LncRNA NONRATT014888.2 contributes to cancer-induced bone pain through downregulation of natriuretic peptide receptor 3 in rats.

Long noncoding RNA (lncRNA) is implicated in both cancer development and pain process. However, the role of lncRNA in the development of cancer-induced bone pain (CIBP) is unclear. LncRNA NONRATT014888.2 is highly expressed in tibia related dorsal root ganglions (DRGs) in CIBP rats which function is unknown. CIBP was induced by injection of Walker 256 mammary gland tumor cells into the tibia canal of female SD rats. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of rats were measured. Down-regulation of NONRATT014888.2 by siRNA in CIBP rats markedly attenuated hind-paw mechanical pain hypersensitivity. LncRNA-predicted target mRNAs analysis and mRNA sequencing results cued Socs3, Npr3 were related with NONRATT014888.2. Intrathecal injection of NONRATT014888.2-siR206 upregulated Npr3 both in mRNA and protein level. Npr3 was co-expressed in NONRATT014888.2-positive DRGs neurons and mainly located in cytoplasm, but not in Glial fibrillary acidic protein (GFAP)-positive cells. Intrathecal injection of ADV-Npr3 upregulated Npr3 expression and enhanced the PWT of CIBP rats. Our results suggest that upregulated lncRNA NONRATT014888.2 contributed to hyperalgesia in CIBP rats, and the mechanism may through downregulation of Npr3.

A novel prognostic model associated with the overall survival in patients with breast cancer based on lipid metabolism-related long noncoding RNAs.

BACKGROUND: Lipid metabolism is closely related to the occurrence and development of breast cancer. Our purpose was to establish a novel model based on lipid metabolism-related long noncoding RNAs (lncRNAs) and evaluate the potential clinical value in predicting prognosis for patients suffering from breast cancer. METHODS: RNA data and clinical information for breast cancer were obtained from the cancer genome atlas (TCGA) database. Lipid metabolism-related lncRNAs were identified via the criteria of correlation coefficient |R2 | > 0.4 and p < 0.001, and prognostic lncRNAs were identified to establish model through Cox regression analysis. The training set and validation set were established to certify the feasibility, and all samples were separated into high-risk group or low-risk group. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were conducted to evaluate the potential biological functions, and the immune infiltration levels were explored through Cibersortx database. RESULTS: A total of 14 lncRNAs were identified as protective genes (AC022150.4, AC061992.1, AC090948.3, AC092794.1, AC107464.3, AL021707.8, AL451085.2, AL606834.2, FLJ42351, LINC00926, LINC01871, TNFRSF14-AS1, U73166.1 and USP30-AS1) with HRs < 1 while 10 lncRNAs (AC022150.2, AC090948.1, AC243960.1, AL021707.6, ITGB2-AS1, OTUD6B-AS1, SP2-AS1, TOLLIP-AS1, Z68871.1 and ZNF337-AS1) were associated with increased risk with HRs >1. A total of 24 prognostic lncRNAs were selected to construct the model. The patients in low-risk group were associated with better prognosis in both training set (p < 0.001) and validation set (p < 0.001). The univariate and multivariate Cox regression analyses revealed that risk score was an independent prognostic factors in both training set (p < 0.001) and validation set (p < 0.001). GO and GSEA analyses revealed that these lncRNAs were related to metabolism-related signal pathway and immune cells signal pathway. Risk score was negatively correlated with B cells (r = -0.097, p = 0.002), NK cells (r = -0.097, p = 0.002), Plasma cells (r = -0.111, p = 3.329e-04), T-cells CD4 (r = -0.064, p = 0.039) and T-cells CD8 (r = -0.322, p = 2.357e-26) and positively correlated with Dendritic cells (r = 0.077, p = 0.013) and Monocytes (r = 0.228, p = 1.107e-13). CONCLUSION: The prognostic model based on lipid metabolism lncRNAs possessed an important value in survival prediction of breast cancer patients.

