Relationship Between Resilience, Social Support, Existential Well-Being and Negative Emotions in Cervical Cancer Patients: a Mediation Analysis.

Background: The patients of cervical cancer have more negative emotions and lower quality of life. The aim of this study was to explore the relationships between existential well-being (EWB), social support, resilience, negative emotions in patients with cervical cancer, and to examine whether resilience mediates the associations between EWB or social support and negative emotions. Material and methods: This study enrolled patients with cervical cancer who were treated at the Tianjin Medical University Cancer Institute and Hospital in China during 2012-2019. The Hospital Anxiety and Depression Scale (HADS), the Resilience Scale of 14 items (RS-14) and the McGill Quality of Life Questionnaire (MQOL) were utilized to assess patient's anxiety, depression, resilience, social support and EWB via telephone. Spearman's correlation analyses were used to assess bivariate correlations, and mediation analyses were applied to examine whether resilience mediated the relationship between social support or EWB and negative emotions. Results: A total of 150 (92.0%) out of 163 eligible patients completed the questionnaires. EWB and social support were negatively correlated with anxiety (r=-0.560 and r=-0.561) and depression (r=-0.508 and r=-0.526), and positively correlated with resilience (r=0.691 and r=0.652). Resilience was negatively associated with anxiety (r=-0.545) and depression (r=-0.505). Negative direct effects of social support on anxiety and EWB on anxiety and depression were statistically significant (P<0.05). Resilience played a partial mediating role in the relationship between EWB and depression (ß=-0.085, 95%CI: -0.150 to -0.020), accounting for 37.12% of the total effect. It also served as a partial mediator in the association between EWB and anxiety (ß=-0.061, 95%CI: -0.107 to -0.015), explaining 34.46% of the overall effect. Additionally, resilience partially mediated the connection between social support and depression (ß=-0.173, 95%CI: -0.312 to -0.053), explicating 57.48% of the total effect. Conclusions: A combination of existential, supportive and resilient interventions may help reduce psychological distress and improve quality of life among cervical cancer patients, thereby promoting both physical and psychological health.

Erratum: [Corrigendum] MicroRNA­23a inhibits endometrial cancer cell development by targeting SIX1.

[This corrects the article DOI: 10.3892/ol.2019.10694.].

Elevated Expression of ADAM10 Induced by HPV E6 Influences the Prognosis of Cervical Cancer.

Objective: To explore the abnormal expression of ADAM10, its cause, and its clinical value in the prognosis of cervical lesions. Methods: The abnormal expression of ADAM10 was explored using the Gene Expression Profiling Interactive Analysis database, and the abnormal expression in cervical lesions was verified using immunohistochemistry (IHC). The transfection effect of shRNA was evaluated using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression of ADAM10 in cells was analyzed using western blotting. Results: ADAM10 was highly expressed in multiple cancers. As the disease progressed, the expression of ADAM10 gradually increased (p < 0.05). Patients with higher expression of ADAM10 had poorer survival outcomes than those with lower expression levels (p < 0.05). The expression levels of ADAM10 decreased after expression levels of E6 was inhibited. Conclusion: ADAM10 is highly expressed in cervical cancer; the higher the expression levels, the worse the survival outcome. HPV E6 is the critical driver of the elevated expression of ADAM10 in cervical cancer.

Downregulation of BRD4 attenuates high glucose-induced damage of trophoblast cells by inhibiting activation of AKT/mTOR pathway.

It was elucidated that bromodomain-containing protein 4 (BRD4) has involvement with diabetic complication. However, the role and molecular mechanism of BRD4 in gestational diabetes mellitus (GDM) are still unclear. In this study, the mRNA and protein contents of BRD4 in placenta tissues of GDM patients and high glucose (HG)-induced HTR8/SVneo cells were detected by qRT-PCR and western blot assay. CCK-8, EdU staining, flow cytometry as well as western blot were applied for the appraisement of cell viability and apoptosis. Wound healing assay and transwell assay were conducted for the assessment of cell migration and invasion. Oxidative stress and inflammatory factors were detected. Additionally, the contents of AKT/mTOR pathway-related proteins were estimated applying western blot. It was discovered that BRD4 expression was ascended in tissues and HG-induced HTR8/SVneo cells. BRD4 downregulation cut down the contents of p-AKT and p-mTOR but had no effects on the total protein levels of AKT or mTOR in HG-induced HTR8/SVneo cells. BRD4 depletion promoted cell viability, enhanced proliferative capability, and reduced cell apoptotic level. Moreover, BRD4 depletion facilitated cell migrative and invasive capabilities, and repressed the oxidative stress as well as inflammatory damage in HG-induced HTR8/SVneo cells. The activation of Akt reversed the protective impacts of BRD4 depletion on HG-induced HTR8/SVneo cells. To sum up, BRD4 silencing may alleviate HG-induced HTR8/SVneo cell damage through the inhibition of the AKT/mTOR pathway.

