A Stapled Peptide Inhibitor Targeting the Binding Interface of N6-Adenosine-Methyltransferase Subunits METTL3 and METTL14 for Cancer Therapy.

METTL3, a primary methyltransferase catalyzing the RNA N6-methyladenosine (m6A) modification, has been identified as an oncogene in several cancer types and thus nominated as a potentially effective target for therapeutic inhibition. However, current options using this strategy are limited. In this study, we targeted protein-protein interactions at the METTL3-METTL14 binding interface to inhibit complex formation and subsequent catalysis of the RNA m6A modification. Among candidate peptides, RM3 exhibited the highest anti-cancer potency, inhibiting METTL3 activity while also facilitating its proteasomal degradation. We then designed a stapled peptide inhibitor (RSM3) with enhanced peptide stability and formation of the α-helical secondary structure required for METTL3 interaction. Functional and transcriptomic analysis in vivo indicated that RSM3 induced upregulation of programmed cell death-related genes while inhibiting cancer-promoting signals. Furthermore, tumor growth was significantly suppressed while apoptosis was enhanced upon RSM3 treatment, accompanied by increased METTL3 degradation, and reduced global RNA methylation levels in two in vivo tumor models. This peptide inhibitor thus exploits a mechanism distinct from other small-molecule competitive inhibitors to inhibit oncogenic METTL3 activity. Our findings collectively highlight the potential of targeting METTL3 in cancer therapies through peptide-based inhibition of complex formation and proteolytic degradation.

Computed tomography angiography-based radiomics model to identify high-risk carotid plaques.

Background: Extracranial atherosclerosis is one of the major causes of stroke. Carotid computed tomography angiography (CTA) is a widely used imaging modality that allows detailed assessments of plaque characteristics. This study aimed to develop and test radiomics models of carotid plaques and perivascular adipose tissue (PVAT) to distinguish symptomatic from asymptomatic plaques and compare the diagnostic value between radiomics models and traditional CTA model. Methods: A total of 144 patients with carotid plaques were divided into symptomatic and asymptomatic groups. The traditional CTA model was built by the traditional radiological features of carotid plaques measured on CTA images which were screened by univariate analysis and multivariable logistic regression. We extracted and screened radiomics features from carotid plaques and PVAT. Then, a support vector machine was used for building plaque and PVAT radiomics models, as well as a combined model using traditional CTA features and radiomics features. The diagnostic value between radiomics models and traditional CTA model was compared in identifying symptomatic carotid plaques by Delong method. Results: The area under curve (AUC) values of traditional CTA model were 0.624 and 0.624 for the training and validation groups, respectively. The plaque radiomics model and PVAT radiomics model achieved AUC values of 0.766, 0.740 and 0.759, 0.618 in the two groups, respectively. Meanwhile, the combined model of plaque and PVAT radiomics features and traditional CTA features had AUC values of 0.883 and 0.840 for the training and validation groups, respectively, and the receiver operating characteristic curves of combined model were significantly better than those of traditional CTA model in the training group (P<0.001) and validation group (P=0.029). Conclusions: The combined model of the radiomics features of carotid plaques and PVAT and the traditional CTA features significantly contributes to identifying high-risk carotid plaques compared with traditional CTA model.

Predictive Value of the Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Monocyte-to-Lymphocyte Ratio Esophageal Stricture After Endoscopic Submucosal Dissection of Early Esophageal Cancer.