Identification of lncRNA and mRNA expression profiles in dorsal root ganglion in rats with cancer-induced bone pain.

BACKGROUND: Cancer-induced bone pain (CIBP) is one of the most severe types of chronic pain which the involved mechanisms are largely unknown. LncRNA has been found to play critical roles in chronic pain. However, its function in peripheral nervous system in CIBP remains unknown. Identifying the different lncRNA expression pattern is essential for understanding the genetic mechanisms underlying the pathogenesis of CIBP. METHODS: The model was induced by injection of Walker 256 cells into the rat tibia canal. Behavior tests and X-ray microtomography (MicroCT) analysis were performed to verify the model's establishment. L2-L5 DRGs were harvested at 14-day post operation and the differential lncRNA and mRNA expression patterns were investigated by microarray analyses. RT-qPCR analysis and RNA interference were performed for expression and function verifications. Bioinformatics analysis was conducted for further function study. RESULTS: CIBP rats showed hyperalgesia and the MicroCT analysis showed tibia destruction. A total of 73 lncRNAs and 187 mRNAs were dysregulated. The expressions of several lncRNAs and mRNAs were validated by RT-qPCR experiment. Biological analyses showed that the changed mRNAs were mainly related to cellular and single-organism process, cell and cell part, binding function and immune system pathway. The top 30 lncRNA-predicted mRNAs are mainly related to peroxisome, DNA-dependent DNA replication, double-stranded RNA binding, tuberculosis and purine metabolism. 56 lncRNAs (30 downregulated and 26 upregulated) and 179 DEGs (35 downregulated and 144 upregulated) have a significant correlation and constructed a co-expression network. Downregulation of lncRNA NONRATT021203.2 by siRNA intrathecal injection increased PWL and WBD in CIBP rats, alleviating cancer induced bone hyperalgesia. CONCLUSION: LncRNA played important roles in regulation of CIBP or mRNA expression in peripheral neuropathy in CIBP. These alterd mRNAs and lncRNAs might be potential therapeutic targets for the treatment of CIBP.

Growth differentiation factor-15 and lactoferrin immuno-expression in breast cancer: relationship with body iron-status and survival outcome.

We aimed to evaluate the expression of growth differentiation factor-15 (GDF-15) and lactoferrin (Lf) in tumor and their relationship with the body iron-status and overall survival (OS) outcome of patients with breast cancer. A retrospective cohort study of female patients with primary breast cancer was performed. Clinical tumor samples from the Second Affiliated Hospital of Soochow University between December 2008 and June 2014 were collected. The immuno-expression of GDF-15 and Lf was stratified into positive or negative expression. Kaplan-Meier method and Cox proportional hazards regression model were used for data analysis. 74 breast cancer patients with a mean age of 52 years were included into our study. 14 (18.9%) patients were died by the end of August 1, 2019. The serum iron level of patients with GDF-15 (+)/Lf(-) expression was higher than that of patients with other expression patterns (18.2 ± 5.4 vs. 15.5 ± 5.0 µmol/L, P = 0.038), but was not associated with OS. In univariate Cox analyses, GDF-15(+) and GDF-15(+)/Lf(-) were significantly correlated with high mortality risk (HR = 3.75, 95%CI 1.05-13.48, P = 0.025; HR = 5.00, 95%CI 1.56-16.04, P = 0.004, respectively). After adjusted for age, menopause status and primary tumor grade, the association between GDF-15 and OS disappeared. However, the association between GDF-15/Lf and OS still existed in GDF-15(+)/Lf(-) (HR = 4.50, 95%CI 1.31-15.51, P = 0.017). The combined immuno-expression pattern of GDF-15 and Lf was significant associated with high serum iron level. GDF-15/Lf could be a powerful biomarker to predict survival outcome of patients with breast cancer but still needed to be confirmed by future studies.

