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Context: Lung cancer, the most common type of cancer, has a high mortality rate. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae plants, has antitumor effects. Objective: We investigated the role of CuB on lung cancer and its potential mechanisms. Materials and methods: A549 cells were treated with 0.1, 0.3, 0.6, and 0.9 lM CuB for 12, 24, and 48 h or untreated. Gene and protein levels were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Enzyme-linked immunosorbent assay (ELISA) detected inflammatory factors levels (TNF-a and IL-10). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and colony formation assays measured cell viability, apoptosis, and proliferation. The interaction between miR-let-7c and long non-coding RNA X inactive-specific transcript (XIST) or interleukin-6 (IL-6) was verified by dual-luciferase reporter assays. Results: CuB treatment inhibited the proliferation of lung cancer cells and promoted cell apoptosis, and increased the expression of Bax and cleaved caspase3, decreased cyclin B1 and Bcl-2 expression. CuB suppressed XIST and IL-6 expression, and enhanced miR-let-7c expression. XIST silencing enhanced the inhibitory effect of CuB on cell proliferation and the promotion effect on apoptosis via upregulating miR-let-7c. Moreover, XIST targeted miR-let-7c to activate the IL-6/STAT axis. MiR-let-7c overexpression enhanced the regulatory effect of CuB on proliferation and apoptosis via suppressing the IL-6/STAT3 pathway. Discussion and conclusion: CuB regulated cell proliferation and apoptosis by inhibiting the XIST/miR-let-7c/IL-6/STAT3 axis in lung cancer. These findings indicate CuB may have the possibility of clinical application in lung cancer treatment. [ABSTRACT FROM AUTHOR]

Telomeric repeat binding factor 1 (TERF1) has been identified as a tumor suppressor gene in numerous types of human cancer. However, the expression of TERF1 and its mechanism in prostate cancer (PCa) remains unclear. The present study aimed to explore the expression and functions of TERF1 in PCa. The UALCAN database was used to analyze the differential expression of TERF1 between normal prostate tissue and primary PCa tissue. Cell apoptosis was analyzed by Annexin V/propidium iodide staining, and wound healing and Transwell assays were used to detect the cell migration and invasion abilities, respectively. The cell viability was analyzed using an MTT assay. Reverse transcription‑quantitative PCR and western blotting were used to analyze the mRNA and protein expression levels, respectively, of epithelial‑mesenchymal transition (EMT) markers following TERF1 knockdown in the PC3 cell line. A dual luciferase reporter assay was used to verify the association between TERF1 and microRNA (miR)‑155 predicted by bioinformatics analysis. Rescue experiments were performed to determine the role of the miR‑155/TERF1 axis in regulating the cellular behaviors of PCa. The results demonstrated that the expression levels of TERF1 in the primary prostate tumors were significantly downregulated compared with in prostate normal tissue. TERF1 silencing was discovered to significantly promote cell viability, migration and invasion, while suppressing cell apoptosis. The impact of TERF1 on PC3 cells was suggested to occur through the EMT pathway. TERF1 was confirmed to be the direct target of miR‑155. The overexpression of miR‑155 promoted the viability, migration and invasion, while suppressing the apoptosis of the PC3 cell line, while the knockdown of miR‑155 in PC3 cells achieved the opposite trends. In addition, TERF1 overexpression reversed the promotive effects of upregulated miR‑155 expression levels on the migration and apoptosis of PC3 cells. On the contrary, the knockdown of TERF1 reversed the migration and apoptosis abilities of the downregulated miR‑155 expression levels on the cellular behaviors of PC3 cells. In conclusion, TERF1, as a direct target of miR‑155, was discovered to be significantly downregulated in PCa, which was suggested to promote the migration and invasion of PCa via the EMT pathway. [ABSTRACT FROM AUTHOR]