BACKGROUND Endoscopic submucosal dissection (ESD) has become a preferred treatment method for patients with early esophageal cancer (EEC), but it can easily be complicated by esophageal stricture. In this study, we aimed to analyze the predictive value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) for post-ESD esophageal stricture of EEC. MATERIAL AND METHODS A retrospective study of 285 patients with EEC who underwent ESD was conducted. Patients were divided into 2 groups according to whether there were complications of esophageal stricture: the stricture group (n=72) and the non-stricture group (n=213). A t test or chi-squared test was used to compare the clinical differences in different subgroups. Receiver operating characteristic (ROC) curves were plotted to determine and compare the predictive value of NLR, PLR, and MLR in post-ESD esophageal stricture. Spearman correlation was used to detect the relationship between NLR, PLR, and MLR and the severity of esophageal stricture. RESULTS The NLR, PLR, and MLR values in the stricture group were higher than those in the non-stricture group, and there was a positive correlation between NLR and MLR and the severity of stricture according to the Spearman correlation test (P<0.05). ROC analysis showed that the area under the ROC curve value of the combination of NLR, PLR, and MLR (0.850) was higher than the NLR (0.792), PLR (0.774), and MLR (0.768). CONCLUSIONS The combination of NLR, PLR, and MLR could help clinicians to predict post-ESD esophageal stricture in the early stage.

MC1R Peptide Agonist Self-Assembles into a Hydrogel That Promotes Skin Pigmentation for Treating Vitiligo.

Vitiligo, a common skin disease that seriously affects 0.5-2.0% of the worldwide population, lacks approved therapeutics due to a wide range of adverse side effects. As a key regulator of skin pigmentation, MC1R may be an effective therapeutic target for vitiligo. Herein, we report an MC1R peptide agonist that directly self-assembles into nanofibrils that form a hydrogel matrix under normal physiological conditions. This hydrogel exhibits higher stability than free peptides, sustained release, rapid recovery from shear-thinning, and resistance to enzymatic proteolysis. Furthermore, this peptidal MC1R agonist upregulates tyrosinase, tyrosinase-related protein-1 (TYRP-1), and tyrosinase-related protein-2 (TYRP-2) to stimulate melanin synthesis. More importantly, MC1R agonist hydrogel promotes skin pigmentation in mice more potently than free MC1R agonist. This study supports the development of this MC1R agonist hydrogel as a promising pharmacological intervention for vitiligo.

Cation-π Interaction Trigger Supramolecular Hydrogelation of Peptide Amphiphiles.

As an important noncovalent interaction, cation-π interaction plays an essential role in a broad area of biology and chemistry. Despite extensive studies in protein stability and molecular recognition, the utilization of cation-π interaction as a major driving force to construct supramolecular hydrogel remains uncharted. Here, a series of peptide amphiphiles are designed with cation-π interaction pairs that can self-assemble into supramolecular hydrogel under physiological condition. The influence of cation-π interaction is thoroughly investigated on peptide folding propensity, morphology, and rigidity of the resultant hydrogel. Computational and experimental results confirm that cation-π interaction could serve as a major driving force to trigger peptide folding, resultant ß-hairpin peptide self-assembled into fibril-rich hydrogel. Furthermore, the designed peptides exhibit high efficacy on cytosolic protein delivery. As the first case of using cation-π interactions to trigger peptide self-assembly and hydrogelation, this work provides a novel strategy to generate supramolecular biomaterials.

Development of biomaterials based on plasticized polylactic acid and tea polyphenols for active-packaging application.

Bioactive-packaging films based on polylactic acid (PLA), acetyl tributyl citrate (ATBC), and tea polyphenol (TP) were prepared by melt blending. Results of mechanical-property test revealed that adding ATBC and TP can significantly improve mechanical properties of PLA. The shift of CO to lower wavelengths in FTIR and the morphology of the films in SEM indicated physical or chemical interactions in the PLA/ATBC/TP films. The antioxidant, and antibacterial activities of the PLA/ATBC films increased dramatically (P<0.05) with increased TP amount. The antioxidant activity of the films with 1 % TP was equivalent to that of 300 mg/L l-ascorbic acid, whereas PLA/ATBC/TP films with 0.5 % and 1 % TP concentration were effective in inhibiting Staphylococcus aureus and Escherichia coli within almost 5 h (P<0.05). The PLA films changed from transparent to opaque and from yellow to red after combining with ATBC or TP, respectively. The overall migration of the films in 3 % acetic acid and 10 % ethanol did not exceed the overall migration limit. All these findings indicated potential of the PLA/ATBC/TP films in active-packaging application.