The role of ferroptosis-related genes for overall survival prediction in breast cancer.

BACKGROUND: Ferroptosis is a novel iron-dependent form of cell death, which is implicated in various diseases including cancers. However, the influence of ferroptosis-related genes on the prognosis of breast cancer remains unclear. METHODS: RNA sequencing data of 1053 breast cancer tissue samples and 111 normal tissue samples from The Cancer Genome Atlas (TCGA) were analyzed. Expression levels of 259 ferroptosis-related genes were compared. Gene Ontology (GO) and the Kyoto Gene and Genomic Encyclopedia (KEGG) analyses were conducted on differentially expressed genes. Cox univariate analysis was conducted to explore the potential prognostic biomarkers of breast cancer. Infiltrating immune cell status was assessed. RESULTS: A total of 66 ferroptosis-related genes were differentially expressed in breast cancer tissues. The enriched GO terms included Biological Process (mainly included response to oxidative stress, cellular response to chemical stress, multicellular organismal homeostasis, cofactor metabolic process, response to metal ion, response to steroid hormone, cellular response to oxidative stress, transition metal ion homeostasis, iron ion homeostasis, and cellular iron ion homeostasis), Cellular Component (mainly included apical plasma membrane, early endosome, apical part of cell, lipid droplet, basolateral plasma membrane, blood microparticle, clathrin-coated pit, caveola, astrocyte projection, and pronucleus) and Molecular Function (mainly included iron ion binding, ubiquitin protein ligase binding, oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor, ferric iron binding, aldo-keto reductase (NADP) activity, oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, steroid dehydrogenase activity, alditol:NADP+1-oxidoreductase activity, and alcohol dehydrogenase (NADP+) activity). The enriched KEGG pathway mainly included the HIF-1 signaling pathway, NOD-like receptor signaling pathway, ferroptosis, IL-17 signaling pathway, central carbon metabolism in cancer, PPAR signaling pathway, PD-L1 expression, and PD-1 checkpoint pathway in cancer. Among them, 38 ferroptosis-related genes were significantly associated with the prognosis of breast cancer. The prognostic model was constructed, and breast cancer patients in low-risk group had a better prognosis. In addition, risk score of ferroptosis prognostic model was negatively correlated with B cells (r = -0.063, p = 0.049), CD8+ T cells (r = -0.083, p = 0.010), CD4+ T cells (r = -0.097, p = 0.002), neutrophils (r = -0.068, p = 0.033), and dendritic cells (r = 0.088, p = 0.006). CONCLUSIONS: The ferroptosis pathway plays a key role in breast cancer. Some differentially expressed ferroptosis-related genes can be used as prognostic biomarkers for breast cancer.

MiR-96-5p promotes breast cancer migration by activating MEK/ERK signaling.

BACKGROUND: Breast cancer is the leading cause of cancer deaths in women worldwide. The purpose of the current study was to investigate the potential role of miR-96-5p in breast cancer. METHODS: Breast cancer tissues and matched para-cancerous tissues were collected. The expression of microRNA-96-5p (miR-96-5p) and arginine kinase 3 (AK3) was detected by quantitative real-time PCR (qRT-PCR). The correlation between miR-96-5p and AK3 was calculated by Pearson's Chi-square test. Moreover, mimics or inhibitors of miR-96-5p were applied to explore whether miR-96-5p influences the migration capacity in Transwell and wound healing assays. Bioinformatics analysis was performed to identify the target genes of miR-96-5p through the TargetScan, miRDB and miRanda databases. A luciferase reporter assay was performed to verify AK3 as a downstream target gene of miR-96-5p. RESULTS: The expression of miR-96-5p was significantly increased in breast cancer tissue and breast cancer cell lines compared with para-cancerous tissue and a breast cell line, respectively. The expression of miR-96-5p negatively correlated with AK3 gene expression. AK3 was demonstrated to be a direct mRNA target of miR-96-5p. AK3 was positively associated with the overall survival of breast cancer patients. Kaplan-Meier curve and log rank test analyses revealed that decreased AK3 levels were significantly associated with reduced overall survival. miR-96-5p was shown to promote the migration of breast cancer cells through the MEK/ERK signaling pathway. CONCLUSION: Our results identify a role for miR-96-5p in promoting breast cancer cell migration through activation of MEK/ERK signaling by targeting AK3.

