[Retracted] MicroRNA­320a suppresses tumour cell proliferation and invasion of renal cancer cells by targeting FoxM1.

Subsequently to the publication of the above paper, the authors drew to the attention of the Editorial Office that they made a couple of errors in terms of the data assembly in Figs. 2 and 4 in their paper; specifically, the Transwell assay data shown for the 'miR-320a+/FoxM1+' panel in Fig. 5D on p. 1923 also appeared as the 'ACTN/NC' data panel in Fig. 4E on the same page (Fig. 4E contained the erroneously duplicated panel). In addition, data featured in Fig. 2D of the above paper were strikingly similar to data that appeared in Fig. 6e of the following paper, published subsequently to this article, written by different authors (although a Dr Shiyue Zhao worked in the molecular biology laboratory of Harbin Medical University from 2017 to 2018, and the research collaboration was conducted with Dr Chenlong Li's research group): Li C, Zheng H, Hou W, Bao H, Xiong J, Che W, Gu Y, Sun H and Liang P: Long non-coding RNA linc00645 promotes. TGF-ß-induced epithelial-mesenchymal transition by regulating miR-205-3p-ZEB1 axis in glioma. Cell Death Dis 10: 17, 2019. Finally, after having conducted an independent investigation of the data in this paper, the Editorial Office noted that one of the Petri dish images in Fig. 2C was also strikingly similar to data that appeared in Fig. 2H of the abovementioned article in the journal Cell Death & Disease. After having considered the authors' request for corrigendum, in view of the problems that were identified with the data, the Editor of Oncology Reports has decided that, owing to a lack of confidence in the presented data, the paper should instead be retracted from the journal. After having informed the authors of this decision, they accepted the decision to retract this paper. The Editor apologizes to the readership for any inconvenience caused.  [Oncology Reports 40: 1917­1926, 2018; DOI: 10.3892/or.2018.6597].

FOXM1 and CHD4 expression is associated with chemoresistance in hepatoblastoma.

Hepatoblastoma (HB) is the most common malignant liver tumor in childhood. Although pre-operative cisplatin (CDDP)-based chemotherapy is often used in cases of HB, about 20％ of HB patients exhibit resistance to CDDP. Forkhead box protein M1 (FOXM1) and chromo-domain-helicase-DNA-binding protein 4 (CHD4) have been associated with CDDP resistance in various tumors. We here analyzed the immunohistochemical expression of FOXM1 and CHD4 in HB specimens of 33 patients (mean age: 20 months) post-chemotherapy. The differentiation of specimens was assessed using the digital pathology software QuPath®, and then the relation between the FOXM1 or CHD4 expression and the differentiation and various other clinicopathological parameters was investigated. The histological type was epithelial in 19 cases (57.6%) and mixed epithelial and mesenchymal in 14 cases (42.4%). Nine cases had only a fetal component, 1 case had only an embryonal component, 22 cases had both fetal and embryonal components, and 1 case had no viable tumor. Both the FOXM1 and CHD4 immunoexpressions were found significantly more frequently in the embryonal than fetal components (p<0.0001 and p<0.0001, respectively). Regarding chemotherapy efficacy, the alpha-fetoprotein (AFP) level after chemotherapy was correlated with both the imaging shrinkage rate (R=-0.52) and histological residual rate (the percentage of the viable tumors of HB after chemotherapy)(R=0.62). High FOXM1 score was correlated with a high-postoperative AFP value (p<0.01) and a low AFP attenuation rate (p<0.05), but the FOXM1 score was not correlated with the imaging shrinkage rate (p=0.4418) or histological residual rate (p=0.4418). High CHD4 score showed a nonsignificant trend toward correlation with high postoperative AFP value (p=0.0849) and was not significantly correlated with the other parameters. Collectively, our results showed that FOXM1 expression may be useful in evaluating the response to CDDP-based chemotherapeutic regimens. Accurate measurement of FOXM1 expression by our scoring system using QuPath® is important in cases with mixed HB components of various differentiation levels.

