Concentration Prediction of Polymer Insulation Aging Indicator-Alcohols in Oil Based on Genetic Algorithm-Optimized Support Vector Machines.

The predictive model of aging indicator based on intelligent algorithms has become an auxiliary method for the aging condition of transformer polymer insulation. However, most of the current research on the concentration prediction of aging products focuses on dissolved gases in oil, and the concentration prediction of alcohols in oil is ignored. As new types of aging indicators, alcohols (methanol, ethanol) are becoming prevalent in the aging evaluation of transformer polymer insulation. To address this, this study proposes a prediction model for the concentration of alcohols based on a genetic-algorithm-optimized support vector machine (GA-SVM). Firstly, accelerated thermal aging experiments on oil-paper insulation are conducted, and the concentration of alcohols is measured. Then, the data of the past 4 days of aging are used as the input feature of SVM, and the GA algorithm is utilized to optimize the kernel function parameter and penalty factor of SVM. Moreover, the concentrations of methanol and ethanol are predicted, after which the prediction accuracy of other algorithms and GA-SVM are compared. Finally, an industrial software program for predicting the concentration of methanol and ethanol is established. The results show that the mean square errors (MSE) of methanol and ethanol concentration predictions of the model proposed in this paper are 0.008 and 0.003, respectively. The prediction model proposed in this paper can track changes in methanol and ethanol concentrations well, providing a theoretical basis for the field of alcohol concentration prediction in transformer oil.

Abnormally elevated ubiquilin­1 expression in breast cancer regulates metastasis and stemness via AKT signaling.

Ubiquilin­1 (UBQLN1) is an essential factor for the maintenance of proteostasis in cells. It is important for the regulation of different protein degradation mechanisms, including the ubiquitin­proteasome system, autophagy and endoplasmic reticulum­associated protein degradation pathways. However, the role of UBQLN1 in cancer progression remains largely unknown. In the present study, the expression, functions and molecular mechanisms of UBQLN1 in breast cancer tissue samples and cell lines were explored. Immunohistochemical and bioinformatics analyses revealed that UBQLN1 expression was significantly upregulated in breast cancer tissues and cell lines. UBQLN1 expression in breast cancer was significantly associated with lymph node metastasis and TNM stage. Moreover, a high UBQLN1 expression was a predictor of an unfavorable survival in patients with breast cancer. In vitro, UBQLN1 silencing markedly inhibited cell migration and invasion, epithelial­to­mesenchymal transition (EMT) and MMP expression. UBQLN1 silencing attenuated the stem cell­like properties of breast cancer cells, including their mammosphere­forming abilities. UBQLN1 knockdown also enhanced breast cancer cell chemosensitivity to paclitaxel. The expression levels of the stem cell markers. Aldehyde dehydrogenase 1 (ALDH1), Oct­4 and Sox2 were significantly decreased in the cells in which UBQLN1 was silenced, whereas breast cancer stem cells exhibited an increased expression of UBQLN1. Mechanistically, UBQLN1 knockdown inhibited the activation of AKT signaling, as revealed by the increased PTEN expression and the decreased expression of phosphorylated AKT in cells in which UBQLN1 was silenced. On the whole, the present study demonstrates that UBQLN1 is aberrantly upregulated in breast cancer and predicts a poor prognosis. The silencing of UBQLN1 inhibited the invasion, EMT and stemness of breast cancer cells, possibly via AKT signaling.

miR-206 as a prognostic and sensitivity biomarker for platinum chemotherapy in epithelial ovarian cancer.