Upregulation of lncRNA-NONRATT021203.2 in the dorsal root ganglion contributes to cancer-induced pain via CXCL9 in rats.

Cancer-induced pain (CIP) is a kind of chronic pain that occurs during cancer progression over time. However, the mechanisms are largely unknown, and clinical treatment remains challenging. LncRNAs have been reported to play critical roles in various biological processes, including chronic pain. The aim of our study was to investigate whether lncRNAs participate in the development of CIP by regulating the expression levels of some molecules related to pain modulation. The CIP model was established by injecting Walker 256 mammary gland tumor cells into the tibial canal of rats. In this study, we found that lncRNA-NONRATT021203.2 was increased in the CIP rats and that lncRNA-NONRATT021203.2-siRNA could relieve hyperalgesia in these rats. For elucidation of the underlying mechanism, we showed that lncRNA-NONRATT021203.2 could target C-X-C motif chemokine ligand 9 (CXCL9), which was increased in the CIP rats, and that CXCL9-siRNA could relieve hyperalgesia. At the same time, silencing lncRNA-NONRATT021203.2 expression decreased the mRNA and protein levels of CXCL9. Immunofluorescence analysis showed that CXCL9 was mainly expressed in the CGRP-positive and IB4-positive DRG neurons. Further research showed that lncRNA-NONRATT021203.2 and CXCL9 were colocalized in the DRG neurons. Our data suggested that lncRNA-NONRATT021203.2 participated in the CIP in rats and likely mediates the upregulation of CXCL9. The present study provided us with a new potential target for the clinical treatment of cancer-induced pain.

Two-stage versus single-stage procedure for the management of cholecystocholedocholithiasis in elderly patients: a retrospectively cohort study.

BACKGROUND: there is an increasing incidence rate of cholecysto-choledocholithiasis associated with the increasing proportion of senile individuals. METHODS: a total of 100 elderly patients (over 80 years of age) suffering both from cholelithiasis and choledocholithiasis were retrospectively studied from January 2010 to December 2016. Patients were scheduled for either a single-stage or two-stage procedure. The LCBDE group (n = 54) included cases that underwent a single stage procedure of laparoscopic exploration of the common bile duct combined with cholecystectomy. The ERCP/EST group (n = 46) included cases that underwent a two stage procedure of preoperative endoscopic retrograde cholangiopancreaticography with endoscopic sphincterotomy followed by cholecystectomy. Comorbidity conditions, presenting symptoms, bile duct clearance, length of hospital stay and the frequency of procedural, postoperative and long-term complications were recorded. RESULTS: the LCBDE group had a higher stones clearance rate than the ERCP/EST group (100.0% vs 89.1%, p < 0.05). Postoperative complications and hospitalization length were comparable in the two groups (p > 0.05). There were more procedural complications in the ERCP/EST group than in the LCBDE group (10.8% vs 0%, p < 0.05). Furthermore, a patient in the ERCP/EST group died due to duodenal perforation. More patients in the ERCP/EST group experienced long-term complications than those in the LCBDE group (23.9% vs 3.7%, p < 0.05) during a mean follow-up period of 28.4 months. CONCLUSIONS: the single-stage procedure is a safe and effective technique for elderly patients with cholecysto-choledocholithiasis. LCBDE provides a good stone clearance rate with few long term complications.

MiR-539 inhibits proliferation and migration of triple-negative breast cancer cells by down-regulating LAMA4 expression.