Protein regulator of cytokinesis 1 accentuates cholangiocarcinoma progression via mTORC1-mediated glycolysis.

This study aimed to investigate the expression of protein regulator of cytokinesis 1 (PRC1) in cholangiocarcinoma (CHOL) and elucidate its potential impact as well as the underlying mechanisms governing the progression of CHOL. In this study, we used CHOL cells (HUCCT1, RBE, and CCLP1) and conducted a series of experiments, including qRT-PCR, cell counting kit-8 assays, EdU assays, flow cytometry, wound healing assays, Transwell assays, western blotting, double luciferase assays, and ELISA. Subsequently, a mouse model was established using cancer cell injections. Haematoxylin-eosin staining, along with Ki67 and TUNEL assays, were employed to assess tissue histopathology, cell proliferation, and apoptosis. Our findings revealed significantly elevated PRC1 expression in CHOL. According to bioinformatics analysis, it was found that the increased PRC1 level is correlated with the high tumour grades, metastases, and unfavourable prognoses. Notably, PRC1 knockdown inhibited cell viability, proliferation, migration, and invasion while promoting apoptosis in CHOL cells. Analysing TCGA-CHOL data and utilising transcription factor prediction tools (hTFtarget and HumanTFDB), we identified that genes positively correlated with PRC1 in TCGA-CHOL intersect with predicted transcription factors, revealing the activation of PRC1 by forkhead box protein M1 (FOXM1). Moreover, PRC1 was found to exert regulatory control over glycolysis and the mammalian target of rapamycin complex 1 (mTORC1) pathway in the context of CHOL based on KEGG and GSEA analysis. Collectively, these results underscore the pivotal role of PRC1 in CHOL progression, wherein it modulates glycolysis and the mTORC1 pathway under the regulatory influence of FOXM1.

Forkhead box transcription factors (FOXOs and FOXM1) in glioma: from molecular mechanisms to therapeutics.

Glioma is the most aggressive and malignant type of primary brain tumor, comprises the majority of central nervous system deaths, and is categorized into different subgroups according to its histological characteristics, including astrocytomas, oligodendrogliomas, glioblastoma multiforme (GBM), and mixed tumors. The forkhead box (FOX) transcription factors comprise a collection of proteins that play various roles in numerous complex molecular cascades and have been discovered to be differentially expressed in distinct glioma subtypes. FOXM1 and FOXOs have been recognized as crucial transcription factors in tumor cells, including glioma cells. Accumulating data indicates that FOXM1 acts as an oncogene in various types of cancers, and a significant part of studies has investigated its function in glioma. Although recent studies considered FOXO subgroups as tumor suppressors, there are pieces of evidence that they may have an oncogenic role. This review will discuss the subtle functions of FOXOs and FOXM1 in gliomas, dissecting their regulatory network with other proteins, microRNAs and their role in glioma progression, including stem cell differentiation and therapy resistance/sensitivity, alongside highlighting recent pharmacological progress for modulating their expression.

MRPL51 is a downstream target of FOXM1 in promoting the malignant behaviors of lung adenocarcinoma.