The NLRP3 inflammasome mediates liver failure by activating procaspase-1 and pro-IL-1 ß and regulating downstream CD40-CD40L signaling.

OBJECTIVES: In this prospective case-control study, we explored the regulatory roles of the NLRP3 inflammasome in hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF). METHODS: Thirty patients with HBV-ACLF, 30 patients with chronic hepatitis B, and 30 healthy individuals were enrolled. Real-time reverse transcription polymerase chain reaction was used to assess mRNA levels in peripheral blood mononuclear cells and serum protein levels were assessed by enzyme-linked immunosorbent assay. RESULTS: Serum levels of alanine aminotransferase, asparagine aminotransferase, total bilirubin, and direct bilirubin in patients with HBV-ACLF were increased. Transcript levels of NLRP3 and ASC and protein levels of interleukin (IL)-1ß, IL-18, and sCD40L were elevated in patients with HBV-ACLF. Expression of the NLRP3 inflammasome signaling pathway components procaspase-1 and pro-IL-1ß was elevated in patients with HBV-ACLF. CONCLUSIONS: This prospective case-control study demonstrated that significant activation of the NLRP3 inflammasome occurs in patients with HBV-ACLF. The activated NLRP3 inflammasome mediated liver failure by stimulating procaspase-1 and pro-IL-1 ß and regulating downstream CD40-CD40L signaling.

Functional and Antioxidant Properties of Plastic Bottle Caps Incorporated with BHA or BHT.

In this study, we prepared new antioxidant active plastic bottle caps by incorporating butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) and 2% (w/w) white masterbatch in high-density polyethylene (HDPE). Fourier-transform infrared (FT-IR) spectrometry revealed that the antioxidants and HDPE were uniformly mixed with noncovalent bonding. In addition, the differential scanning calorimetry (DSC) test revealed that the change in melting point and initial extrapolation temperature of the antioxidant active caps was not significant. Sensory evaluation and removal torque tests validated the suitability of the antioxidant active plastic bottle caps in industrial application. The antioxidant activity increased with a greater concentration of BHA and BHT incorporated in both antioxidant active caps (p < 0.05) and with more impact on the BHA cap compared to BHT cap in terms of antioxidant activity. Migration experiments for 10 days at 40 °C and 2 h at 70 °C showed that active antioxidants in the plastic bottle cap were more easily released into fatty foods and milk products that are highly sensitive to oxidation, and the migration of BHA and BHT did not exceed the maximum amount specified in (EC) No 1333/2008 (<200 mg/kg). As such, the antioxidant active plastic bottle caps inhibited oxidation, thereby ensuring higher food quality.

Highly sensitive detection of cancer cells via split aptamer mediated proximity-induced hybridization chain reaction.

Highly sensitive detection of cancer cells is of great importance for evaluating cancer development and improving survival rates. Here, we developed a split aptamer mediated proximity-induced hybridization chain reaction (HCR) strategy to meet this purpose. In this strategy, two split aptamer initiator probes, Sp-a and Sp-b, and two HCR hairpin probes, H1 and H2 were designed. The split aptamer initiator probes contained two components, split aptamer domains being responsible for target recognition, and the split initiator parts serving as the HCR promoter. In the presence of target cells, Sp-a and Sp-b would self-assemble on the cell surfaces, allowing the formation of an intact nicked initiator to activate the HCR reaction. Benefit from low background split aptamers and HCR amplification, this strategy presented high sensitivity in quantitative detection with a detection limit of 18 cells in 150 µL of binding buffer. Moreover, the approach exhibited excellent specificity to target cells in 10% fetal bovine serum and mixed cell samples, which was favorable for clinical diagnosis in complex biological environment. In addition, by changing the split aptamers attached to the split initiator, the proposed strategy can be expanded to detect various kinds of target cells. It may provide a novel and useful applicable platform for the sensitive detection of cancer cells in biomedicine and tumor-related studies.