Background: Pilocytic astrocytomas (PAs) are slow growing neoplasms and usually located at the cerebellum. There has been certainty regarding the truthful benefit of surgical resection for patients with PA. Gross total resection (GTR) of PAs, especially those being situated in deep regions, remains a surgical challenge. Generally, they are considered as benign and usually develop in young patients. PAs, belonging to WHO I can be cured by radical resection. The patients with PA have excellent prognosis if complete resection can be conducted. The use of fluorescein in vermis PA surgery has not been yet reported. Our data presents fluorescein facilitates surgical resection of vermis PA. Methods: Five milligrams per kilogram of fluorescein sodium was intravenously injected directly before general anesthesia for the three patients with PA. The yellow 560 filter was employed for microsurgical tumor resection. Surgical outcomes were assessed concerning the extent of resection. Results: Most portion of PA in the three cases was found to be highly fluorescent after intravenous fluorescein sodium injection, which markedly enhanced tumor visibility. Gross total resection in all of the patients was achieved without further neurological deficits. No adverse effects and complications resulting from fluorescein sodium were observed over the postoperative course. Conclusions: Intraoperative guidance by fluorescein sodium as a new, simple, safe, and practical procedure can enhance the fidelity of tumor tissue and increase the possibility of completely resecting PAs. [ABSTRACT FROM AUTHOR]

Cordycepin is an active component of the traditional Chinese medicine Cordyceps sinensis and Cordyceps militaris with notable anticancer activity. Though the prominent inhibitory activity was reported in different kinds of cancer cell lines, the concrete mechanisms remain elusive. It was reported that cordycepin could be converted into tri-phosphates in vivo to confuse a number of enzymes and interfere the normal cell function. For the inhibitory mechanism of EGFR inhibitors and the structure similarity of ATP and tri-phosphated cordycepin, human lung cancer cell line H1975 was employed to investigate the inhibitory effect of cordycepin. The results showed that cordycepin could inhibit cell proliferation and induce apoptosis in a dose-dependent manner. Cell cycle analysis revealed that H1975 cells could be arrested at the G0/G1 phase after cordycepin treatment. The expression levels of apoptosis-related protein Caspase-3 and Bcl-2 and phosphorylated expression levels of EGFR, AKT and ERK1/2 were all decreased compared with the control group stimulated with EGF. However, the protein expression levels of proapoptotic protein Bax and cleaved caspase-3 were increased. These results implied that cordycepin could inhibit cell proliferation and induce apoptosis via the EGFR signaling pathway. Our results indicated that there was potential to seek a novel EGFR inhibitor from cordycepin and its chemical derivatives. [ABSTRACT FROM AUTHOR]

Background: MiR-106a is frequently down-regulated in various types of human cancer. However the underlying mechanism of miR-106a involved in glioma remains elusive.Methods: The association of miR-106a with glioma grade and patient survival was analyzed. The biological function and target of miR-106a were determined by bioinformatic analysis and cell experiments (Western blot, luciferase reporter, cell cycle, ntracellular ATP production and glucose uptake assay). Finally, rescue expression of its target SLC2A3 was used to test the role of SLC2A3 in miR-106a-mediated cell glycolysis and proliferation.Results: Here we showed that miR-106a was a tumor suppressor miRNA was involved in GBM cell glucose uptake and proliferation. Decreased miR-106a in GBM tissues and conferred a poor survival of GBM patients. SLC2A3 was identified as a core target of miR-106a in GBM cells. Inhibition of SLC2A3 by miR-106a attenuated cell proliferation and inhibited glucose uptake. In addition, for each biological process we identified ontology-associated transcripts that significantly correlated with SLC2A3 expression. Finally, the expression of SLC2A3 largely abrogated miR-106a-mediated cell proliferation and glucose uptake in GBM cells.Conclusions: Taken together, miR-106a and SLC2A3 could be potential therapeutic approaches for GBM. [ABSTRACT FROM AUTHOR]