Mitochondrial ribosome protein L51 (MRPL51) is a 39S subunit protein of the mitochondrial ribosome. Its dysregulation may be involved in non-small cell lung cancer. The present study aimed to explore MRPL51 expression in lung adenocarcinoma (LUAD) and normal lung tissues, as well as its regulatory effects on malignant LUAD behaviors. In addition, the role of forkhead box protein M1 (FOXM1) in MRPL51 transcription was studied. Bioinformatics analysis and subsequent in vitro experiments, including western blotting, immunofluorescent staining, Transwell invasion assay, dual-luciferase assay and chromatin immunoprecipitation quantitative PCR were conducted. The results demonstrated that MRPL51 expression was upregulated at both the mRNA and protein levels in LUAD tissues compared with normal lung tissues. Gene Set Enrichment Analysis demonstrated that LUAD tissues with higher MRPL51 expression also had higher expression levels of genes enriched in multiple gene sets, including 'DNA_REPAIR', 'UNFOLDED_PROTEIN_RESPONSE', 'MYC_TARGETS_V1', 'OXIDATIVE_ PHOSPHORYLATION', 'MTORC1_SIGNALING', 'REACTIVE_OXYGEN_SPECIES_PATHWAY', 'MYC_ TARGETS_V2', 'E2F_TARGETS' and 'G2M_ CHECKPOINT'. MRPL51 expression was positively correlated with 'cell cycle', 'DNA damage', 'DNA repair', epithelial-mesenchymal transition ('EMT'), 'invasion' and 'proliferation' of LUAD cells at the single-cell level. Compared to the negative control, MRPL51 knockdown decreased N-cadherin and vimentin expression but increased E-cadherin expression in A549 and Calu-3 cells. MRPL51 knockdown suppressed cell proliferation, induced G1 phase arrest and decreased cell invasion. Patients with LUAD and higher MRPL51 expression had a significantly shorter overall survival (OS). FOXM1 could bind to the MRPL51 gene promoter and activate its transcription. In conclusion, MRPL51 was transcriptionally activated by FOXM1 in LUAD and contributed to the malignant behaviors of tumor cells, including EMT, cell cycle progression and invasion. High MRPL51 expression may be a prognostic biomarker indicating poor OS.

FOXM1 Contributes to Chemotherapy Sensitivity in Cervical Cancer by Regulating TTK.

BACKGROUND: The emergence of chemotherapy resistance usually causes therapeutic failure in advanced cervical cancer. Forkhead box protein M1 (FOXM1) and threonine tyrosine kinase (TTK) are closely associated with cancer drug sensitivity, but the mechanism of FOXM1 on TTK involvement in chemo-treated cervical cancer remains unclear. Here, we aimed to observe the effects of FOXM1 on TTK and on chemotherapy sensitivity in cervical cancer. METHODS: The expressions of FOXM1 and TTK in cervical cancer tissues and para-cancerous tissues were analyzed by immunohistochemistry. SiHa and Hela cells were transfected with human lentivirus-FOXM1, small interfering RNA (siRNA) or pcDNA3.1/FOXM1 to analyze the changes in TTK protein expression. Furthermore, the cells were treated with paclitaxel (8 µM) or cisplatin (10 µM) to analyze the effects of FOXM1 on chemotherapy sensitivity. SiHa cells were used to construct a xenograft model to study the effects of FOXM1 expression in response to paclitaxel treatment. The tumor size and weight were observed. The expressions of Ki-67, FOXM1, and TTK protein in tumor tissues were measured by immunohistochemistry. RESULTS: High expression of FOXM1 and TTK were found in the cervical cancer tissues (p < 0.05). The TTK protein expressions were decreased by FOMX1-siRNA transfection in SiHa and Hela cells (p < 0.01). The cell viability and cell cycle were also suppressed by FOMX1-siRNA transfection (p < 0.01) but enhanced by pcDNA3.1/FOXM1 transfection (p < 0.01). For paclitaxel or cisplatin treatment, the cell viability and cell DNA damage were improved due to the FOXM1 overexpression (p < 0.01). TTK inhibitor significantly suppressed the effects of FOXM1 overexpression (p < 0.01). CONCLUSIONS: FOXM1 regulated TTK and affected the therapeutic efficacy of cisplatin and paclitaxel in cervical cancer.

Expression, regulating mechanism and therapeutic target of KIF20A in multiple cancer.

Kinesin family member 20A (KIF20A) is a member of the kinesin family. It transports chromosomes during mitosis, plays a key role in cell division. Recently, studies proved that KIF20A was highly expressed in cancer. High expression of KIF20A was correlated with poor overall survival (OS). In this review, we summarized all the cancer that highly expressed KIF20A, described the role of KIF20A in cancer. We also organized phase I and phase II clinical trials of KIF20A peptides vaccine. All results indicated that KIF20A was a promising therapeutic target for multiple cancer.

Dual-targeting therapy against HER3/MET in human colorectal cancers.