BACKGROUND: Drug resistance is a major obstacle to successful chemotherapy for epithelial ovarian cancer (EOC). We found a subset of miRNAs associated with the response to first-line platinum-based chemotherapy in EOC by microarray, and miR-206 was one of the most significant miRNAs. The purposes of this study were to evaluate the prognostic and platinum-resistance predictive value of miR-206 in EOC patients and to investigate the functional roles of miR-206 in regulating the platinum resistance of EOC and the underlying mechanism. METHODS: MiRNA expression profiling in EOC specimens was performed using a TaqMan miRNA array. miR-206 expression was confirmed by quantitative real-time PCR (qRT-PCR) analysis. Overexpression of miR-206 in EOC cell lines was achieved by the stable transfection of a recombinant plasmid. In vitro assays of cisplatin cytotoxicity, cell cycle distribution, apoptosis, transwell invasion and cell scratching were employed. Connexin 43 (Cx43) expression was detected by Western blotting. Murine xenograft models were used to determine the effects of miR-206 on platinum resistance in vivo. RESULTS: miR-206 expression was increased in primary platinum-resistant EOC. High miR-206 expression was related to poor prognosis in EOC patients who received platinum-based chemotherapy and predicted chemoresistance to platinum treatment. Overexpression of miR-206 in cisplatin-sensitive EOC cell lines significantly increased cell viability, migration and invasion in the presence of cisplatin and decreased cisplatin-induced apoptosis. Cx43, a target gene of miR-206, was negatively regulated by miR-206 in EOC cell lines and significantly related to better prognosis in patients who received platinum-based chemotherapy (KmPlot). miR-206 had high expression and Cx43 had low expression in platinum-sensitive EOC cell lines compared with resistant ones. In vivo murine xenograft models showed that miR-206 profoundly promoted the chemoresistance of EOC to cisplatin treatment. CONCLUSION: miR-206 was highly expressed in primary platinum-resistant EOCs and functionally promoted platinum resistance in part by downregulating Cx43 expression, thereby providing a useful biomarker for prognostic and platinum-resistance prediction.

IL-6 induces tumor suppressor protein tyrosine phosphatase receptor type D by inhibiting miR-34a to prevent IL-6 signaling overactivation.

Protein tyrosine phosphatase receptor type D (PTPRD) is a tumor suppressor gene that is epigenetically silenced and mutated in several cancers, including breast cancer. Since IL-6/STAT3 signaling is often hyperactivated in breast cancer and STAT3 is a direct PTPRD substrate, we investigated the role of PTPRD in breast cancer and the association between PTPRD and IL-6/STAT3 signaling. We found that PTPRD acts as a tumor suppressor in breast cancer tissues and that high PTPRD expression is positively associated with tumor size, lymph node metastasis, PCNA expression, and patient survival. Moreover, breast cancers with high PTPRD expression tend to exhibit high IL-6 and low phosphorylated-STAT3 expression. IL-6 was found to inhibit miR-34a transcription and induce PTPRD expression in breast cancer and breast epithelial cells, whereas PTPRD was shown to mediate activated STAT3 dephosphorylation and to be a conserved, direct target of miR-34a. IL-6-induced PTPRD upregulation was blocked by miR-34a mimics, whereas experimental PTPRD overexpression suppressed MDA-MB-231 cell migration, invasion, and epithelial to mesenchymal transition, decreased STAT3 phosphorylation, and increased miR-34a transcription. Our findings suggest that PTPRD mediates activated STAT3 dephosphorylation and is induced by the IL-6/STAT3-mediated transcriptional inhibition of miR-34a, thereby establishing a negative feedback loop that inhibits IL-6/STAT3 signaling overactivation.

Exosomal transfer of miR-501 confers doxorubicin resistance and tumorigenesis via targeting of BLID in gastric cancer.