BACKGROUND: Recent studies have shown that laminin subunit alpha 4 (LAMA4) plays an important role in carcinogenesis. However, its molecular biological function in triple-negative breast cancer (TNBC) has not been entirely clarified. This study investigated the expression of LAMA4 in TNBC and its effect on cell proliferation, migration and invasion. Furthermore, we also identified the potential miRNA directly targeting LAMA4. METHODS: Western blot, Real-time quantitative PCR (qPCR) and immunohistochemical staining (IHC) were used to detect the expression of LAMA4 in TNBC. The effects of LAMA4 on TNBC cell proliferation, migration and invasion were also explored in vitro. The potential miRNA that targets LAMA4 was determined by dual luciferase reporter assay and verified by qPCR and western blot analysis. RESULTS: Our study showed LAMA4 mRNA (p = 0.001) and protein (p = 0.005) expression in TNBC tissue samples were elevated compared with adjacent normal tissue samples, and LAMA4 was mainly expressed in the cytoplasm of breast carcinoma cells. Knockdown of LAMA4 inhibited TNBC cell proliferation, migration and invasion in vitro. Moreover, further study revealed that LAMA4 was a putative target of miR-539, and miR-539 negatively regulated LAMA4 expression by directly targeting its 3'-UTR. CONCLUSIONS: Our study suggested that miR-539 suppressed the expression of LAMA4. LAMA4 plays an important role in tumor progression and may be an important target in treatment of TNBC.

Overexpression of suppressor of cytokine signaling 3 in dorsal root ganglion attenuates cancer-induced pain in rats.

Background Cancer-induced pain (CIP) is one of the most severe types of chronic pain with which clinical treatment remains challenging and the involved mechanisms are largely unknown. Suppressor of cytokine signaling 3 (SOCS3) is an important intracellular protein and provides a classical negative feedback loop, thus involving in a wide variety of processes including inflammation and nociception. However, the role of SOCS3 pathway in CIP is poorly understood. The present study was designed to investigate the role of SOCS3 in dorsal root ganglion (DRG) in the development of CIP. Method CIP was established by injection of Walker 256 mammary gland tumor cells into the rat tibia canal. Whole-cell patch clamping and Western blotting were performed. Results Following the development of bone cancer, SOCS3 expression was significantly downregulated in rat DRGs at L2-L5 segments. Overexpression of SOCS3, using lentiviral-mediated production of SOCS3 at spinal cord level, drastically attenuated mechanical allodynia and body weight-bearing difference, but not thermal hyperalgesia in bone cancer rats. In addition, overexpression of SOCS3 reversed the hyperexcitability of DRG neurons innervating the tibia, and reduced abnormal expression of toll-like receptors 4 in the DRGs. Conclusions These results suggest that SOCS3 might be a key molecular involved in the development of complicated cancer pain and that overexpression of SOCS3 might be an important strategy for treatment for mechanical allodynia associated with bone cancer.

Silencing of ETS1 reverses adriamycin resistance in MCF-7/ADR cells via downregulation of MDR1.

BACKGROUND: Clinical resistance to chemotherapeutic agents is one of the major hindrances in the treatment of human cancers. Erythroblastosis virus E26 oncogene homolog 1 (ETS1) is involved in the drug resistance of various cancer cells, and is overexpressed in drug-resistant human breast cancer cell lines. In this study, we investigated the effects of ETS1 on adriamycin resistance in MCF-7/ADR cells. METHODS: siRNAs against ETS1 or negative control siRNAs was transfected to MCF-7/ADR breast cancer cells. Reverse transcription-PCR and Western blotting were used to determine the mRNA and protein expression of ETS1 and MDR1. The cytotoxicity of adriamycin was assessed using the MTT assay. Drug efflux was investigated by flow cytometry using the Rhodamine 123 intracellular accumulation assay. RESULTS: ETS1 mRNA and protein was significantly overexpressed in MCF-7/ADR cells, compared to MCF-7 cells. ETS1 siRNA successfully silenced ETS1 mRNA and protein expression. Silencing of ETS1 also significantly reduced the mRNA and protein expression levels of MDR1 (multidrug resistance 1; also known as ABCB1, P-glycoprotein/P-gp), which is a major ATP-binding cassette (ABC) transporter linked to multi-drug resistance in cancer cells. Silencing of ETS1 significantly increased the sensitivity of MCF-7/ADR cells to adriamycin, compared to cells transfected with negative control siRNA. In addition, intracellular accumulation of Rhodamine 123 significantly increased in MCF-7/ADR cells transfected with ETS1 siRNA, indicating that silencing of ETS1 may reduce drug efflux. CONCLUSIONS: This study demonstrates that drug resistance can be effectively reversed in adriamycin-resistant breast carcinoma cells through delivery of siRNAs targeting ETS1.

