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Genetic and dietary factors are important contributors to the development of dental fluorosis (DF). This study investigated the association between DF and dietary carotenoids, and explored whether the association was modified by polymorphisms of the antioxidant enzyme superoxide dismutase 2 (SOD2 rs11968525) in Guizhou, China.A cross-sectional study with a total of 899 adults aged 18-75 years were enrolled in the study. Face-to-face interviews were conducted to assess dietary habits using a validated 75 item food frequency questionnaire (FFQ). Sociodemographic and lifestyle information, and blood and urine samples were also collected. Genotypes were evaluated using TaqMan single nucleotide polymorphism (SNP) Genotyping Assay.There were significant dose-dependent inverse associations of the prevalence of DF with intake of α-carotene, β-carotene, lutein/zeaxanthin, lycopene and total carotenoids (p-trend ranged from0.001-0.004). The odds ratios (ORs) and 95% confidence intervals (CIs) of DF comparing the highest against lowest quartile were 0.56 (0.35, 0.92) for α-carotene, 0.53 (0.35, 0.81) for β-carotene, 0.44 (0.27, 0.74) for lycopene, 0.35 (0.21, 0.58) for lutein/zeaxanthin in combination and 0.42 (0.25, 0.69) for total carotenoids (all p-trend0.005). Intake of β-cryptoxanthin was not found to be related to DF. The inverse association of DF with dietary intake of α-carotene and β-carotene was more evident in individuals with the AG+AA genotype (p-interaction0.05).Higher dietary carotenoids were associated with a lower occurrence of DF, polymorphisms in SOD2 (rs 11968525) modified the associations between dietary intake of carotene and DF. These findings provide evidence for precision prevention of fluorosis.

Background. Coronary artery disease (CAD) is one of the most common causes of sudden death with high morbidity in recent years. This paper is aimed at exploring the early peripheral blood biomarkers of sudden death and providing a new perspective for clinical diagnosis and forensic pathology identification by integrated bioinformatics analysis. Methods. Two microarray expression profiling datasets (GSE113079 and GSE31568) were downloaded from the Gene Expression Omnibus (GEO) database, and we identified differentially expressed lncRNAs, miRNAs, and mRNAs in CAD. Gene Ontology (GO) and KEGG pathway analyses of DEmRNAs were executed. A protein-protein interaction (PPI) network was constructed, and hub genes were identified. Finally, we constructed a competitive endogenous RNA (ceRNA) regulation network among lncRNAs, miRNAs, and mRNAs. Also, the 5 miRNAs of the ceRNA network were verified by RT-PCR. Results. In total, 86 DElncRNAs, 148 DEmiRNAs, and 294 DEmRNAs were dysregulated in CAD. We received 12 GO terms and 5 pathways of DEmRNAs. 31 nodes and 78 edges were revealed in the PPI network. The top 10 genes calculated by degree method were identified as hub genes. Moreover, there were a total of 26 DElncRNAs, 5 DEmiRNAs, and 13 DEmRNAs in the ceRNA regulation network. We validated the 5 miRNAs of the ceRNA network by RT-PCR, which were consistent with the results of the microarray. Conclusions. In this paper, a CAD-specific ceRNA network was successfully constructed, contributing to the understanding of the relationship among lncRNAs, miRNAs, and mRNAs. We identified potential peripheral blood biomarkers in CAD and provided novel insights into the development and progress of CAD.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer of the digestive tract that has a high potential for metastasis and a poor prognosis. Girdin was first reported in 2005 as an actin-binding protein and was designated as Akt-phosphorylation enhancer (APE); thus, Girdin has been revealed to have an important role in regulating cancer development. There is additional evidence indicating that Girdin is associated with cell proliferation, migration, invasion and survival in certain cancers. However, the potential mechanisms involving Girdin and mobility in pancreatic cancer have not been elucidated. In the present study, it was revealed that Girdin was highly expressed in pancreatic cancer tissue and was associated with tumor grade. The present study, to the best of our knowledge, is the first aimed at investigating the unknown role of Girdin in PDAC metastasis. A short hairpin RNA for Girdin (sh-Girdin) was successfully constructed with recombinant adenoviral vectors to suppress the expression of Girdin in pancreatic cancer cell lines (PANC-1 and BXPC-3). The silencing efficiency of the Girdin shRNA was determined by RT-qPCR and western blot analysis, and decreased Girdin expression in the cytoplasm was revealed by immunofluorescence detection. Then, sulforhodamine B (SRB) and colony formation assays were used to confirm that the knockdown of Girdin inhibited proliferation in vitro, and Transwell assays were used to examine the influence of Girdin knockdown on cellular mobility. Animal experiments also confirmed that silencing the expression of Girdin in pancreatic cancer cells inhibited the growth and metastasis of pancreatic cancer in vivo. Transforming growth factor-β (TGF-β) is a common inducer of epithelial-mesenchymal transition (EMT) and can effectively induce EMT in PDAC. Notably, TGF-β-treated cells exhibited changes in the classic biological markers of EMT. The expression of E-cadherin, a marker of the epithelial phenotype, increased, and the expression of N-cadherin and vimentin, markers of the interstitial phenotype, decreased in response to sh-Girdin. According to these experiments, Girdin may affect pancreatic cancer progression and development by interacting with vimentin. Therefore, there is evidence indicating that Girdin could be designated as a prognostic biological indicator and a candidate therapeutic target for pancreatic 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.