BACKGROUND: Colorectal cancer (CRC) is the most common malignancy in the world, and novel molecular targeted therapies for CRC have been vigorously pursued. We searched for novel combination therapies based on the expression patterns of membrane proteins in CRC cell lines. RESULTS: A positive correlation was observed between the expression of human pidermal growth factor receptor (HER) 3 and mesenchymal-to-epithelial transition factor (MET) on the cell surface of CRC cell lines. The brief stimulation of HER3/MET-high SW1116 CRC cells with both neuregulin-1 (NRG1) and hepatocyte growth factor enhanced ERK phosphorylation and cell proliferation more than each stimulation alone. In addition, a prolonged NRG1 stimulation resulted in the tyrosine phosphorylation of MET. In this context, the Forkhead Box protein M1 (FOXM1)-regulated tyrosine phosphorylation of MET by NRG1 was demonstrated, suggesting the existence of a signaling pathway mediated by FOXM1 upon the NRG1 stimulation. Since the co-expression of HER3 and MET was also demonstrated in in vivo CRC tissues by immunohistochemistry, we investigated whether the co-inhibition of HER3 and MET could be an effective therapy for CRC. We established HER3-and/or MET-KO SW1116 cell lines, and HER3/MET-double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti-HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D-colony formation, and in vivo tumor growth in nude mice by SW1116 cells CONCLUSION: The dual targeting of HER3/MET has potential as CRC therapy.

PRRX1/FOXM1 reduces gemcitabin-induced cytotoxicity by regulating autophagy in bladder cancer.

Background: Bladder cancer (BC) is a common urological malignancy with high mortality worldwide. Many proteins can influence tumorigenesis by participating in cellular processes. Recently, abundant evidence has illustrated that paired related homeobox 1 (PRRX1) is closely related to the progression and development of human cancers. However, the function of PRRX1 in BC remains poorly understood. The aim of our study is to explore the role of PRRX1 in BC progression. Methods: The expression of genes (PRRX1, FOXM1, LC3B, and Beclin-1) was examined through real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. The expression of proteins (PRRX1, FOXM1, LC3B, and Beclin-1) was measured through immunohistochemistry. Cell viability and the half-maximal inhibitory concentration were detected using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Cell apoptosis was assessed through flow cytometry. Autophagy was tested by GFP-LC3 immunofluorescence assay. Tumors were grown in nude mice in vivo, and the tumor size, volume, and weight were evaluated. Results: In our study, PRRX1 was highly expressed in BC tissues and cells, and high PRRX1 expression resulted in poor overall survival in patients with BC. PRRX1 accelerated the viability and hindered the apoptosis of BC cells. It also weakened gemcitabine-induced cytotoxicity and strengthened gemcitabine-induced autophagy. PRRX1 was found to cooperate with forkhead box protein M1 (FOXM1) to influence downstream genes, and FOXM1 was found to regulate Beclin-1 and microtubule-associated protein 1 light chain 3 (LC3) genes to influence autophagy. PRRX1 up-regulated the expression of LC3 and Beclin-1 by cooperating with FOXM1. In rescue assays, FOXM1 reversed the effects of PRRX1 on gemcitabine-induced cytotoxicity and autophagy. Knockdown of PRRX1 enhanced the inhibitive effects of gemcitabine on tumor growth in vivo. Conclusions: PRRX1 reduces gemcitabine-induced cytotoxicity in BC cells by regulating the expression of the autophagy proteins LC3 and Beclin-1. This discovery suggests that PRRX1 may be a useful therapeutic biomarker for BC.

FOXM1 Inhibition Enhances the Therapeutic Outcome of Lung Cancer Immunotherapy by Modulating PD-L1 Expression and Cell Proliferation.