[The characteristics and trends of acute pesticide poisoning of Shaoxing in 2006 to 2011].

OBJECTIVE: To describe the epidemiological characteristics of acute pesticide poisoning in Shaoxing, China during 2006-2011 and to provide a reference for the prevention and control of pesticide poisoning. METHODS: The data on pesticide poisoning in Shaoxing during 2006-2011 were obtained from the China Information System for Disease Control and Prevention and were then analyzed. RESULTS: A total of 2024 cases of acute pesticide poisoning were reported in Shaoxing during 2006-2011, and 44 cases were missed, accounting for 2.1% (44/2068) of all cases. Among the 2024 cases, 119 (5.9%) died; the fatality rates of productive poisoning and unproductive poisoning were 1.0% (3/289) and 6.7% (116/1735), respectively. The reported cases included 1038 (51.3%) females and 986 (48.7%) males, and there were no significant differences in the ratio between male and female cases of acute pesticide poisoning from 2006 to 2011 (χ2 = 9.16, P = 0.10). The 2024 cases had a mean age of 47.0±18.7 years; the male cases had a significantly higher mean age than the female cases (50.7±19.0 vs 43.4±17.8 years, t = 9.01, P < 0.001). Among the 2024 cases, 289 (14.3%) suffered productive poisoning, and 1735 (85.7%) suffered unproductive poisoning. In the 986 male cases, 219 (22.2%) suffered productive poisoning; in the 1038 female cases, 968 (93.3%) suffered unproductive poisoning. The pesticides that caused poisoning included insecticide (86.7%, 1754/2024), herbicide (5.1%, 104/2024), rodenticide (3.6%, 72/2024), and bactericide, mixed preparation, biochemical pesticides, and other four categories of pesticides (4.6%, 94/2024); of the 1754 cases caused by insecticide, 1455 (83.0%) were attributed to organophosphorus insecticide. CONCLUSION: The incidence of unproductive acute pesticide poisoning is high in Shaoxing, and it mainly affects females. Most cases of acute pesticide poisoning are aged 30∼60 years. Insecticide is the main cause of poisoning. It is necessary to enhance health knowledge popularization and safety management of pesticides.

Recent advances in photothermal therapy-based multifunctional nanoplatforms for breast cancer.

Breast cancer (BC) is one of the most common cancers in women worldwide; however, the successful treatment of BC, especially triple-negative breast cancer (TNBC), remains a significant clinical challenge. Recently, photothermal therapy (PTT), which involves the generation of heat under irradiation to achieve photothermal ablation of BC with minimal invasiveness and outstanding spatial-temporal selectivity, has been demonstrated as a novel therapy that can overcome the drawbacks of chemotherapy or surgery. Significantly, when combining PTT with chemotherapy and/or photodynamic therapy, an enhanced synergistic therapeutic effect can be achieved in both primary and metastatic BC tumors. Thus, this review discusses the recent developments in nanotechnology-based photothermal therapy for the treatment of BC and its metastasis to provide potential strategies for future BC treatment.