Ubiquilin‑1 (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 ubiquitin‑proteasome system, autophagy and endoplasmic reticulum‑associated 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, epithelial‑to‑mesenchymal transition (EMT) and MMP expression. UBQLN1 silencing attenuated the stem cell‑like properties of breast cancer cells, including their mammosphere‑forming abilities. UBQLN1 knockdown also enhanced breast cancer cell chemosensitivity to paclitaxel. The expression levels of the stem cell markers. Aldehyde dehydrogenase 1 (ALDH1), Oct‑4 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.

Background: Breast cancer is an aggressive malignancy that is unresponsive to conventional therapies. Parthenolide has been demonstrated to have anticancer effects against various types of cancer, including breast cancer. The aim of the present study was to investigate the effect and underlying mechanism of parthenolide in human breast cancer. Methods: Autophagy was measured through immunofluorescence and western blotting. DAPI staining and flow cytometry analysis were used to measure apoptosis. Western blot analysis was used to investigate the mechanism of autophagy induced by parthenolide on the expression levels of phosphoinositide 3‑kinase (PI3K), AKT, phosphorylated (p‑) AKT, mammalian target of rapamycin (mTOR), ATG13 and ATG14. Furthermore, apoptosis was confirmed via western blot analysis. Conclusion: Parthenolide inhibits breast cancer cell proliferation and induces autophagy and apoptosis, and suggested that the PI3K/AKT/mTOR pathway serves an important role in autophagy and apoptosis.

Background Ursolic acid (UA), a plant extract from traditional Chinese medicines as well as edible vegetables, exhibits a potent anticancer activity in various tumor cells. Annexin A1(AnxA1) is dysregulated and play a pivotal role in various tumor. However, the function of AnxA1 in breast cancer(BC) remains unclear. Methods Western blot, real-time quantitative polymerase chain reaction(qRT- PCR), transwell, wound healing and immunofluorescence were used to study the biological features of AnxA1 in breast cancer. The stemness of cancer cells was assessed by sphere formation assay. CCK-8 and flow cytometry assay were used to detect the effects of ursolic acid on the growth, proliferation and apoptosis of breast cancer cells in vitro. A nude mice xenograft model was employed in vivo. The potential mechanism by which Ursolic acid regulates the biological behaviors of breast cancer stem cells through AnxA1 via the wnt/β-catenin signaling pathway was tested by western blot, qRT- PCR and immunohistochemistry. Results AnxA1 was highly expressed in MDA-MB-231 cell line compared with MCF-7 cell line, Down-regulation of AnxA1 could reduce the mammosphere formation, inhibit EMT, decrease the ability of migration and invasion in MCF-7 and MDA-MB-231 cells. Ursolic acid can reduce the expression of AnxA1 and inhibit proliferation of breast cancer cells, stemness, EMT, migration and invasion, promote cell apoptosis of breast cancer cell. This studies suggest that the anticancer effects of AnxA1 knockdown and UA treatment may be realized by affecting the EMT process and the wnt/β-catenin signaling pathway. Conclusions This research suggest that AnxA1 knockdown enhanced the sensitivity of breast cancer cells to UA, the combination of UA treatment and AnxA1 knockdown possesses multiple anti-tumor activities against breast cancer, as it, in particular, inhibited the cancer stem cell and attenuated EMT. Therefore, it is emerging as a promising therapeutic strategy to inhibit breast cancer.