Therapeutic effect of metformin in the treatment of endometrial cancer.

The present review aims at reviewing the role of metformin in the treatment of endometrial cancer (EC). According to the literature, excessive estrogen levels and insulin resistance are established risk factors of EC. As a traditional insulin sensitizer and newly discovered anticancer agent, metformin directly and indirectly inhibits the development of EC. The direct mechanisms of metformin include inhibition of the LKB1-AMP-activated protein kinase-mTOR, PI3K-Akt and insulin-like growth factor 1-related signaling pathways, which reduces the proliferation and promotes the apoptosis of EC cells. In the indirect mechanism, metformin increases the insulin sensitivity of body tissues and decreases circulating insulin levels. Decreased levels of insulin increase the blood levels of sex hormone binding globulin, which leads to reductions in circulating estrogen and androgens. The aforementioned findings suggest that metformin serves an important role in the treatment of EC. Increased understanding of the mechanism of metformin in EC may provide novel insights into the treatment of this malignancy.

Extracellular pH-manipulated in situ reconfiguration of aptamer functionalized DNA monomer enables specifically improved affinity, detection and drug delivery.

Aptamers are promising in cancer diagnosis and therapy, but their poor affinity under physiological conditions is a challenge. In view of the acidic microenvironment of solid tumors, we herein developed an extracellular pH-manipulated multivalent approach to exclusively improve the affinity to target cells at physiological temperature. Specifically, an aptamer based DNA monomer (AptDM) with split i-motif fragments overhanging was rationally designed, it possessed pH-responsiveness and doxorubicin loading capacity. At neutral pH, AptDMs existed as well dispersed small units, showing weakly undesired binding and internalization. In acidic extracellular conditions, AptDMs tended to crosslink of each other into multivalent DNA assemblies (MDAs) via formation of an intermolecular i-motif structure. Due to the multivalent effect, the resulting MDAs showed greatly enhanced affinity (Kd = 9.96 ± 1.06 nM) and stable binding ability at 37 °C, thus allowing highly sensitive diagnosis, efficient drug delivery, and improved inhibition to target tumor cells, but decreased cytotoxicity to nontarget cells. It is believed that this multivalent approach may boost the development of novel aptamer functionalized nanodevices for clinical validation.

The tumor suppressive effect of long non-coding RNA FRMD6-AS2 in uteri corpus endometrial carcinoma.

Uterine corpus endometrial cancer (UCEC) is one of the most common gynecological malignancies with increasing incidence and high morbidity and mortality. The currently acknowledged molecular mechanism of UCEC is still not adequate. Here, we reported that the expression of a novel long non-coding RNA (lncRNA) FRMD6-AS2 was reduced in UCEC compared to noncancerous endometrium tissues using the data from The Cancer Genome Atlas (TCGA) Project database. The gene ontology (GO) analysis on differential expressed targeted genes of FRMD6-AS2 in UCEC suggested that FRMD6-AS2 might impact with the function of actin-mediated cell movement and contraction. By over-expressing FRMD6-AS2 in UCEC cell lines, we observed that FRMD6-AS2 played a suppressive role in tumor growth, migration and invasion via activation of Hippo signaling pathway including FRMD6. Moreover, we also demonstrated that FRMD6-AS2 could interact with the 30 kb upstream beyond FRMD6 and facilitate the chromatin looping towards the promoter region of FRMD6 to enhance the expression of FRMD6. We concluded that lncRNA FRMD6-AS2 repressed UCEC, at least in part, by increasing FRMD6.

Icariin exerts a protective effect against d-galactose induced premature ovarian failure via promoting DNA damage repair.