Human adenoid cystic carcinoma (ACC) is characterized by diffused invasion of the tumor into adjacent organs and early distant metastasis. Anoikis resistance and epithelial mesenchymal transition (EMT) are considered prerequisites for cancer cells to metastasize. Exploring the relationship between these processes and their underlying mechanism of action is a promising way to better understand ACC tumors. We initially established anoikis-resistant sublines of ACC cells; the variant cells revealed a mesenchymal phenotype through Slug-mediated EMT-like transformation and displayed enhanced metastatic potential both in vitro and in vivo. Suppression of EMT by knockdown of Slug significantly impaired anoikis resistance, migration, and invasion of the variant cells. With overexpression of Slug and Twist, we determined that induction of EMT in normal ACC cells could prevent anoikis, albeit partially. These findings strongly suggest that EMT is indispensable in anoikis resistance, at least in ACC cells. Furthermore, we found that the EGFR/PI3K/Akt pathway acts as the common regulator for EMT-like transformation and anoikis resistance, as confirmed by their specific inhibitors. Gefitinib and LY294003 restored the sensibilities of anoikis-resistant cells to anoikis and simultaneously impaired their metastatic potential. In addition, the results from our in vivo model of metastasis suggest that pretreatment with gefitinib promotes mouse survival by alleviating pulmonary metastasis. Most importantly, immunohistochemistry of human ACC specimens showed a correlation between the overexpression of Slug and EGFR staining. This study has demonstrated that Slug-mediated EMTlike transformation is required by human ACC cells to achieve anoikis resistance and their metastatic potential. Targeting the EGFR/PI3K/Akt pathway holds potential as a preventive strategy against distant metastasis of ACC. [ABSTRACT FROM AUTHOR]

Background: Autophagy is an evolutionarily conserved protein degradation pathway. A defect in autophagy may contribute to tumorigenesis. Autophagy inducers could have a potential function in tumor prevention and treatment. Methodology/Principal Findings: Our results showed that Rhabdastrellic acid-A, an isomalabaricane triterpenoid isolated from the sponge Rhabdastrella globostellata, inhibited proliferation of human cancer cell lines Hep3B and A549 and induced caspase-independent cell death in both the cell lines. Further investigation showed that Rhabdastrellic acid-A induced autophagy of cancer cells determined by YFP-LC3 punctation and increased LC3-II. The pretreatment with autophagy inhibitor 3-MA inhibited Rhabdastrellic acid-A-induced cell death. Knockdown of autophagy-related gene Atg5 inhibited Rhabdastrellic acid-A-induced cell death in A549 cells. Also, phospho-Akt and its downstream targets significantly decreased after treatment with Rhabdastrellic acid-A in both cancer cell lines. Transfection of constitutive active Akt plasmid abrogated autophagy and cell death induced by Rhabdastrellic acid-A. Conclusions/Significance: These results suggest that Rhabdastrellic acid-A could induce autophagy-associated cell death through blocking Akt pathway in cancer cells. It also provides the evidence that Rhabdastrellic acid-A deserves further investigation as a potential anticancer or cancer preventive agent. [ABSTRACT FROM AUTHOR]

Aim: To provide experimental data for further research on the signal transduction of apoptosis in lung adenocarcinoma cells, we examined the effects of exogenous C2-ceramide administration on several members of the mitogen-activated protein kinase (MAPK) superfamily and caspase-3 in A549 cells. Methods: Cell viability and apoptosis were analyzed by cell counting kit-8 assay and flow cytometry. Various MAPK and caspase-3 proteins were detected by Western blotting. Results: C2-ceramide selectively altered the phosphorylation state of members of the MAPK superfamily, causing hyperphosphorylation of mitogen-activated protein kinase kinase (MEK) 1/2 and the p38 MAPK, but not affecting the phosphorylation of extracellular signal-regulated kinase 1/2 and the c-Jun N-terminal kinase. SB-203580 (a p38 MAPK inhibitor) and p38 siRNA, but not U0126 (a MEK inhibitor), partially rescued cell death induced by C2-ceramide. C2-ceramide promoted the activation of caspase-3. Conclusion: Exogenous C2-ceramide induced apoptosis in human lung adenocarcinoma A549 cells. The activation of MAPK and caspase-3 were involved in the mechanisms of C2-ceramide-induced apoptosis in A549 cells. [ABSTRACT FROM AUTHOR]