Background: The evolution of adriamycin (ADR) resistance in the treatment of breast cancer often leads to a poor prognosis in patients. Ubiquitin-specific peptidase 37 (USP37) has been recently identified as a modulator in regulating the stemness of breast cancer cells, but its underlying mechanism remains unclear. In this study, we investigated whether USP37 knockdown could hamper the chemical resistance of MCF-7 and MCF-7/ADR cells to adriamycin and elucidated the potential mechanism. Methods: Immunohistochemistry, western blotting, and RT-qPCR assays were performed to detect the USP37 expression in MCF-7 and MCF-7/ADR cells. The efficiency of USP37 knockdown in breast cancer cells was confirmed by western blotting and RT-qPCR assays. We also performed CCK-8 assay, flow cytometry, western blotting, and TUNEL assays to evaluate cell viability and apoptosis in breast cancer cells. In vivo study was performed to detect the tumorigenicity of MCF-7/ADR cells transfected with shScramble or shUSP37#1 under adriamycin treatment. Results: Bioinformatic analysis indicated that USP37 overexpression was positively correlated with adriamycin resistance. The expression levels of USP37 in both MCF-7 and MCF-7/ADR cells increased significantly with the exposure to adriamycin in a dose-dependent manner. It was verified by the observation that USP37 downregulation elevated the inhibitory effects of adriamycin on breast cancer cells, suppressed cell proliferation caused by cell cycle arrest in G1/S transition, as well as induced apoptosis. Furthermore, in vivo study showed that knockdown of USP37 expression also decreased tumorigenicity of MCF-7/ADR cells in mice. TUNEL assay and observation of cell morphology magnified USP37 knockdown synergized with Adriamycin could elevate the apoptosis of MCF-7 and MCF-7/ADR cells. Western blotting assay illustrated that the combination of USP37 knockdown with adriamycin treatment significantly upregulated the expression levels of cleaved caspase 3 and Bax, whereas the expression level of Bcl-2 was inhibited. Conclusion: Knockdown of USP37 gene expression can reverse the resistance of breast cancer cells to adriamycin, and down-regulating USP37 might be a valuable strategy against ADR resistance in breast cancer therapy.

Knockdown of Annexin A7 (ANXA7) or C-Jun N-terminal kinase (JNK) inhibits the proliferation, migration, invasion, and lymphatic adhesion of hepatocellular carcinoma (HCC) cells, suggesting that ANXA7 and JNK signaling pathways contribute to HCC growth and lymph node metastasis (LNM). While the intervening molecular pathways are largely unknown, emerging evidence suggests that long noncoding RNAs (lncRNAs) participate in ANXA7 and JNK signaling. To identify potential therapeutic targets for HCC, we screened for lncRNAs differentially expressed among Hca-P cells stably expressing shRNA-ANXA7, shRNA-JNK, or control-shRNA. RNA sequencing identified 216 lncRNAs differentially expressed between shRNA-ANXA7 and control-shRNA cells, of which 101 were downregulated and 115 upregulated, as well as 436 lncRNAs differentially expressed between shRNA-JNK and control-shRNA cells, of which 236 were downregulated and 200 upregulated. Fifty-six lncRNAs were differentially expressed under both ANXA7 and JNK knockdown. We selected 4 of these for verification based on putative involvement in cancer regulation according to GO and KEEG analyses of target genes. Knockdown of ANXA7 or JNK suppressed expression of NONMMUT012084.2, NONMMUT024756.2, and ENSMUST00000130486, and enhanced expression of ENSMUST00000197932. These lncRNAs are intriguing candidate targets for mechanistic analysis of HCC progression and therapeutic intervention.

Parthenolide has been demonstrated to have anticancer effects against various types of cancer. However, the functional role of parthenolid has yet to be clearly reported in renal cell carcinoma (RCC). The aim of the present study was to investigate the effect of parthenolide in RCC 786‑O and ACHN cells. CCK‑8 and colony‑formation assays were used to observe the proliferation of RCC 786‑O and ACHN cells. Migration and invasion abilities were assessed through Transwell assays. The stem cell‑like properties of RCC cell lines were evaluated by mammosphere formation assay. Western blot analysis was used to investigate the metastasis and epithelial‑mesenchymal transition (EMT) induced by parthenolide on the expression levels of MMP2, MMP9, E‑cadherin, N‑cadherin, vimentin and snail. The results revealed that when the cells were treated with various concentrations of parthenolide, the rate of proliferation and growth was decreased in 786‑O and ACHN cells. The number of invasive cells in a field was approximately 170, 90, 40 and 190, 150, 70 in 786‑O and ACHN cells with 0, 4 and 8 µM of parthenolide treatment. MMP‑2/‑9 expression (P

Cancer immunotherapy has been accompanied by promising results over the past few years. Programmed Cell Death Protein 1 (PD-1) plays a vital role in inhibiting immune responses and promoting self-tolerance through modulating the activity of T-cells, activating apoptosis of antigen-specific T cells and inhibiting apoptosis of regulatory T cells. Programmed Cell Death Ligand 1 (PD-L1) is a trans-membrane protein that is considered to be a co-inhibitory factor of the immune response, it can combine with PD-1 to reduce the proliferation of PD-1 positive cells, inhibit their cytokine secretion and induce apoptosis. PD-L1 also plays an important role in various malignancies where it can attenuate the host immune response to tumor cells. Based on these perspectives, PD-1/PD-L1 axis is responsible for cancer immune escape and makes a huge effect on cancer therapy. This review is aimed to summarize the role of PD-1 and PD-L1 in cancer, looking forward to improve the therapy of cancer.