Icariin is one of the most common active ingredients in traditional Chinese medicine, while its function against Premature ovarian failure (POF) has not been explored. POF animal model was induced by d-galactose, and icariin at different doses was administered. Ovarian structure and follicle counting were observed via hematoxylin and eosin staining. The levels of serum hormones were measured by ELISA. Primary ovarian granulosa cells were cultured to compare the protective effects of icariin on cell aging, and DNA damage markers including γH2AX and 53BP1 were assessed by Western Blot. Administration of icariin promoted ovary/body weight, follicles numbers and fertility outcomes. In addition, icariin downregulated the levels of follicle stimulating hormone and luteinizing hormone, and upregulated the levels of estradiol and anti-Müllerian hormone. Icariin protected ovarian granulosa cells from d-galactose induced aging, with increased cell viability and lower endogenous ß-galactosidase activity. The alterations of expression level of γH2AX and 53BP1 by icariin indicated that the protection is via promoting DNA damage repair. In this study we tested the biological function of icariin against the d-galactose induced POF. Our results demonstrated that icariin effectively attenuated ovarian injury via promoting DNA damage repair, suggesting that icariin can be developed as a protective agent against POF.

FAM98A promotes cancer progression in endometrial carcinoma.

To investigate the expression status of FAM98A and its potential involvement in endometrial carcinoma, the relative expression of FAM98A in clinical endometrial carcinoma tissues was analyzed by immunohistochemistry and real-time polymerase chain reaction. Endogenous FAM98A protein was determined by Western blotting. The overall survival was calculated by the Kaplan-Meier's analysis. Cell growth/viability/proliferation was evaluated by cell counting, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide assay, and clonogenic assay, respectively. Cell apoptosis was determined by the Annexin V/7-AAD double-staining methods followed by flow cytometry analysis. The regulatory effect of miR-142-3p on FAM98A was interrogated by luciferase reporter assay. Aberrant overexpression of FAM98A was found in endometrial carcinoma both in vitro and in vivo. Furthermore, high level of FMA98A was associated with poor prognosis. FAM98A deficiency in Ishikawa and RL95-2 cells significantly inhibited cell growth, cell viability, and cell proliferation. In addition, FAM98A-knockdown stimulated remarkable cell apoptosis, which might be mediated by down-regulation of BCL2 and up-regulation of BAX. Mechanistically, it was demonstrated that miR-142-3p directly targeted FAM98A, and modulated its expression. In conclusion, we unraveled the oncogenic properties of FAM98A in endometrial carcinoma and highlighted the miR-142-3p-FAM98A signaling in this disease.

Ovarian microcystic stromal tumors: clinical, radiological, and pathological studies of two cases.

We observed two unusual cases of ovarian microcystic stromal tumors (MST). These two patients had no obvious clinical symptoms, and the imaging findings were separately diagnosed as cystic teratoma and ovarian malignant tumors. Significantly, during the operation, none of the pathologists considered the possibility of MST. The two cases showed similar morphological and immunophenotypic characteristics: some nests were made up of microcysts with round or oval shapes, and the cavity was bright and empty. In some areas, the cell nests of micro cysts were not obvious and were identified as solid cell nests. The tumor cells contained eosinophilic cytoplasms and neutral nuclei. Mitotic figures were rare. Immunohistochemistry indicated that the tumor cells were all positive for CD10, vimentin, WT1, and ß-catenin, but negative for Cytokeratin, α-inhibin, CD99, ER, PR, S-100, EMA, CD56, CgA, Syn, Pax-8, Desmin, SMA, and calretinin. The Ki67 index was less than 5%. Based on the above characteristics, a diagnosis of ovarian MST was made after the operation. The final repeated CT scan revealed no recurrence during the post-surgical course. Here the clinical, radiological and pathological characteristics of these two cases diagnosed as ovarian MST are presented in order to help avoid future misdiagnosis and over-treatment.