B7-H6 as a Diagnostic Biomarker for Cervical Squamous Cell Carcinoma.

Background: B7-H6, a newly discovered member of the immunoglobulin superfamily, exerts antitumor effects by binding to NKP30 receptor on natural killer cells; it has important clinical implications. Cell surface ectodomain shedding of B7-H6 generates soluble B7-H6 (sB7-H6), which is highly expressed and serves as a valuable biomarker in multiple tumors, but the clinical significance and diagnostic value of B7-H6 in cervical squamous cell carcinoma (CSCC) remains unclear. Objective: To assess the expression and diagnostic value of B7-H6 in CSCC. Methods: In this study, 69 cervical specimens were analyzed for B7-H6 expression: 25 paired CSCC tissues were examined using quantitative real-time polymerase chain reaction, and 24 paraffin-embedded CSCC tissues and 20 normal tissues were analyzed immunohistochemically. Furthermore, plasma samples from 30 CSCC patients and 24 healthy controls were examined using ELISA. Results: B7-H6 mRNA and protein levels were significantly higher in CSCC tissues than in adjacent normal cervical tissues (p < 0.05). Immunohistochemical analysis revealed that high B7-H6 expression correlated with stromal invasion (p = 0.043), lymphovascular space involvement (p = 0.005), lymph node metastasis (p = 0.019), and International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.002). Moreover, ELISA results demonstrated that the sB7-H6 concentration in peripheral blood was higher in CSCC patients than in healthy controls (p < 0.0001). Notably, at the optimal cutoff point of 0.076 ng/mL, sB7-H6 showed 93.3% sensitivity and 62.5% specificity in the discrimination of CSCC patients from healthy controls. Conclusions: B7-H6 mRNA and protein levels are markedly increased in CSCC tissues and peripheral blood samples, and the B7-H6 level can be used as a biomarker for predicting the severity of CSCC disease and discriminating CSCC patients from healthy controls.

B7 homolog 6 promotes the progression of cervical cancer.

B7 homolog 6 (B7-H6) was recently discovered to act as a co-stimulatory molecule. In particular, the expression of B7-H6 has been found to play an important biological role in several types of tumors. The aim of the present study was to determine the role of B7-H6 in cervical cancer. Immunohistochemistry was used to analyze the expression levels of B7-H6 in cervical precancerous and cancerous tissues. Furthermore, the expression of B7-H6 was knocked down in HeLa cells using short hairpin RNA and the effects of B7-H6 on HeLa cell proliferation, migration and invasion were determined using Cell Counting Kit-8, colony formation, wound healing and Transwell invasion assays, respectively. In addition, flow cytometry was used to analyze the levels of cell apoptosis and the cell cycle distribution. The results of the immunohistochemical staining revealed that the expression levels of B7-H6 were upregulated in cervical lesions. Furthermore, the expression levels of B7-H6 were positively associated with the clinical stage of the cervical lesions. B7-H6 knockdown suppressed the invasive, migratory and proliferative abilities of HeLa cells, and promoted G1 cell cycle arrest and apoptosis. In conclusion, the findings of the present study suggested that B7-H6 may serve as a novel oncogene and may hold promise as a potential therapeutic target for cervical cancer.

LINC01133 and LINC01243 are positively correlated with endometrial carcinoma pathogenesis.