Programmed death-ligand 1 (PD-L1) is a major target to cancer immunotherapy, and anti-PD-L1 and anti-PD-1 antibody-mediated immunotherapy are being increasingly used. However, immune checkpoint inhibitors (ICIs) are ineffective in treating large tumors and cause various immune-related adverse events in nontarget organs, including life-threatening cardiotoxicity. Therefore, the development of new therapeutic strategies to overcome these limitations is crucial. The focus of this study is the forkhead box protein M1 (FOXM1), which is identified as a potential therapeutic target for cancer immunotherapy and is associated with the modulation of PD-L1 expression. Selective small interfering RNA knockdown of FOXM1 or treatment with thiostrepton (TST) significantly reduces PD-L1 expression in non-small-cell lung cancer (NSCLC) cells and inhibits proliferation. Chromatin immunoprecipitation-PCR reveals that FOXM1 selectively upregulates PD-L1 expression by binding directly to the PD-L1 promoter. In vivo animal studies have shown that TST treatment significantly downregulates PD-L1 expression in human NSCLC tumors, while greatly reducing tumor size without side effects on normal tissues. Combined treatment with TST and anti-4-1BB antibody in the LLC-1 syngeneic tumor model induces synergistic therapeutic outcomes against immune resistant lung tumors as well as 2.72-folds higher CD3+ T cells in tumor tissues compared to that in the anti-4-1BB antibody treatment group.

The correlation of forkhead box protein M1 (FOXM1) with gestational diabetes mellitus in maternal peripheral blood and neonatal umbilical cord blood.

OBJECTIVE: The transcription activator FOXM1 was found to be essential for beta cell expansion and glucose homeostasis during pregnancy in a mouse model. We assumed that the mechanism would be similar in humans. Thus, we aimed to determine the correlation, if any, between FOXM1 and gestational diabetes mellitus in pregnant women. MATERIALS AND METHODS: Participants were recruited and collected from a single tertiary medical center in Taiwan. Participants' maternal peripheral blood was retrieved upon their admission for labor. The postpartum cord blood was harvested within 5 min after delivery of the fetus to test the FOXM1 mRNA expression level, as well as glucose, insulin, and C-peptide protein concentrations. RESULT: We recruited 83 pregnant women, 63 without GDM and 20 with GDM. The non-GDM maternal samples had a FOXM1ΔCt of 9.2 ± 1.53, whereas it was 8.92 ± 1.48 in the GDM group (p = 0.504). In the cord blood group, the GDM and non-GDM FOXM1ΔCt were 7.7 ± 1.02 and 7.95 ± 1.56, respectively (p = 0.416). CONCLUSION: This is the first study to prove a relationship between FOXM1 and GDM in humans. Although the exact linear correlation is still unknown, our results may provide an impetus for further research.

Expression of FOXM1 and PLK1 predicts prognosis of patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most frequently encountered malignant tumor types and to improve its treatment, effective prognostic biomarkers are urgently required. Cell cycle dysregulation is a significant feature of cancer progression. The aim of the present study was to estimate the expression levels of forkhead box protein M1 (FOXM1) and polo-like kinase 1 (PLK1), both of which have essential roles in cell cycle regulation, and determine their prognostic value in HCC. To this end, FOXM1 and PLK1 expression levels were assessed in The Cancer Genome Atlas and International Cancer Genome Consortium Japan HCC cohorts, and the associations between their co-expression were determined via Pearson's correlation analysis. Furthermore, the overall survival and disease-free survival in these cohorts for different FOXM1 and PLK1 expression statuses were analyzed. In vitro knockdown experiments were also performed using Huh7 cells. The results obtained indicated overexpression of FOXM1 and PLK1 in HCC tumor tissues as well as a positive correlation between FOXM1 and PLK1 expression. The results also suggested that both FOXM1 and PLK1 are required for HCC cell proliferation. In addition, upregulation of FOXM1 and PLK1 was indicated to be associated with poor prognosis of patients with HCC. However, only their coordinated overexpression was identified as an independent prognostic factor for HCC.

Downregulation of sperm-associated antigen 5 inhibits melanoma progression by regulating forkhead box protein M1/A disintegrin and metalloproteinase 17/NOTCH1 signaling.