The study was conducted to evaluate the effects of dietary yeast β-glucan (YG) on performance and immune functions in breeder hens in a non-challenged setting. A total of 512 43-week-old Hy-Line Brown breeder hens were assigned into four treatments, and fed a basal diet with YG at 0, 50, 100 and 200 mg /kg for 8 weeks, respectively. Results showed that supplementation of YG did not affect production performance, but linearly increased hatchability (P 0.05). Compared with the control, hens fed with 200 mg/kg YG had improved eggshell color and reduced mortality. Moreover, feeding 200 mg/kg YG significantly (P 0.05) enhanced lymphocyte proliferation response to LPS, increased the percentage of peripheral blood CD3

Exosomes have been demonstrated as an important factor to influence cancer invasion and metastasis. Previous studies have shown that CXC chemokine recepter-4 (CXCR4) and stromal cell-derived factor-1α (SDF-1α) mediates matrix metalloproteinases (MMPs) secretions to facilitate lymph node metastasis of hepatocarcinoma cells. In this study, we demonstrated that exosomes containing elevated CXCR4 from high lymph node metastatic mouse hepatocarcinoma Hca-F cells were able to promote the migration and invasion of a paired syngeneic Hca-P cells that have low metastatic potential. Such impact on enhanced migratory and invasive capacities of Hca-P cells was triggered by the internalization of exosomes isolated from Hca-F cells. This was possibly due to the horizontal transferring of CXCR4 via exosomes. The lymphatic endothelial cells (LECs) increased the migration and invasion of Hca-F cells probably by expressing SDF-1α which bound with CXCR4 in the Hca-F cells and subsequently enhanced the secretions of MMP-9, MMP-2 and vascular endothelial growth factor C (VEGF-C). Exosomal CXCR4 from Hca-F cells promoted LECs proliferative rate and lymphatic tube formation ability. Our findings suggest that horizontal transfer of exosomal CXCR4 can promote murine hepatocarcinoma cell migration, invasion and lymphangiogenesis, and exosomal CXCR4 might be a novel therapeutic target against tumor lymphatic metastasis.

Doxorubicin is a widely used anthracycline-based anti-tumor agent for both solid and liquid tumors. Mounting evidence has demonstrated that microRNAs (miRNAs) are involved in chemoresistance and tumorigenesis. However, the roles of microRNA-501-5p (miR-501) in doxorubicin resistance and gastric cancer cell proliferation and invasion are still not fully understood. In this study, we identified that BLID (BH3-like motif-containing protein, cell death inducer) was directly regulated by miR-501 at the post-transcriptional level in multiple gastric cancer cell lines. Endogenous miR-501 was higher, whereas BLID was lower, in doxorubicin-resistant gastric cancer SGC7901/ADR cells compared with their parental SGC7901 cells. miR-501 suppressed gastric cancer cell apoptosis, induced resistance to doxorubicin, and enhanced cell proliferation, migration, and invasion. Subcutaneous injection of miR-501 lentivirus-infected SGC7901 cells resulted in rapid growth of xenograft tumors and resistance to doxorubicin treatment, unlike injection of negative miRNA lentivirus-infected SGC7901 cells. This is achieved at least partially by directly targeting BLID and subsequent inactivation of caspase-9 and caspase-3 and phosphorylation of Akt. Taken together, miR-501 induces doxorubicin resistance and enhances the tumorigenesis of gastric cancer cells by suppressing BLID. miR-501 might be a potential target for doxorubicin resistance and gastric cancer therapy. Keywords: microRNA-501-5p, chemoresistance, doxorubicin, BLID, gastric cancer

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.

MicroRNAs (miRNAs) are a group of small non-coding single-stranded RNAs molecules, the dysregulation of which plays a critical role in the initiation and biological progression of malignancies. The current study demonstrated that miR-140-5p was frequently downregulated in breast cancer stem cells (BCSCs), and miR-140-5p mimics could inhibit the proliferation of BCSCs. Moreover, Wnt1 was a direct target of miR-140-5p, as was proved by luciferase reporter assays. miR-140-5p mimics could downregulate the wnt1 mRNA and protein levels in MCF-7 and MDA-MB-231 cells. Furthermore, miR-140 mimics could enhance the sensitivity of BCSCs to doxorubicin (Dox) through the Wnt1/ABCB1 pathway both in vitro and vivo. Our findings have presented a novel miRNA-mediated regulatory network for BCSCs, which may provide a potential therapeutic target for breast cancer.

Breast cancer is the leading cause of cancer incidence and cancer-related mortality among women and is becoming a major public health problem around the world. The current study aims to investigate the possible role and mechanism of recombinant Apoptin (rApoptin), a potential anticancer candidate that minimally impacts normal cells, in the breast cancer cell proliferation and apoptosis in vitro and in vivo. We found that rApoptin could effectively inhibit the proliferation and apoptosis in MCF-7 and MDA-MB-231 cells in vitro, which was further confirmed by flow cytometry analysis. Apoptin partially inhibited MCF-7 cell xenograft tumor development in vivo. Furthermore, we found via western blot that rApoptin-induced apoptosis in MCF-7 and MDA-MB-231 cells was associated with the phosphorylation of Nur77 (p-Nur77) and Akt (p-Akt). In addition, compared with the control groups, rApoptin-treated tissues showed significantly higher expression of Bax and Cyt c while Bcl-2 expression was decreased by rApoptin treatment. Together, our results are the first to demonstrate that rApoptin was able to effectively induce breast cancer cell apoptosis both in vitro and in vivo and that this activity could be regulated by the phosphorylation of Nur77 and Akt and the mitochondrial pathway. Our findings highlight the potential application of rApoptin as a breast cancer treatment.