HOXD9 transcriptionally induced UXT facilitate breast cancer progression via epigenetic modification of RND3.

BACKGROUND: Ubiquitously expressed transcript (UXT) is a prefoldin-like protein. It was reported that UXT played vital role in several cancer types. However, functional role of UXT in breast cancer need further investigation. METHODS: mRNA level or protein level of were determined by qRT-PCR or western blots. Proliferation of breast cancer cells was evaluated by CCK-8 assay and EdU assay. Migrative and invasive ability of cells were determined by wound healing assay and transwell assay. Transcriptional activation of UXT was determined by dual luciferase activity. The enrichment of H3K27me3 and EZH2 on the promoter of RND3 was evaluated by ChIP assay. The methylation of RND3 promoter was determined by MSP assay. In vivo function of UXT was evaluated by xenograft model. RESULTS: Our results indicated that UXT was elevated in breast cancer and associated with poor prognosis. HOXD9 elevated expression of UXT via transcriptional activation. UXT knockdown impaired the proliferation, migration and invasion. Rescue experiments suggested that UXT promoted malignant phenotypes of breast cancer cells via epigenetically repressing RND3. Moreover, UXT promoted tumorigeneses and metastasis of breast cancer cell in vivo. CONCLUSION: Inhibition of UXT impaired proliferation and metastasis of cancer cell via promoting RND3. Moreover, UXT epigenetically repressed the expression of RND3 via recruiting EZH2 in the promoter of RND3.

KLF14 alleviated breast cancer invasion and M2 macrophages polarization through modulating SOCS3/RhoA/Rock/STAT3 signaling.

PURPOSE: To study the functions and underlying network of KLF14 in breast cancer invasion and tumor-associated macrophages (TAMs). METHODS: The expressions of gene or protein were assessed by qRT-PCR and western blot assays, respectively. Cell proliferation and invasion were investigated by colony formation, CCK-8 and transwell assays, respectively. Macrophage M2 polarization was identified by flow cytometry assay. The methylation level was tested by methylation Specific PCR (MSP). The molecular relationship between KLF14 and SOCS3 was validated by dual luciferase and ChIP assays. In vivo model was established to confirm effect of KLF14 on tumor growth and metastasis. RESULTS: KLF14 was downregulated in breast cancer, and its level was modified by CpG-mediated methylation. Overexpression of KLF14 significantly inhibited the proliferation and invasion of breast cancer in vitro and in vivo. Moreover, KLF14-overexpressing breast cancer cells notably reduced M2 macrophages polarization and it related promoting factor of tumor microenvironment (EGF, TGFß, MMP9 and VEGF). Mechanistically, KLF14 could positively activate SOCS3 transcription, then blocking the activation of RhoA/Rock/STAT3 signaling. Further rescue experiments identified that either SOCS3 silencing and activation of RhoA/Rock/STAT3 signaling dramatically restrained the regulatory roles of KLF14 overexpression in breast cancer invasion and M2 macrophages polarization. CONCLUSION: Collectively, KLF14 suppressed breast cancer cell invasion and M2 macrophage polarization through modulating SOCS3/RhoA/Rock/STAT3 signaling, and these findings would provide a new potential target against breast cancer.

ATF3 Demethylation Promotes the Transcription of ARL4C, Which Acts as a Tumor Suppressor in Human Breast Cancer.