PURPOSE: To characterize the role of two long non-coding RNAs (lncRNAs), LINC01133 and LINC01243, in endometrial carcinoma (EC) pathogenesis. LINC01133 is an lncRNA that has been implicated in many cancers, and LINC01243 is a newly identified lncRNA identified from the NCBI GEO database. METHODS: We studied the effect of LINC01133 and LINC01243 on EC malignancy using siRNA knockdown and real-time quantitative polymerase chain reaction (RT-qPCR), flow cytometry, Annexin V-FITC/propidium iodide double staining, Transwell, and scratch invasion assays in two EC cell lines (Ishikawa and HEC-1-A cells). RESULTS: We first confirmed the partial knockdown of both LINC01133 and LINC01243 expression in Ishikawa and HEC-1-A cells using RT-qPCR. Following confirmation of lncRNA knockdown, we assessed the effect of knockdown on EC malignancy. We observed reduced EC cell proliferation using the CCK-8 assay, as well as cell cycle arrest and increased apoptosis in both EC cell lines. Furthermore, Transwell and scratch invasion assays revealed decreased migration and invasion of the two EC cell lines, respectively. CONCLUSION: We demonstrated that LINC01133 and LINC01243 expression are associated with EC development and progression. Our findings suggest a potential role for these lncRNAs as novel EC biomarkers.

CYPA promotes the progression and metastasis of serous ovarian cancer (SOC) in vitro and in vivo.

Ovarian cancer (OC) is a type of gynaecological malignancy with high mortality in females. Serous ovarian cancer (SOC) is a distinct subtype of OC with poor early diagnosis. Given the limitations of traditional therapies, such as chemotherapy, targeted treatment is therefore a promising therapy to improve the survival rate of SOC patients. Cyclophilin A (CYPA) is a member of Cyclophilin family and thought to participates in multiple cellular processes such as cell transduction and immune modulation. Recently, various of studies indicated that CYPA has critical impact on cancer progression. CYPA could regulate cell proliferation, invasion, and chemoresistance of multiple types of cancers. However, it is still unclear whether it could affect ovarian cancer. In this study, we demonstrated that CYPA was highly expressed in SOC tissues compared with adjacent tissues. Further, CYPA was significantly associated with clinical stage and lymphnode metastasis of SOC patients. Additionally, data indicated that knockdown of CYPA by its shRNA dramatically reduces migration and invasion capacity of SOC cells in vitro and blocks tumor metastasis in vivo. Our study investigates the involvement of CYPA in the progression and metastasis of SOC, and therefore provides CYPA as a promising therapeutic target for SOC treatment.

MicroRNA-23a inhibits endometrial cancer cell development by targeting SIX1.

The present study focused on exploring the inhibitory mechanism of microRNA (miR)-23a in endometrial cancer. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to investigate miR-23a expression in endometrial tissues and endometrial cancer cells. A colony formation assay using crystal violet staining was performed to compare cell proliferation, while wound-healing and Transwell assays were performed to compare cell migration and invasion. Subsequently, bioinformatics and a luciferase reporter gene assay were used to investigate the effect of miR-23a on sine oculis homeobox homolog 1 (SIX1) expression, and the biological function of SIX1 was analyzed. Additionally, a nude mouse tumorigenicity assay was performed to test the inhibitory effect of miR-23a and Taxol® therapy in endometrial cancer. Finally, immunohistochemistry and RT-qPCR were used to explore the association between miR-23a and SIX1 expression in endometrial cancer tissues. miR-23a was underexpressed in endometrial cancer tissues compared with in para-carcinoma tissues, and the overexpression of miR-23a inhibited proliferation and invasion of endometrial cancer cells. Furthermore, SIX1 was demonstrated to be a downstream target of miR-23a, and miR-23a reduced SIX1 expression. Additionally, SIX1 inversely promoted cell proliferation, migration and invasion. In addition, the effects of reduced cell proliferation and increased cell invasion following miR-23a overexpression could be reversed by adding SIX1 to in vitro culture. Furthermore, the inhibitory effect of miR-23a and Taxol therapy, which reduced SIX1 expression in endometrial cancer, was demonstrated in vivo. Finally, a negative association between miR-23a and SIX1 expression was demonstrated in endometrial cancer tissues. The results of the present study revealed that miR-23a may inhibit endometrial cancer development by targeting SIX1.