Sperm-associated antigen 5 (SPAG5) has been identified as a driver in several type of cancers. In this study, we aimed to reveal the role of SPAG5 in melanoma and clarify whether FOXM1 (forkhead box protein M1) /ADAM17 (A disintegrin and metalloproteinase 17) /NOTCH1 signaling was involved. The expression of SPAG5 in malignant melanoma (MM) tissues and matched normal tissues was detected using qRT-PCR, immunohistochemistry and Western blotting. Cell viability was tested using CCK-8 (Cell Count Kit-8), colony formation and EdU staining. Cell migration and epithelial to mesenchymal transition (EMT) were measured using transwell chambers and immunofluorescent staining. Cell cycle distribution and tumorigenesis were assessed by flow cytometry and in vivo tumor-bearing experiments, respectively. The results demonstrated that the expression of SPAG5 was increased in MM tissues and cells. Downregulation of SPAG5 inhibited cell viability, migration, invasion and EMT, and induced a G1-phase arrest. In addition, downregulation of SPAG5 decreased the expression of FOXM1, thereafter inhibiting the expression of ADAM17, NOTCH1 and HES1. Furthermore, deletion of SPAG5 expression decreased the tumorigenesis of MM A375 cells. In conclusion, this study demonstrated that SPAG5 was overexpressed in MM. Downregulation of SPAG5 repressed MM cell growth and EMT, which might be induced by inactivation of the FOXM1/ADAM17/NOTCH1 signaling.

Development of a FOXM1-DBD Binding Assay for High-Throughput Screening Using TR-FRET Assay.

Electrophoretic mobility shift assay (EMSA) technology has been widely employed for the analysis of transcription factors such as Forkhead box protein M1 (FOXM1). However, the application of high-throughput screening (HTS) in performing, such analyses are limited as it uses time consuming electrophoresis procedure and radioisotopes. In this study, we developed a FOXM1-DNA binding domain (DBD) binding assay based on time-resolved fluorescence energy transfer (TR-FRET) that enables HTS for the inhibitors of FOXM1-DNA interaction. This assay was robust, highly reproducible and could be easily miniaturized into 384-well plate format. The signal-to-background (S/B) ratio and Z' factor were calculated as 7.46 and 0.74, respectively, via a series of optimization of the assay conditions. A pilot library screening of 1019 natural compounds was performed using the FOXM1-DBD binding assay. Five hit compounds, namely, AC1LXM, BRN5, gangaleoidin, leoidin, and roemerine were identified as the inhibitors of FOXM1. In a cell viability assay, it was demonstrated that cell proliferation of FOXM1 overexpressed cell lines was suppressed in cell lines such as MDA-MB-231 and MCF-7 by five hit compounds. These results indicate that developed FOXM1-DBD binding assay can be applied to highly efficiency HTS of compound libraries.

Identification of JAK2 and FOXM1 expression as novel candidate biomarkers for predicting the benefit of immunotherapy in lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC) accounts for about 30% of all non-small cell lung cancers (NSCLC). However, only a small percentage of LUSC patients gain benefit from immune checkpoint inhibitors (ICIs). METHODS: This study analyzed LUSC patients from The Cancer Genome Atlas (TCGA), which were divided into 2 groups: PD-L1 high-expression/TMB-high (TPH) and PD-L1 low-expression/TMB-low (TPL) group based on programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) status. The differences in tumor-infiltrating immune cells were estimated between the 2 groups. The overlap of differentially expressed genes and proteins (DEGs and DEPs) between 2 groups were used as candidate biomarkers. Kaplan-Meier curves were used to evaluate the association between risk score and overall survival (OS). RESULTS: More abundant immune infiltration fractions were found in TPH group. Janus kinase 2 (JAK2) and forkhead box protein M1 (FOXM1) were identified as DEGs between the TPH and TPL groups. Subsequently, we developed a risk score that combined the expression of JAK2 and FOXM1 in an effort to accurately determine the survival risk of LUSC patients. Patients with high-risk [hazard ratio (HR), median OS, 43.1 months 1.924; 95% confidence interval (CI): 1.256 to 2.945; P=0.002) had shorter survival than those with low-risk (median OS, 70.0 months). External data verification found that JAK2 and FOXM1 were significantly expressed at a higher level in the responders receiving immunotherapy (P=0.038 and P=0.009, respectively). CONCLUSIONS: The expressions of JAK2 and FOXM1 can be used as novel candidate biomarkers for predicting the benefit of immunotherapy in LUSC.