We had previously shown that the expression of heparin/heparan sulfate interacting protein/ribosomal protein L29 (HIP/RPL29) was upregulated in colon cancer tissues. The present study investigated the role of HIP/RPL29 in differentiation in colon cancer cells. Inducing cellular differentiation in HT-29 cells by both sodium butyrate and glucose deprivation resulted in a significant downregulation of HIP/RPL29 expression. The β-catenin/Tcf-4 pathway is the most important pathway controlling the switch between cellular differentiation and proliferation in intestinal epithelial cells. Inducing differentiation by dominant-negative inhibition of the β-catenin/Tcf-4 complexes in LS174T cells also resulted in downregulation of HIP/RPL29. To determine whether a lower expression of HIP/RPL29 could induce differentiation in cancer cells, small interfering RNA (siRNA) targeting HIP/RPL29 was transfected into LS174T cells. The resultant knockdown of HIP/RPL29 expression induced cellular differentiation, as shown by the increased expression of two known markers of differentiation in LS174T cells, galectin-4 and mucin-2. In addition, the differentiation process induced by repression of HIP/RPL29 expression was accompanied by the upregulation of p21 and p53. In conclusion, HIP/RPL29 plays a role in the cellular differentiation process in colon cancer cells. The differentiation process is at least partially mediated by the upregulation of p21 and p53 pathways. J. Cell. Physiol. 207: 287–292, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Previously we have shown that 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), which is isolated from the buds of Cleistocalyx operculatus, significantly inhibits the growth of human liver cancer SMMC-7721 cells and is able to induce apoptosis of SMMC-7721 cells in vitro. Here we report the antitumor effects of DMC in vivo, using a solid human tumor xenograft mouse model using human liver cancer SMMC-7721 cells. The average tumor weights in the control group and in mice injected with 150 mg/kg DMC were 1.42±0.11 g and 0.59±0.12 g, respectively. Flow cytometric analysis of the tumor cell population demonstrated an aneuploid peak (representing 33.60±0.80% of the total in mice injected with 150 mg/kg DMC). To our knowledge, this is the first time that chalcone compounds have been applied to a human tumor xenograft model. [ABSTRACT FROM AUTHOR]

Five new analogs 4-8 of rubiyunnanin B (1), mainly modified on the tetrapeptide subunit, were synthesized. These agents 4-8 were substituted d-Ala-l-Ala-l-Tyr(OMe)-l-Ala, d-Ala-l-Ala-l-Phe-l-Ala, d-Ala-l-Ala-l-Try-l-Ala, d-Ala-l-Ala-l-Pro-l-Ala, and d-Ala-l-Ala-l-Ala for the d-Ala-l-Ala-l-N-Me-Tyr(OMe)-l-Ala tetrapeptide subunit. Unlike the natural product, the synthetic agents 4-8 adopt only a single solution conformation, and the central peptide bond in the cyclodityrosine subunit of compounds 4-8 adopt trans stereochemistry. Cytotoxic activities of analogs 4-8 against three human cancer cell lines including A549, BGC-823, and HeLa were evaluated and all the five synthesized peptides exhibited no effects against the test cell lines. These compounds were also evaluated for their antiinsulin resistance and insulin sensitizing activities and none of them showed activity in these assays. [ABSTRACT FROM AUTHOR]

Neoplastic epithelia may remain dormant and clinically unapparent in human patients for decades. Multiple risk factors including mutations in tumor cells or the stromal cells may affect the switch from dormancy to malignancy. Gene mutations, including p53 mutations, within the stroma of tumors are associated with a worse clinical prognosis; however, it is not known if these stromal mutations can promote tumors in genetically at-risk tissue. To address this question, ApcMin/+and ApcMin/+Rag2−/−mice, which have a predilection to mammary carcinoma (as well as wild-type (wt) mice), received mesenchymal stem cells (MSC) with mutant p53 (p53MSC) transferred via tail vein injection. In the wt mouse, p53MSC circulated in the periphery and homed to the marrow cavity where they could be recovered up to a year later without apparent effect on the health of the mouse. No mammary tumors were found. However, in mice carrying the ApcMin/+mutation, p53MSC homed to mammary tissue and significantly increased the incidence of mammary carcinoma. Tumor necrosis factor (TNF)-α-dependent factors elaborated from mesenchymal cells converted quiescent epithelia into clinically apparent disease. The increased cancer phenotype was completely preventable with neutralization of TNF-α or by transfer of CD4+regulatory T cells from immune competent donors, demonstrating that immune competency to regulate inflammation was sufficient to maintain neoplastic dormancy even in the presence of oncogenic epithelial and stromal mutations. The significant synergy between host immunity and mesenchymal cells identified here may restructure treatments to restore an anticancer microenvironment. [ABSTRACT FROM AUTHOR]