Background As an important component of the Hippo pathway, WW domain-containing transcription regulator 1 (TAZ), is a transcriptional coactivator that is responsible for the progression of various types of cancers. Programmed cell death protein 1 (PD-1) receptors in activated T cells and their ligand programming death force 1 (PD-L1) are the main checkpoint signals that control T cell activity. Studies have shown high levels of PD-L1 in various cancers and that PD-L1/PD-1 signals to evade T-cell immunity. Recent data have demonstrated that TAZ can regulate the characteristics of cancer cells via PD-L1. Cervical cancer is a common gynecological disease worldwide. In this study, we attempted to evaluate the effects of TAZ and PD-L1 on cervical cancer. Methods Hela cervical cancer cells were transfected with TAZ plasmid or TAZ siRNA or PD-L1 siRNA by using Lipofectamine 2000. The relationship between TAZ and PD-L1 in cervical cancer cells was determined by qRT-PCR and western blotting. The functional roles of TAZ were confirmed via CCK-8, Transwell and flow cytometry assays. Western blotting was utilized to observe the expression of BCL-2 and Caspase-3. The clinicopathological correlation of TAZ and PD-L1 was evaluated via relevant databases. Result TAZ is upregulated in cervical cancer and induces the growth and metastasis of cervical cancer cells by targeting PD-L1and inhibiting the ratio of apoptotic of cancer cells. High TAZ and PD-L1 expression was observed in different stage, grade, histological patterns, and ages of cervical cancer groups compared with normal cervix groups. Furthermore, high TAZ expression was positively correlated with the infiltration levels of immune cells and the expression of PD-L1.

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.

The mogrosides in the fruit of Siraitia grosvenori can serve as a sugar substitute for diabetics due to their sweetness, low calorie and positive effects on blood glucose level control. The present study was to purify the mogrosides from the fruit of S. grosvenori and evaluate their enhancement of glucose uptake rate in HepG2 cells in vitro. As a result, eighteen mogrosides were isolated, including six new ones and a known but new naturally occurring compound. The chemical structures of the new compounds were identified by 1D, 2D-NMR and HR-ESI-MS techniques, together with chemical methods. Compared to the positive control (metformin), all the obtained mogrosides showed equivalent or more potent effects on the glucose uptake in HepG2 cells in vitro. These results suggested the mogrosides in the fruit of S. grosvenori were worthy of further research to confirm their potential benefits for obese and diabetic patients.

Background The interaction of integrin and extracellular matrix (ECM) has a profound implication on pathological conditions such as tumor growth and infiltration. Related reports have confirmed that integrin α3 (ITGA3) influences the development of bladder cancer, head and neck cancer, colorectal cancer and other cancers. However, the mechanism of ITGA3 in breast cancer is unknown. Methods The impact of ITGA3 on the biological features of breast cancer cells was explored using the Transwell and wound healing assays. In addition, its influence on stemness of breast cancer cells was examined with the sphere formation assay. The possible mechanism by which ITGA3 regulates breast cancer was explored using Western blot. The interaction between ITGA3 and VASP was determined by co-immunoprecipitation and immunofluorescence staining assays. Results Results show that downregulation of ITGA3 promotes breast cancer cell proliferation, apoptosis, invasion and migration. Indeed, suppression of ITGA3 negatively regulates the stemness of breast cancer cells and EMT process. Our findings indicate that ITGA3 interacts with VASP and regulates its expression, and knockdown of ITGA3 inhibits the activity of the PI3K-AKT axis. Conclusion Our results show that ITGA3-VASP modulates breast cancer cell stemness, EMT and PI3K-AKT pathways. Therefore, ITGA3 might be a druggable target for clinical breast cancer management.