Exosomal transfer of oncogenic miRNAs can enhance recipient cell growth, metastasis and chemoresistance. Currently we found that microRNA-501-5p (miR-501) was overexpressed in doxorubicin-resistant gastric cancer (GC) SGC7901/ADR cell-secreted exosomes (ADR Exo) than that in SGC7901 cell-secreted exosomes (7901 Exo). ADR Exo was internalized by SGC7901, and a Cy3-miR-501 mimic was transferred from SGC7901/ADR to SGC7901 via exosomes. ADR Exo conferred doxorubicin resistance, proliferation, migration and invasion abilities to negative control miRNA inhibitor-expressing GC cells, whereas it inhibited apoptosis. MiR-501 knockdown or BH3-like motif-containing protein, cell death inducer (BLID) overexpression could reverse the effects of ADR Exo on recipient cells. SGC7901 cells cocultured with SGC7901/ADR prior to treatment with GW4869 or transfection of a miR-501 inhibitor were sensitive to doxorubicin and exhibited attenuated proliferation, migration and invasion and increased apoptosis. The intratumoral injection of ADR Exo into negative control miRNA inhibitor-expressing SGC7901 cells induced rapid subcutaneous tumor growth and resistance to doxorubicin compared to that of miR-501 knockdown or BLID-overexpressing cells. This effect is possibly achieved by exosomal miR-501-induced downregulation of BLID, subsequent inactivation of caspase-9/-3 and phosphorylation of Akt. Exosomal miR-501 might be a therapeutic target for GC.

The role and mechanism of transforming growth factor beta 3 in human myocardial infarction-induced myocardial fibrosis.

Transforming growth factor beta (TGFß) plays a crucial role in tissue fibrosis. A number of studies have shown that TGFß3 significantly attenuated tissue fibrosis. However, the mechanism involved in this effect is poorly understood. In this study we found that the expression level of TGFß3 was higher in human myocardial infarction (MI) tissues than in normal tissues, and interestingly, it increased with the development of fibrosis post-myocardial infarction (post-MI). In vitro, human cardiac fibroblasts (CFs) were incubated with angiotensin II (Ang II) to mimic the ischaemic myocardium microenvironment and used to investigate the anti-fibrotic mechanism of TGFß3. Then, fibrosis-related proteins were detected by Western blot. It was revealed that TGFß3 up-regulation attenuated the proliferation, migration of human CFs and the expression of collagens, which are the main contributors to fibrosis, promoted the phenotype shift and the cross-linking of collagens. Importantly, the expression of collagens was higher in the si-smad7 groups than in the control groups, while silencing smad7 increased the phosphorylation level of the TGFß/smad signalling pathway. Collectively, these results indicated that TGFß3 inhibited fibrosis via the TGFß/smad signalling pathway, possibly attributable to the regulation of smad7, and that TGFß3 might serve as a potential therapeutic target for myocardial fibrosis post-MI.

Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity.

BACKGROUND: Recent studies have indicated that deubiquitinating enzymes (DUBs) are related to the stem-cell pathway network and chemo-resistance in cancer. Ubiquitin-specific peptidase 37 (USP37), a novel DUB, was identified to be a potential factor associated with tumor progression. However, the biological functions of USP37 in breast cancer remain unclear. METHODS: The distribution of USP37 expression in breast cancer and the correlation between USP37 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was utilized to evaluate potential mechanism of USP37 in breast cancer. The USP37 expression in breast cancer tissues and breast cancer cell lines were detected by immunohistochemistry and western blotting. Sorting of breast cancer stem cells (BCSCs) were by using MACS assay. In vitro and in vivo assays were performed to examine the biological functions of USP37 in breast cancer cells. MG132, CHX chase, immunofluorescence staining and co-immunoprecipitation assays were used to test the interaction between USP37 and Gli-1. RESULTS: Bioinformatics analysis demonstrated that USP37 gene was elevated in breast cancer tissues and its overexpression was strongly correlated with the increased mortality rate. GSEA analysis showed that USP37 expression was positively associated with cell growth and metastasis while negatively related to cell apoptosis in the TCGA breast cancer samples. USP37 expression was elevated in breast cancer tissues and breast cancer cell lines. Moreover, we also detected that USP37 was overexpressed in BCSCs. USP37 regulated the ability of cell invasion, epithelial-mesenchymal transition (EMT), stemness and cisplatin sensitivity in breast cancer cell lines. Additionally, USP37 knockdown inhibited tumorigenicity and increased anticancer effect of cisplatin in vivo. Knockdown of USP37 significantly decreased hedgehog (Hh) pathway components Smo and Gli-1. Gli-1 was stabilized by USP37 and they interacted with each other. Further studies indicated that USP37 knockdown could inhibit the stemness, cell invasion and EMT in breast cancer via downregulation of Hh pathway. CONCLUSIONS: These findings reveal that USP37 is highly expressed in BCSCs and is correlated with poor prognosis in breast cancer patients. USP37 can regulate the stemness, cell invasion and EMT via Hh pathway, and decreased USP37 confers sensitivity to cisplatin in breast cancer cells. USP37 is required for the regulation of breast cancer progression, as well as a critical target for clinical treatment of breast cancer.