Silencing of long non-coding RNA KCNQ1OT1 alleviates LPS-induced lung injury by regulating the miR-370-3p/FOXM1 axis in childhood pneumonia.

PURPOSE: Long non-coding RNAs (lncRNAs) play important roles in the development of pneumonia. We aimed to explore the role of the lncRNA KCNQ1OT1 in pneumonia and its underlying mechanisms. METHODS: The expression of KCNQ1OT1, FOXM1, and miR-370-3p was detected in the serum of 24 children with pneumonia and in 24 healthy controls. Normal human embryonic lung-derived diploid fibroblasts (WI-38 cells) were stimulated with LPS (10 µg/mL) to simulate the cellular model of pneumonia, and cell viability, apoptosis, and inflammation were analysed. Dual luciferase reporter and/or RNA binding protein immunoprecipitation assays were performed to test the relationship between miR-370-3p and KCNQ1OT1/FOXM1. Mice were intratracheally administered LPS (5 mg/kg) to induce an in vivo model of pneumonia, and pathological injury and inflammation were analysed. RESULTS: The expression of KCNQ1OT1 and FOXM1 was up-regulated, and miR-370-3p was down-regulated in the serum of children with pneumonia, LPS-treated WI-38 cells, and in lung tissues of LPS-treated mice. Silencing of KCNQ1OT1 or overexpression of miR-370-3p suppressed cell apoptosis and inflammation and facilitated cell viability in LPS-treated WI-38 cells. KCNQ1OT1 directly targets miR-370-3p and negatively regulates its expression. FOXM1 was targeted by miR-370-3p and negatively modulated by miR-370-3p. In addition, silencing of KCNQ1OT1 mitigated LPS-induced lung injury and inflammation in mice. The protective effects of KCNQ1OT1 silencing in LPS-treated WI-38 cells and mice were reversed by silencing of miR-370-3p or overexpression of FOXM1. CONCLUSION: Silencing of KCNQ1OT1 alleviates LPS-induced lung injury by regulating the miR-370-3p/FOXM1 axis in pneumonia.

New possible silver lining for pancreatic cancer therapy: Hydrogen sulfide and its donors.

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H2S) undertakes essential functions, encompassing various signaling complexes that occupy key processes in human biology. Accumulating evidence indicates that H2S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H2S are thought to promote cancer, whereas high doses of exogenous H2S suppress tumor proliferation. Similarly, inhibition of endogenous H2S production also suppresses tumor proliferation. Accordingly, H2S biosynthesis inhibitors and H2S supplementation (H2S donors) are two distinct strategies for the treatment of cancer. Unfortunately, modulation of endogenous H2S on pancreatic cancer has not been studied so far. However, H2S donors and their derivatives have been extensively studied as potential therapeutic agents for pancreatic cancer therapy by inhibiting cell proliferation, inducing apoptosis, arresting cell cycle, and suppressing invasion and migration through exploiting multiple signaling pathways. As far as we know, there is no review of the effects of H2S donors on pancreatic cancer. Based on these concerns, the therapeutic effects of some H2S donors and NO-H2S dual donors on pancreatic cancer were summarized in this paper. Exogenous H2S donors may be promising compounds for pancreatic cancer treatment.

The mechanisms of mitochondrial dysfunction and glucose intake decrease induced by Microcystin-LR in ovarian granulosa cells.