Oldhamianoside inhibits the growth of ovarian cancer both in vitro and in vivo via adjusting inflammation and angiogenesis signals.

OBJECTIVE: The aim of this study was to determine the effects and possible mechanisms of oldhamianoside on the growth of human ovarian cancer both in vitro and in vivo. MATERIALS AND METHODS: CCK-8 assay was applied to estimate the effect of oldhamianoside on cell proliferation inhibition in vitro. Nude mice bearing human ovarian SKOV3 xenograft tumors were treated with oldhamianoside to investigate the effects of compound administration on tumor growth in vivo. To further investigate the mechanisms of inhibition effects of oldhamianoside on ovarian cancer growth in vivo, the levels of TNF-α, IL-6, and MCP-1 in plasma from the mice were measured by ELISA. Western blot was used to detect the expression of angiogenesis- and/or apoptosis-related proteins. RESULTS: We found that oldhamianoside treatment inhibited SKOV3 proliferation and growth both in vitro and in vivo. Meanwhile, the levels of TNF-α, IL-6, and MCP-1 in plasma were markedly suppressed in oldhamianoside-treated mice. Additionally, oldhamianoside treatment inhibited the expression of VEGF and VEGFR2 and decreased the expression of caspase-3 and Bax/Bcl-2 ratio. CONCLUSION: Our data indicate that oldhamianoside has an obvious inhibition effect on SKOV3 proliferation, and the mechanisms might be related to inhibition of cell growth, apoptosis induction, and adjusting the inflammatory response and angiogenesis signal.

Retracted: MicroRNA-92a promotes tumor growth and suppresses immune function through activation of MAPK/ERK signaling pathway by inhibiting PTEN in mice bearing U14 cervical cancer.

Cervical cancer is known as the possible outcome of genital infection, while the molecular mechanisms of initiation, development, and metastasis of cervical cancer have not yet been fully elucidated. Our study aims to investigate the effects of microRNA-92a (miR-92a) on tumor growth and immune function by targeting PTEN via the MAPK/ERK signaling pathway in tumor-bearing mice. C57BL/6 female mice were used for tumor-bearing mouse models and their tumor and adjacent normal tissues were collected, and normal cervical tissues were obtained from normal mice. Serum levels of tumor necrosis factor-α (TNF-α) and soluble interleukin-2 receptor (sIL-2R) were detected by ELISA. The cells were divided into the normal, blank, negative control (NC), miR-92a mimic, miR-92a inhibitor, siRNA-PTEN, and miR-92a inhibitor + siRNA-PTEN groups. Dual-luciferase reporter assay was adopted to determine the relationship between PTEN and miR-92a. Expressions of miR-92a, PTEN, TNF-α, sIL-2R, ERK1, and ERK2 were tested by RT-qPCR and Western blotting. Cell proliferation was detected by cell count kit-8 (CCK-8); cell cycle and apoptosis were detected by flow cytometry. Compared with the normal cervical tissues and adjacent normal tissues, the cervical cancer tissues exhibited increased expressions of miR-92a, p-ERK1/2, and serum levels of TNF-α and sIL-2R while decreased PTEN expression. PTEN was confirmed to be the target gene of miR-92a. As compared with the blank and NC groups, expressions of miR-92a, ERK1 and ERK2 increased, and expressions of PTEN decreased in the miR-92a mimic group. The miR-92a mimic group exhibited increased expression levels of TNF-α and sIL-2R, cell proliferation, and cell number in S phase but decreased cell apoptosis, and cell number in G0/G1 phase, while the miR-92a inhibitor group followed opposite trends. miR-92a promotes tumor growth and suppresses immune function by inhibiting PTEN via activation of the MAPK/ERK signaling pathway in mice bearing U14 cervical cancer.

Enhanced Imaging of Specific Cell-Surface Glycosylation Based on Multi-FRET.