Background Long non-coding RNA PTENP1, the pseudogene of PTEN tumor suppressor, has been reported to exert its tumor suppressive function via modulation of PTEN expression in many malignancies, including breast cancer (BC). However, whether the PTENP1/miR-20a/PTEN axis exists and how it functions in BC progression remains elusive. Methods The levels of PTENP1, PTEN and miR-20a were measured by qRT-PCR. Furthermore, the breast cancer cells proliferation was further measured by CCK8 assay, colony formation assays, EDU and Ki67 staining. The migratory and invasive ability was determined by transwell assay. Flow cytometry, JC-1 and TUNEL assays were conducted to show the occurrence of apoptosis. Xenograft model was used to show the tumorigenesis of breast cancer cells. Results We analyzed PTENP1 and PTEN levels in clinical BC samples and cell lines, and found that PTENP1 and PTEN were confirmed and closely correlated with the malignancy of BC cell lines and poor clinical prognosis. Moreover, alteration of PTENP1 affects BC cell proliferation, invasion, tumorigenesis and chemoresistance to adriamycin (ADR). Bioinformatic analysis and dual-luciferase reporter gene assay predicted that PTENP1 was a direct target of miR-20a, which was clarified an alternative effect on BC aggressiveness phenotype. In addition, PTENP1 functioned as an endogenous sponge of miR-20a to regulate PTEN expression, which mediated BC cells proliferation, invasion and drug resistance via activation the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. PI3K inhibitor LY294002 or siAkt also prevented BC cells progression. Conclusion Collectively, these data indicated that PTENP1/miR-20a/PTEN axis involved in the malignant behaviors of BC cells, illuminating the possible mechanism mediated by PTEN via PI3K/Akt pathway. Targeting PTENP1/miR-20a/PTEN may provide a potential diagnosis and treatment strategy for BC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1260-6) contains supplementary material, which is available to authorized users.

Colorectal cancer (CRC) is one of the most common malignancies in the world. microRNA-140-5p (miR-140) has been shown to be involved in cartilage development and osteoarthritis (OA) pathogenesis. Some contradictions still exist concerning the role of miR-140 in tumor progression and metastasis, and the underlying mechanism is uncertain. Immunohistochemistry was performed to determine the expressions of ADAMTS5 and IGFBP5 in CRC tissues. Human CRC cell lines HCT116 and RKO were transfected with miR-140 mimic, inhibitor, or small interfering RNA (siRNA) against ADAMTS5 or IGFBP5, respectively, using oligofectamine or lipofectamine 2000. Scratch-wound assay and transwell migration and invasion assays were used to evaluate the effects of miR-140 on the capabilities of migration and invasion. The levels of miR-140 and ADAMTS5 and IGFBP5 mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to examine the expression of ADAMTS5 and IGFBP5 proteins. miR-140 was significantly reduced, whereas ADAMTS5 and IGFBP5 were upregulated, in the human CRC tissues compared to the corresponding normal colorectal mucosa. miR-140 downregulation and ADAMTS5 or IGFBP5 overexpression were associated with the advanced TNM stage and distant metastasis of CRC. There was a reverse correlation between miR-140 levels and ADAMTS5 and IGFBP5 expression in CRC tissues. ADAMTS5 and IGFBP5 were downregulated by miR-140 at both the protein and mRNA levels in the CRC cell lines. The gain-of- and loss-of-function studies showed that miR-140 inhibited CRC cell migratory and invasive capacities at least partially via downregulating the expression of ADAMTS5 and IGFBP5. These findings suggest that miR-140 suppresses CRC progression and metastasis, possibly through downregulating ADAMTS5 and IGFBP5. miR-140 might be a potential therapeutic candidate for the treatment of CRC.

Hypoxia microenvironment widely exists in solid tumor tissues, which is mainly due to the rapid growth of cells within the tumor more than the speed of capillary in neoplasm, resulting in tumor tissue hypoxia. In hypoxia, hypoxia inducible factor 1 (HIF-1) is activated and regulate the expression of a series of hypoxia inducible genes, resulting in a series of hypoxia adaptation reaction. Researchs proved that, HIF-1 is closely related to the invasion, metastasis, prognosis of the tumor, and the expression of HIF-1 is higher in metastatic tissues compared with primary cancer tissues. In the evolution process of breast cancer, epithelial mesenchymal transition (EMT) define the characteristics of migration and invasion of breast cancer cells, which can also allow cancer cells to acquire the ability of self-renewing and stemness, so as to promote the generation of breast cancer stem cells. The incidence of EMT cancer stem cells are higher within the resistant to conventional treatment. This review focuses on breast cancer (stem cells), targeting the mechanism between hypoxia and EMT in tumor (stem cells), with the purpose of finding the new therapy to breast cancer.

Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays critical roles in malignant transformation and tumor progression. In this study, in order to investigate the association of miR-138 with breast cancer we investigated the role of miR-138 in breast cancer metastasis. Levels of miR-138 were determined by qRT-PCR in 45 breast cancer samples. Cell migration and invasion assays were performed in a stably expressing miRNA-138 breast cancer cell line established using a lentivirus expression system. Epithelial-mesenchymal transition (EMT) was evaluated using qRT-PCR and Western Blots to detect epithelial marker E-cadherin and mesenchymal marker, vimentin. Luciferase reporter assays were used to identify downstream targets and biological function of miR-138. Breast cancer tissues had significantly lower expression of miR-138 compared to non-tumor tissues. Low miR-138 levels were associated with lymph node metastasis and invasion. miR-138 overexpression inhibited metastasis of breast cancer cells. miR-138 overexpression also down-regulated vimentin expression and upregulated E-cadherin expression, suggesting that miR-138 inhibited EMT. Our results support the involvement of miR-138 in breast tumorigenesis, especially lymph node metastasis. We propose that miR-138 might be used as therapeutic agent for breast cancer.