Protein tyrosine phosphatase receptor-type δ acts as a negative regulator suppressing breast cancer.

Protein tyrosine phosphatase receptor-type δ (PTPRD) is frequently inactivated in human cancers. This study investigated the role of PTPRD in the regulation of stemness, epithelial-mesenchymal transition (EMT), and migration and invasion in breast cancer cells. In vitro, PTPRD silencing using siRNA enhanced the stem cell-like properties of breast cancer cells, including their mammosphere- and holoclone-forming abilities, and it promoted tumorigenicity in vivo. PTPRD knockdown also increased the CD44+/CD24- breast cancer stem cell (BCSC) population and the expression of the stem cell markers ALDH1 and OCT4. It also promoted migration and invasion by breast cancer cell, EMT, and activation of signal transducer and activator of transcription 3 (STAT3). BCSCs expressed low levels of PTPRD, displayed mesenchymal phenotypes, and were more sensitive to IL-6-mediated STAT3 activation than non-BCSCs. PTPRD expression was upregulated by IL-6 in breast cancer cells, thereby establishing a negative feedback circuit by which IL-6 induced canonical STAT3 phosphorylation and transiently upregulated PTPRD, which in turn dephosphorylated STAT3 and prevented downstream signaling via the IL-6/STAT3 cascade. These data suggest that therapies aimed at restoring or enhancing PTPRD expression may be effective in controlling breast cancer progression and metastasis.

MiR-770-5p inhibits cisplatin chemoresistance in human ovarian cancer by targeting ERCC2.

In this study, we examined the role of the miRNA miR-770-5p in cisplatin chemotherapy resistance in ovarian cancer (OVC) patients. miR-770-5p expression was reduced in platinum-resistant patients. Using a 6.128-fold in expression as the cutoff value, miR-770-5p expression served as a prognostic biomarker and predicted the response to cisplatin treatment and survival among OVC patients. Overexpression of miR-770-5p in vitro reduced survival in chemoresistant cell lines after cisplatin treatment. ERCC2, a target gene of miR-770-5p that participates in the NER system, was negatively regulated by miR-770-5p. siRNA-mediated silencing of ERCC2 reversed the inhibition of apoptosis resulting from miR-770-5p downreglation in A2780S cells. A comet assay confirmed that this restoration of cisplatin chemosensitivity was due to the inhibition of DNA repair. These findings suggest that endogenous miR-770-5p may function as an anti-oncogene and promote chemosensitivity in OVC, at least in part by downregulating ERCC2. miR-770-5p may therefore be a useful biomarker for predicting chemosensitivity to cisplatin in OVC patients and improve the selection of effective, more personalized, treatment strategies.

miR-221/222 enhance the tumorigenicity of human breast cancer stem cells via modulation of PTEN/Akt pathway.