Cell-surface glycosylation contains abundant biological information that reflects cell physiological state, and it is of great value to image cell-surface glycosylation to elucidate its functions. Here we present a hybridization chain reaction (HCR)-based multifluorescence resonance energy transfer (multi-FRET) method for specific imaging of cell-surface glycosylation. By installing donors through metabolic glycan labeling and acceptors through aptamer-tethered nanoassemblies on the same glycoconjugate, intramolecular multi-FRET occurs due to near donor-acceptor distance. Benefiting from amplified effect and spatial flexibility of the HCR nanoassemblies, enhanced multi-FRET imaging of specific cell-surface glycosylation can be obtained. With this HCR-based multi-FRET method, we achieved obvious contrast in imaging of protein-specific GalNAcylation on 7211 cell surfaces. In addition, we demonstrated the general applicability of this method by visualizing the protein-specific sialylation on CEM cell surfaces. Furthermore, the expression changes of CEM cell-surface protein-specific sialylation under drug treatment was accurately monitored. This developed imaging method may provide a powerful tool in researching glycosylation functions, discovering biomarkers, and screening drugs.

Reduced m6A mRNA methylation is correlated with the progression of human cervical cancer.

The m6A mRNA methylation involves in mRNA splicing, degradation and translation. Recent studies have revealed that reduced m6A mRNA methylation might promote cancer development. However, the role of m6A mRNA methylation in cervical cancer development remains unknown. Therefore, we investigated the role of m6A methylation in cervical cancer in the current study. We first evaluated the m6A mRNA methylation level in 286 pairs of cervical cancer samples and their adjacent normal tissues by dot blot assay. Then the role of m6A on patient survival rates and cervical cancer progression were assessed. The m6A level was significantly reduced in the cervical cancer when comparing with the adjacent normal tissue. The m6A level reduction was significantly correlated with the FIGO stage, tumor size, differentiation, lymph invasion and cancer recurrence. It was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with cervical cancer. Reducing m6A level via manipulating the m6A regulators expression promoted cervical cancer cell proliferation. And increasing m6A level significantly suppressed tumor development both in vitro and in vivo. Our results showed that the reduced m6A level is tightly associated with cervical cancer development and m6A mRNA methylation might be a potential therapeutic target in cervical cancer.

PD98059 impairs the cisplatin-resistance of ovarian cancer cells by suppressing ERK pathway and epithelial mesenchymal transition process.

BACKGROUND: The study was aimed at investigating the role of PD98059 on impairing the cisplatin-resistance of ovarian cancer cells and figuring out the potential mechanism. MATERIAL AND METHODS: Treated with low dose of cisplatin (DDP), DDP-resistant ovarian cancer cells were built and named as SKOV-3/DDP. The cell viabilities of ovarian cancer cell line SKOV-3 and SKOV-3/DDP were detected using MTT assay. Wound healing assay and flow cytometry were performed to detect the migratory ability and cell cycle variation of the two cells and assess the sensibility to DDP in the two cell lines. However, cotreated with DDP and PD98059, cell viability, migration and cell cycle of SKOV-3/DDP were determined again. The DDP-resistance varied a lot and the potential mechanism was studied via western blot assay. RESULTS: Both treated with DDP, SKOV-3/DDP showed an intense resistance than SKOV-3 including stronger cell viability, larger migration area and less G1/G0 arrest, which confirmed the successfully established DDP-resistant cell line. The phosphorylation of ERK and the activation of epithelial mesenchymal transition (EMT) process contributes to the enhanced resistance. PD98059, a MEK inhibitor, suppresses the ERK pathway and the EMT process of SKOV-3/DDP. Co-treated by DDP and PD98059, cell proliferation and migratory area decreased, meantime more cell were arrested in G0/G1 phase compared to simple treatment of DDP or PD98059. CONCLUSION: PD98059 efficiently impairs the DDP-resistance of ovarian cancer cells via downregulating the ERK pathway and the EMT process.