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.

Girdin functions as an Akt phosphorylation enhancer (APE), which expedites the proliferation and survival of many types of tumours. However, the influence of Girdin on pancreatic cancer and the underlying molecular mechanisms have yet to be uncovered. Hence, in the present study, we sought to elucidate the function of Girdin in pancreatic cancer malignancy, particularly its role in pancreatic cancer cell proliferation, migration and apoptosis. Immunohistochemistry (IHC) was used to evaluate Girdin expression in pancreatic cancer tissues and to analyse its correlation with pathological grade. Girdin expression was further validated in pancreatic cancer cell lines (AsPC‑1, BxPC‑3 and PANC‑1), and human pancreatic ductal epithelial (HPNE) cells were used as a control. Recombinant adenovirus vectors containing Girdin‑siRNA were constructed to inhibit Girdin expression and were used in subsequent experiments to determine the effects of Girdin silencing on pancreatic cancer cells. Girdin silencing suppressed pancreatic cancer cell proliferation and induced pancreatic cancer cell apoptosis in vitro and in vivo. According to the results of further mechanistic investigations, Girdin may regulate cell processes through the phosphatidylinositol‑3‑kinase/protein kinase B (PI3K/Akt) signalling pathway to exert additive effects on pancreatic cancer.

Metastatic Renal cell carcinoma (RCC) remains a difficult oncologic challenge. Salinomycin is a monocarboxylic polyether antibiotic, which has been proved to possess anti-tumor activities in multiple types of cancer cells. However, its effects on RCC cells remains unclear. In our study, salinomycin could inhibit the proliferation and viability of RCC cell lines 786-O and ACHN. The TUNEL assay revealed that treatment with salinomycin induced DNA breaking in RCC cells. Consistently, Western blotting showed up-regulation of pro-apoptotic biomarkers (cleaved caspase3/9 and cleaved PARP1) and down-regulation of anti-apoptotic biomarker (survivin) in RCC cells after salinomycin treatment, suggesting that salinomycin could induce RCC cell apoptosis. salinomycin treatment also suppressed the sphere formation ability of RCC cells and decreased the expressions of CD105, ALDH1 and CD44, biomarkers for reflecting the stemness of RCC cells. salinomycin treatment effectively down-regulated SMO and Gli1, two key proteins in Hedghog signaling pathway, in a dose-dependent manner. Moreover, salinomycin could suppress the invasion and migration of RCC cells in the presence of TGF-β1, as observed in wound-healing and Transwell assays. salinomycin treatment attenuated TGF-β1-induced epithelial-mesenchymal transition (EMT), as evidenced by its ability to increase E-cadherin expression and decrease N-cadherin, Snail and MMP-2 expressions in RCC cells. Finally, salinomycin inhibited the tumorigenecity of RCC cells in vivo. Our study provides the evidence that salinomycin possess multiple anti-tumor activities against RCC, as it, in particular, suppressed the cancer stem cell properties and attenuated TGF-β-induced EMT. Therefore, it may serve as a potentially therapeutic candidate for metastatic RCC and improve the prognosis of RCC patients.

Autophagy is a key catabolic process, in which cytosolic cargo is engulfed by the formation of a double membrane and then degraded through the fusing of autophagosomes with lysosomes. Autophagy is a constitutively active, evolutionarily conserved, catabolic process important for the maintenance of homeostasis in cellular stress responses and cell survival. Although the mechanisms of autophagy have not yet been fully elucidated, emerging evidence suggests that it plays a dual role in breast cancer and in maintaining the activity of breast cancer stem cells (CSCs). However, it may play a complex role in breast CSC therapy. Breast CSCs, a population of cells with the ability to self-renew, differentiate, and initiate and sustain tumor growth, play an essential role in cancer recurrence, anticancer resistance and metastasis. In addition, the elucidation of the association between autophagy and apoptosis in the tumor context is crucial in order to better address appropriate therapy strategies. In the present review, a summary of the mechanisms and roles of autophagy in breast cancer and CSCs is presented. The potential value of such autophagy modulators in the development of novel breast cancer therapies is discussed.