BACKGROUND: The miR-221/222 cluster has been discovered to function as oncogene in human malignancies including breast cancer. However, the role of miR-221/222 in the self-renewal of breast cancer stem cells (BCSCs) is not fully understood. In this study, we examined the impact and mechanism of miR-221/222 on the breast cancer cell viability, migration and invasion, and propagation of BCSCs. METHODS: Human breast cancer cell line MCF-7 was transfected with miR-221/222 mimics or inhibitors to overexpress or knock down miR-221/222 respectively using Lipofactamine 2000. The biological effects of miR-221 and miR-222 were then assessed by cell proliferation assay, colony formation assay and transwell chamber assays. CD44/CD24 staining and mammosphere formation assay were performed to evaluate the ability of BCSCs self-renewal. Potential target gene phosphatase and tensin homolog (PTEN) and its downstream effector, phosphorylated Akt (p-Akt) were identified by Western blot and qRT-PCR methods. RESULTS: PTEN, a tumor suppressor gene, was confirmed as a target of miR-221/222 in breast cancer cell line MCF-7. Downregulation of PTEN by miR-221/222 increased the phosphorylation of Akt. Enforced expression of miR-221/222 promoted breast cancer cell proliferation, migration and invasion via targeting PTEN/Akt pathway. Importantly, ectopic expression of miR-221/222 enriched the proportion of CD44(+)/CD24(-) BCSCs and improved the mammosphere formation capacity through targeting PTEN/Akt pathway. Blocking the endogenous miR-221/222 restored PTEN expression and subsequently decreased Akt phosphorylation, and thereby reversed this phenotype. CONCLUSIONS: Our results suggested that miR-221/222 enhance breast cancer growth, migration and invasion, meanwhile propagate the self-renewal of BCSCs. This is achieved possibly through targeting PTEN/Akt pathway. miR-221/222 might be a novel therapeutic candidate for human breast cancer.

Epidermal growth factor receptor expression and gene copy number analysis in gastric carcinoma samples from Chinese patients.

Epidermal growth factor receptor (EGFR) expression and gene copy number have been observed to be associated with a positive clinical response to EGFR inhibitors. The present study aimed to evaluate EGFR expression and gene copy number in samples of gastric carcinoma (GC) from Chinese patients. EGFR expression and gene copy number were detected using immunohistochemistry and fluorescence in situ hybridization, in tissue array slides containing 150 individual samples of GC tissue. The association between EGFR status, clinicopathological features and overall patient survival was analyzed. Out of the 150 cases of GC evaluated, 63 (42.00%) demonstrated weak EGFR expression and 20 (13.33%) demonstrated EGFR overexpression. EGFR expression was observed to be associated with tumor location (P<0.05). Out of 104 cases of GC, which produced a clear FISH signal, 6 (5.77%) exhibited EGFR gene amplification and 5 (4.80%) exhibited balanced polysomy. Patients exhibiting GC, who demonstrated weak EGFR expression, EGFR overexpression or increased EGFR gene copy number, possessed an unfavorable prognosis. Multivariate analysis revealed that EGFR expression, tumor/node/metastasis stage and tumor location were potential independent unfavorable prognostic factors for GC patients. In conclusion, EGFR overexpression, gene amplification and polysomy were observed in GC patients and were associated with an unfavorable prognosis. Evaluation of EGFR status may therefore facilitate the identification of a subset of GC patients sensitive to treatment with EGFR-targeted therapies.

Salinomycin suppresses TGF-ß1-induced epithelial-to-mesenchymal transition in MCF-7 human breast cancer cells.

Epithelial-to-mesenchymal transition (EMT) is the major cause of breast cancer to initiate invasion and metastasis. Salinomycin (Sal) has been found as an effective chemical compound to kill breast cancer stem cells. However, the effect of Sal on invasion and metastasis of breast cancer is unclear. In the present study, we showed that Sal reversed transforming growth factor-ß1 (TGF-ß1) induced invasion and metastasis accompanied with down-regulation of MMP-2 by experiments on human breast cancer cell line MCF-7. Sal was able to inhibit TGF-ß1-induced EMT phenotypic transition and the activation of key signaling molecules involved in Smad (p-Smad2/3,Snail1) and non-Smad (ß-catenin, p-p38 MAPK) signals which cooperatively regulate the induction of EMT. Importantly, in a series of breast cancer specimens, we found strong correlation among E-cadherin expression, ß-catenin expression, and the lymph node metastatic potential of breast cancer. Our research suggests that Sal is promised to be a chemotherapeutic drug by suppressing the metastasis of breast cancer.