Microcystin-LR (MC-LR) is a cyclic heptapeptide; it is an intracellular toxin released by cyanobacteria that exhibits strong reproductive toxicity. Previous studies have demonstrated that MC-LR induces oxidative stress in granulosa cells by damaging the mitochondria, which eventually leads to follicle atresia and female subfertility. In the present study, granulosa cells were exposed to 0, 0.01, 0.1 and 1 µM MC-LR. After 24 h, we observed changes in mitochondrial cristae morphology and dynamics by analyzing the results of mitochondrial transmission electron microscopy and detecting the expression of DRP1. We also evaluated glucose intake using biochemical assays and expression of glucose transport related proteins. MC-LR exposure resulted in mitochondrial fragmentation and glucose intake decrease in granulosa cells, as shown by increasing mitochondrial fission via dynamin-related protein 1 (DRP1) upregulation and decreasing glucose transporter 1 and 4 (GLUT1 and GLUT4). Furthermore, the expression levels of forkhead box protein M1 (FOXM1) significantly increased due to the overproduction of reactive oxygen species (ROS) after MC-LR exposure. Our results proved that MC-LR exposure causes mitochondrial fragmentation and glucose intake decrease in granulosa cells, which provides new insights to study the molecular mechanism of female reproductive toxicity induced by MC-LR.

Silencing of CASC8 inhibits non-small cell lung cancer cells function and promotes sensitivity to osimertinib via FOXM1.

In a meta-analysis, the long noncoding RNA cancer susceptibility candidate 8 (CASC8) was found to be a cancer susceptibility gene closely related to lung cancer, but its functions in lung cancer are unknown. In the Cancer Genome Atlas database, the expression of CASC8 was significantly higher in non-small cell lung cancer than in adjacent normal tissues, and high expression of CASC8 was associated with poor prognosis in patients with lung adenocarcinoma. Silencing CASC8 inhibited proliferation, migration, and invasion in non-small cell lung cancer cell lines. Silencing CASC8 also promoted sensitivity to osimertinib through Forkhead box M1 (FOXM1). Therefore, this pathway can be exploited in patients with lung cancer resistant to targeted therapies. Our study revealed for the first time that silencing CASC8 inhibited the proliferation, migration, and invasion of non-small cell lung cancer cells and promoted their sensitivity to osimertinib, suggesting that CASC8 is closely related to the occurrence and development of non-small cell lung cancer. This may provide insight into mechanisms of treatment for non-small cell lung cancer.

Expression, association with clinicopathological features and prognostic potential of CEP55, p-Akt, FoxM1 and MMP-2 in astrocytoma.

Centrosomal protein 55 (CEP55) is a member of the centrosomal-associated protein family and participates in the regulation of cytokinesis during cell mitosis. However, aberrant CEP55 protein expression has been observed in human tumors. In addition, CEP55 regulates the biological functions of tumors by inducing the Akt pathway and upregulating forkhead box protein M1 (FoxM1) and matrix metalloproteinase-2 (MMP-2). In the present study, the levels, clinicopathological features and prognostic potential of CEP55, phosphorylated Akt (p-Akt), FoxM1 and MMP-2 in astrocytoma were evaluated. CEP55, p-Akt, FoxM1 and MMP-2 levels were examined in 27 normal brain tissues and 262 astrocytoma tissues by using immunohistochemistry. Furthermore, Kaplan-Meier analysis and Cox proportional hazards models were applied to predict the prognosis of patients with astrocytoma. The results indicated that expression levels of CEP55 and other proteins were elevated in human astrocytoma compared with those in normal brain tissue. The levels of the selected proteins were increased as the tumor grade increased. Furthermore, CEP55 expression was positively correlated with p-Akt, FoxM1 and MMP-2 levels in astrocytoma. Overall survival analysis revealed that patient prognosis was associated with CEP55, p-Akt, FoxM1 and MMP-2 levels, as well as with the tumor grade and patient age. Furthermore, CEP55, FoxM1, tumor grade and patient age were independent prognostic factors in astrocytoma according to multivariate analysis. Taken together, the present results suggested that CEP55, p-Akt, FoxM1 and MMP-2 have crucial roles in the progression and prognosis of human astrocytoma and that CEP55 and FoxM1 may be potential therapeutic targets.