MAPK signaling pathways. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a primary malignant tumor of the bone, with a tendency to metastasize early. Despite the advances in treatment options, more than 30% of patients develop distant metastases, and the prognosis of these patients with metastases is extremely poor. Celastrol has been demonstrated to manifest multiple pharmacological activities, including induction of apoptosis in numerous types of cancer cell lines. Our previous studies have also suggested that Celastrol is capable of inducing apoptosis of human osteosarcoma cells via the mitochondrial-dependent pathway. The purpose of this study was to investigate the effects of Celastrol on the migration and invasion of human osteosarcoma U-2OS cells in vitro. Cell migration and invasion were investigated using wound healing and Boyden chamber Transwell assays. We observed that Celastrol suppressed cell invasion and migration in human osteosarcoma U-2OS cells. Furthermore, protein expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K), Akt, inhibitor of κB kinase α/β, inhibitor of κB α, nuclear factor-κB (NF-κB subunit p65) and matrix metalloproteinase (MMP)-2 and -9 were measured by western blot analysis. We observed that the PI3K/Akt/NF-κB signaling pathway was inhibited following Celastrol treatment. In addition, the expression levels of MMP-2 and -9 proteins were also reduced significantly following Celastrol treatment. Therefore, we confirmed that Celastrol suppressed osteosarcoma U-2OS cell metastasis via downregulation of the PI3K/Akt/NF-κB signaling pathway in vitro. [ABSTRACT FROM AUTHOR]

Despite great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinomas remains unspecialized. As a major subgroup, high-grade serous ovarian carcinomas (HGSOCs) require novel therapies. In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations, the molecular diagnostic method of next generation sequencing (NGS) was performed to identify 'druggable' targets that could provide access to innovative therapy. The present study was performed in 45 HGSOC patients (mean age, 59.1 years; range, 25-87 years) with histologically proven HGSOC. Breast cancer 1/2 (BRCA1/2) germline mutations were screened in 17 patients with a familial or personal history of cancer, which was justified by oncogenetic investigations. Tumor protein 53 (P53) and phosphatase and tensin homolog (PTEN) expression were assessed in formalin-fixed paraffin-embedded tissues using immunohistochemistry. Somatic mutations of Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and MET proto-oncogene, receptor tyrosine kinase (MET) were screened using NGS on DNA extracts from frozen tumor specimens obtained at diagnosis. With a median follow-up of 38 months (range, 6-93 months), 20 patients are alive, 10 patients are disease-free and 14 patients progressed within 6 months following platinum-based therapy. P53 overexpression was detected in 67% of patients and PTEN loss was detected in 38% of the patients. The overexpression of mutant P53 was found to be associated with a longer progression-free and overall survival. In total, 2 NRAS (exon 3), 3 PIK3CA (exon 5 and 10) and 5 MET mutations (exons 14 and 18) were detected. In HGSOCs, in addition to P53 and PTEN alterations, somatic genetic abnormalities can be detected using NGS and provide molecular rationale for targeted therapies, potentially offering novel therapeutic opportunities to patients. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide and has a very poor prognosis. Its occurrence has been on the increase in recent years. Surgical resection and liver transplantation are the primary methods of treatment for HCC patients, but can only be applied to 15% of patients. The median survival time of unresectable or metastasizing HCC patients is only a few months. Existing systemic treatment methods are not effective for advanced HCC patients and a new method of treatment is needed for these patients. It has been established that the HCC occurs in multiple stages, however, the pathogenesis at a molecular level is not clear and many key factors are yet to be determined. In the past 30 years, it has become evident that the Ras/Raf/MEK/extracellular signal-regulated k inase (ERK) signaling pathway plays a significant role in the occurrence and development of HCC. This review focused on the association between the Ras/Raf/MEK/ERK signaling pathway and HCC. [ABSTRACT FROM AUTHOR]