[Inhibitory effect of salinomycin on human breast cancer cells MDA-MB-231 proliferation through Hedgehog signaling pathway].

OBJECTIVE: To investigate the inhibitory effect of salinomycin on human breast cancer cells in vitro, and to explore the related molecular mechanism. METHODS: Human breast cancer MDA-MB-231 cells were treated with salinomycin at different concentrations and at various time points. The effect of salinomycin on MDA-MB-231 cells proliferation was studied by CCK-8 method. The cell cycle status was examined by flow cytometry. RT-PCR and Western blot were used to detect the expression of Shh, Smo and Gli1 in the Hedgehog pathway at mRNA and protein levels. RESULTS: Proliferation of MDA-MB-231 cells treated with salinomycin was markedly inhibited in a concentration and time dependent manner. Salinomycin at concentrations of 0, 0.4, 0.8 and 1.6 µmol/L inhibited the growth at the rates of 11.18%, 25.88%, 50.03%, 92.65%, respectively. Salinomycin prevented MDA-MB-231 cells from G1 into S phase. Salinomycin at concentrations of 0, 0.8 and 1.6 µmol/L resulted in S-phase percentage of 25.03%, 11.85% and 35.21%, respectively (P < 0.05). RT-PCR and Western blot showed that the expression of key elements Shh, Smo and Gli1 in the Hedgehog pathway was inhibited by salinomycin in a concentration dependent manner (P < 0.05). CONCLUSION: Salinomycin prevents breast cancer cell transition from G1 to S phase through downregulation of the target genes of Hedgehog signaling pathway, leading to an effective inhibition of MDA-MB-231 cells.

Profile of differentially expressed miRNAs in high-grade serous carcinoma and clear cell ovarian carcinoma, and the expression of miR-510 in ovarian carcinoma.

Improved insight into the molecular and genetic profile of different types of epithelial ovarian cancer (EOC) is required for understanding the carcinogenesis of EOC and may potentially be exploited by future targeted therapies. The aim of the present study was to identify a unique microRNA (miRNA) patterns and key miRNAs, which may assist in predicting progression and prognosis in high­grade serous carcinoma (HGSC) and clear cell carcinoma (CCC). To identify unique miRNA patterns associated with HGSC and CCC, a miRNA microarray was performed using Chinese tumor bank specimens of patients with HGSC or CCC in a retrospective analysis. The expression levels of four deregulated miRNAs were further validated using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) in an external cohort of 42 cases of HGSC and 36 cases of CCC. Kaplan­Meier analysis was performed to analyze the correlation between the expression levels of the four miRNAs and patient prognosis. Among these validated miRNAs, miR­510 was further examined in another cohort of normal ovarian tissues, as well as the HGSC, low­grade serous carcinoma (LGSC) and CCC specimens using RT­qPCR and in situ hybridization. The results revealed that, of the 768 miRNAs analyzed in the microarray, 33 and 50 miRNAs were significantly upregulated and downregulated, respectively, with at least a 2­fold difference in HGSC, compared with CCC. The quantitative analysis demonstrated that miR­510 and miR­129­3p were significantly downregulated, and that miR­483­5p and miR­miR­449a were significantly upregulated in CCC, compared with HGSC (P<0.05), which was consistent with the microarray results. Kaplan­Meier analysis revealed low expression levels of miR­510 and low expression levels of miR­129­3p, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymphatic metastasis and that HGSC was significantly associated with the poorer overall survival rates (P<0.05). The expression of miR­510 was significantly higher in the LGSC and CCC tissues, compared with the HGSC and normal ovarian tissues. The results of the present study suggested that different subtypes of EOC have specific miRNA signatures, and that miR­510 may be involved differently in HGSC and CCC. Thus, miR­510 and miR­129­3p may be considered as potential novel candidate clinical biomarkers for predicting the outcome of EOC.