Background. Aidi injection is an important adjuvant anticancer drug commonly used in China. Can Aidi injection plus docetaxel-based chemotherapy improve clinical efficacy with good safety in NSCLC? To further reveal its clinical effectiveness, we systematically evaluated all the related studies. Method. We collected all the studies about Aidi injection plus docetaxel-based chemotherapy for NSCLC on Medline, Embase, Web of Science, CNKI, VIP, Wanfang, CBM, CENTRAL, Chi-CTR, and US-clinical trials. We evaluated their methodological bias risk according to the Cochrane evaluation handbook (5.1.0), extracted data following the predesigned data extraction form according to the PICO principle, and synthesized the data using meta-analysis. Results. We included 36 RCTs with 2837 patients, and most studies had unclear bias risk. The merged RR values and their 95% CI of meta-analysis for ORR, DCR, and QOL were as follows: 1.30 (1.19, 1.42), 1.17, (1.12, 1.22), and 1.73 (1.54, 1.95). The merged RR values for neutropenia, thrombocytopenia, anemia, gastrointestinal toxicity, hepatorenal dysfunctions, and alopecia were as follows: 0.70 (0.61, 0.79), 0.63 (0.53, 0.75), 0.60 (0.48, 0.75), 0.76 (0.65, 0.89), 0.56 (0.36, 0.88), and 0.58 (0.36, 0.93). Compared with chemotherapy alone, all differences were statistically significant. Subgroup analysis showed that, with 100 ml, 80-100 ml, and 50 ml, Aidi injection could increase the tumor response and Aidi injection plus DP, DC, and DO could increase the tumor response. Meta-analysis results had good stability. Conclusions. Aidi injection plus docetaxel-based chemotherapy, especially plus DP, DC, and DO, may significantly improve the clinical efficacy and QOL in NSCLC. It may also have low risk of hematotoxicity, gastrointestinal toxicity, and low risk of inducing hepatorenal dysfunctions. Aidi injection may have attenuation and synergistic efficacy to docetaxel chemotherapy. All these need to have new evidence to be proved.

miRNAs have been implicated in processing of cardiac hypoxia/reoxygenation (H/R)-induced injury. Recent studies demonstrated that miR-19a might provide a potential cardioprotective effect on myocardial disease. However, the effect of miR-19a in regulating myocardial ischemic injury has not been previously addressed. The present study was to investigate the effect of miR-19a on myocardial ischemic injury and identified the potential molecular mechanisms involved. Using the H/R model of rat cardiomyocytes H9C2 in vitro, we found that miR-19a was in low expression in H9C2 cells after H/R treatment and H/R dramatically decreased cardiomyocyte viability, and increased lactate dehydrogenase (LDH) release and cardiomyocyte apoptosis, which were attenuated by co-transfection with miR-19a mimic. Dual-luciferase reporter assay and Western blotting assay revealed that PTEN was a direct target gene of miR-19a, and miR-19a suppressed the expression of PTEN via binding to its 3′-UTR. We further identified that overexpression of miR-19a inhibited the expression of PTEN at the mRNA and protein levels. Moreover, PTEN was highly expressed in H/R H9C2 cells and the apoptosis induced by H/R was associated with the increase in PTEN expression. Importantly, miR-19a mimic significantly increased p-Akt levels under H/R. In conclusion, our findings indicate that miR-19a could protect against H/R-induced cardiomyocyte apoptosis by inhibiting PTEN /PI3K/p-Akt signaling pathway.

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

Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment. Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy. Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size. Aptamers, as "chemical antibodies", are 15-20 times smaller than antibodies. To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications. Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model. We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation. As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively. The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody. Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively. In addition, the aptamer achieved at least a 4-time better tumor penetration in xenograft tumors than that of the antibody at a 200 μm distances from the blood vessels 3 h after intravenous injection. Taken together, these data indicate that aptmers are superior to antibodies in cancer theranostics due to their better tumor penetration, more homogeneous distribution and longer retention in tumor sites. Thus, aptamers are promising agents for targeted tumor therapeutics and molecular imaging.

MicroRNAs play pivotal roles in cancer stem cell regulation. Previous studies have shown that microRNA-34a (miR-34a) is downregulated in human breast cancer. However, it is unknown whether and how miR-34a regulates breast cancer stem cells. Notch signaling is one of the most important pathways in stem cell maintenance and function. In this study, we verified that miR-34a directly and functionally targeted Notch1 in MCF-7 cells. We reported that miR-34a negatively regulated cell proliferation, migration, and invasion and breast cancer stem cell propagation by downregulating Notch1. The expression of miR-34a was negatively correlated with tumor stages, metastasis, and Notch1 expression in breast cancer tissues. Furthermore, overexpression of miR-34a increased chemosensitivity of breast cancer cells to paclitaxel (PTX) by downregulating the Notch1 pathway. Mammosphere formation and expression of the stemness factor ALDH1 were also reduced in the cells treated with miR-34a and PTX compared to those treated with PTX alone. Taken together, our results indicate that miR-34a inhibited breast cancer stemness and increased the chemosensitivity to PTX partially by downregulating the Notch1 pathway, suggesting that miR-34a/Notch1 play an important role in regulating breast cancer stem cells. Thus miR-34a is a potential target for prevention and therapy of breast cancer.