INTRODUCTION: Breast cancer is a common malignancy in females worldwide. In this study, we investigated the role of activating transcription factor 3 (ATF3) and ADP-ribosylation factor like-4 (ARL4) in human breast cancer, and the associated mechanisms. MATERIALS AND METHODS: We measured ATF3 and ATL4C expressions in 15 paired breast cancer tissues using qRT-PCR, Western blotting and IHC. Cell growth, migration and invasion were tested in ATF3 or ARL4C overexpression breast cancer cells. TCGA database analysis was done to identify the correlation between ATF3 and ARL4C. We evaluated the binding of ATF3 to ARL4C promoter sequences and the effect of hypermethylation and demethylation of ATF3. A meta-analysis was done to investigate the relationship between the expression of ATF3 and/or ARL4C and the poor prognoses. RESULTS: Our results showed that ATF3 and ARL4C were decreased in breast cancer specimens at both mRNA and protein levels. Restoration of ATF3 or ARL4C reduced breast cancer tumorigenesis, evidenced by decreased cell growth, migration and invasion. The expression of ATF3 was positively correlated with ARL4C in breast cancer specimens, and ATF3 was shown to bind to the ARL4C promoter sequences. Furthermore, the expression of ATF3 was negatively regulated by hypermethylation, and demethylation of ATF3 stimulated ATF3 expression, which further promoted ARL4C transcription. Finally, a meta-analysis showed that patients with breast cancer with lower expression levels of ATF3 and/or ARL4C had worse prognoses. CONCLUSION: Our results suggest that the ATF3/ARL4C axis may be a prospective biomarker for diagnosis and determination of prognosis, and a potential target for breast cancer treatment.

LKB1 inactivation leads to centromere defects and genome instability via p53-dependent upregulation of survivin.

Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.

Cluster-to-cluster charge transfer in a compound with a co-crystallized dye-anchored Ti6 cluster and a classical Ti12 cluster.

A new titanium-oxo cluster (TOC) with a co-crystallized dye-anchored Ti6 cluster and a classical Ti12 cluster was isolated. The Ti6 cluster is anchored by mixed dyes of photoactive triphenylamine and catechol. This is the first co-crystallized neutral TOC. TOC (Ti6) to TOC (Ti12) charge transfer was studied using electronic spectra and DFT calculations based on their precise structures. The improved photocurrent response properties of the TOC-modified TiO2 electrode are due to the influence of charge transfer and co-condensation of the Ti6 and Ti12 clusters. The photocurrent response properties of the compound for fructose and glucose were tested.

Dexamethasone-sparing regimen is an effective and safe alternative in overall antiemetic protection: A systematic review and meta-analysis.

OBJECTIVE: We performed a meta-analyisis to evaluate the efficacy of maintenance dexamethasone against acute or delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetic risk chemotherapy regimen. METHODS: PubMed, Embase, and Cochrane Library were searched for eligible studies. Data comparing maintenance dexamethasone with single-dose dexamethasone during the acute, delayed, and overall phase of CINV were extracted. Overall risk ratio (RR) was used to estimate the efficacy and adverse effects. RESULTS: Nine studies were included. In delayed phase, maintenance dexamethasone has similar efficacy to single-dose dexamethasone for no emetic episodes (RR, 1.06; 95% confidence interval [CI], 1.00-1.14), complete response (RR, 1.04; 95% CI, 0.98-1.11), complete control (RR, 1.07; 95% CI, 0.98-1.16), and total control (RR, 1.06; 95% CI, 0.91-1.23). In overall phase, maintenance dexamethasone has similar efficacy to single-dose dexamethasone for no emetic episodes (RR, 1.02; 95% CI, 0.94-1.11), complete response (RR, 1.02; 95% CI, 0.95 -1.09), complete control (RR, 1.03; 95% CI, 0.94-1.13), total control (RR, 1.05; 95% CI, 0.90-1.23), and no rescue medication (RR, 1.07; 95% CI, 0.97-1.19). Maintenance dexamethasone was only superior to single-dose dexamethasone for no rescue medication during delayed phase (RR, 1.10; 95% CI, 1.01-1.21, P = .034). The incidence of hiccup was observed higher in maintenance dexamethasone group (RR = 3.16, 95% CI, 1.12-8.92). CONCLUSION: The single-dose dexamethasone regimen offers high and similar overall control of symptoms as the maintenance dexamethasone regimen in this population. Multiple-day dexamethasone was suitable for patients who used rescue medication during the delayed phase.