Expression and activation of EGFR and STAT3 during the multistage carcinogenesis of intrahepatic cholangiocarcinoma induced by 3'-methyl-4 dimethylaminoazobenzene in rats.

The purpose of this study was to investigate whether the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription-3 (STAT3) signal pathway contributes to the carcinogenesis of intrahepatic cholangiocarcinoma (ICC) induced by 3'-methyl-4 dimethylaminoazobenzene (3'Me-DAB) in rats. EGFR, TGFα, STAT3 and p-STAT3 in different stages of carcinogenesis were detected by immunohistochemistry (IHC). In situ hybridization (ISH) was applied to investigate the expression of STAT3 mRNA. Oval cells were verified by the immunohistochemical staining of alpha-fetoprotein (AFP), CD133 and epithelial cell adhesion molecules (EpCAM). Sequential development of necrosis, oval cell proliferation, cholangiofibrosis (CF) and ICC was observed in the liver of rats administered 3'Me-DAB. Oval cells showed positive expression of AFP, CD133 and EpCAM. The expression of EGFR was significantly higher in the ICC than in oval cells, CF or normal bile ducts (p<0.05), but there was no difference in EGFR expression between the other groups. The highest expression of p-STAT3 and TGFα was observed in CF. The expression of these two molecules in the ICC and oval cells was significantly higher than in normal bile ducts (p<0.05). Elevation of STAT3 mRNA was detected during carcinogenesis as shown by ISH, strong intensity was observed in the ICC and moderate intensity was observed in oval cells and CF. These observations suggest that the EGFR and STAT3 signal pathway contributes to the carcinogenesis of ICC. High activity of STAT3 during the carcinogenesis of ICC may be the result of high activity of EGFR triggered by TGFα.

Dysregulation of the miR-34a-SIRT1 axis inhibits breast cancer stemness.

Enforced expression of miR-34a eliminates cancer stem cells in some malignant tumors. Sirtuin-1 (SIRT1) is a direct target of miR-34a. Here we found low levels of miR-34a and high levels of SIRT1 in CD44+/CD24- breast cancer stem cells (BCSCs). MiR-34a overexpression and knockdown of SIRT1 decreased proportion of BSCSs and mammosphere formation. Expression of CSC markers, ALDH1, BMI1 and Nanog was decreased. In nude mice xenografts, stable expression of miR-34a and silencing of SIRT1 reduced tumor burden. Taken together, our results demonstrated that miR-34a inhibits proliferative potential of BCSCs in vitro and in vivo, at least partially by downregulating SIRT1. The miR-34a-SIRT1 axis may play role in self-renewal of BCSCs.

Salinomycin exerts anticancer effects on human breast carcinoma MCF-7 cancer stem cells via modulation of Hedgehog signaling.

Breast cancer tissue contains a small population of cells that have the ability to self-renew, these cells are known as breast cancer stem cells (BCSCs). The Hedgehog signal transduction pathway plays a central role in stem cell development, its aberrant activation has been shown to contribute to the development of breast cancer, making this pathway an attractive therapeutic target. Salinomycin (Sal) is a novel identified cancer stem cells (CSCs) killer, however, the molecular basis for its anticancer effects is not yet clear. In the current study, Sal's ability to modulate the activity of key elements in the Hedgehog pathway was examined in the human breast cancer cell line MCF-7, as well as in a subpopulation of cancer stem cells identified within this cancer cell line. We show here that Sal inhibits proliferation, invasion, and migration while also inducing apoptosis in MCF-7 cells. Interestingly, in a subpopulation of MCF-7 cells with the CD44(+)/CD24(-) markers and high ALDH1 levels indicative of BCSCs, modulators of Hedgehog signaling Smo and Gli1 were significantly down-regulated upon treatment with Sal. These results demonstrate that Sal also inhibits proliferation and induces apoptosis of BCSCs, further establishing it as therapeutically relevant in the context of breast cancers and also indicating that modulation of Hedgehog signaling is one potential mechanism by which it exerts these anticancer effects.