[Role of epidermal growth factor signaling system in the pathogenesis of endometriosis under estrogen deprivation conditions].

OBJECTIVE: To study the role of epidermal growth factor (EGF) , epidermal growth factor receptor(EGFR), extracellular signal-regulated kinase 1/2 (p-ERK1/2) in the pathogenesis of endometriosis under estrogen deprivation conditions. METHODS: The estrogen was quickly-stripped in medium and the female nude mice were castrated by bilateral oophorectomy to build estrogen deprivation in vitro and in vivo experimental models, respectively. (1) In vitro experiments:according to different treatments the estrogen deprived ectopic endometrial cells were classified into 4 groups: a. EGF group:the ectopic endometrial cells were cultured for 72 hours with different concentrations of EGF (0.01, 0.1, 1, 10, 50, 100 ng/ml), the results of EGF group were represented by the result of cells treated by 10 ng/ml EGF cultured for 72 hours; b. EGF+PD98059 group:the ectopic endometrial cells were cultured for 72 hours with 5×10(-2) mol/L PD98059 (inhibitor of ERK), followed by a cultivation for 72 hours treated by 10 ng/ml EGF+5×10(-2) mol/L PD98059; c. EGF+ ICI182780 group: the ectopic endometrial cells were cultured for 72 hours with 10(-6) mol/L ICI182780 [inhibitor of estrogen receptor(ER)], followed by a cultivation for 72 hours treated by 10 ng/ml EGF+10(-6) mol/L ICI182780; d. Blank control group:the ectopic endometrial cells were cultured with no treatment. The proliferation activity of ectopic endometrial cells in all groups after treatment were examined by methyl thiazolyl tetrazolium (MTT) method represented by absorbance value (A). The expression of p-ERK1/2 protein were detected by western blot. (2) In vivo experiments: 64 female nude mice were randomly divided into control and castration groups (both n=32) using random number chart. The mice in castration group were castrated by bilateral oophorectomy on 3 weeks after the endometriosis model was established. The levels of EGF, EGFR, p-ERK1/2 protein in ectopic lesions of both groups were measured on 4, 6, 8 and 10 weeks after the endometriosis model was established by western blot. RESULTS: (1) The proliferation activity of ectopic endometrial cells:the proliferation activity of ectopic endometrial cells treated by different concentrations of EGF (0.01, 0.1, 1, 10, 50, 100 ng/ml) for 72 hours were 0.310±0.010, 0.340±0.020, 0.670±0.010, 0.980±0.030, 1.360±0.020, 1.670±0.020, respectively, the proliferation activity was increased along with of EGF concentrations.The proliferation activity was 0.680±0.030 at EGF+ PD98059 group, the differences exhibited significant difference when compared with that at EGF group with 100 ng/ml for 72 hours (P<0.01) .The proliferation activity of EGF+ ICI182780 and blank control groups were 0.330±0.030 and 0.310±0.030, respectively, which did not reached statistical differences (P>0.05). (2) The expression of EGF, EGFR, pERK1/2 protein: a. In vitro experiments:the levels of p-ERK1/2 protein in EGF and blank control groups were 0.670±0.020 and 0.600±0.010, respectively, which reached statistical differences (P<0.05). The level of p-ERK1/2 protein in EGF+ PD98059 group was 0.610±0.020, which exhibited significant differences with that at blank control group (P>0.05). b. In vivo experiments:at 4, 6 and 8 weeks after the endometriosis models were established, the expression of EGF protein in the ectopic lesions of castration group and control group were (0.530±0.015 versus 0.610±0.015), (0.400±0.029 versus 0.620±0.018), (0.560±0.026 versus 0.630±0.021), respectively, the levels of EGFR protein were (0.500±0.030 versus 0.640±0.030), (0.470±0.020 versus 0.630±0.020), (0.510±0.030 versus 0.610±0.020) respectively, and the level of p-ERK1/2 protein were (0.500±0.020 versus 0.580±0.020), (0.490±0.020 versus 0.580±0.020), (0.570±0.020 versus 0.590±0.020), respectively. The difference of EGF, EGFR, p-ERK1/2 protein expression levels between two groups did not exhibited significant difference (P<0.01, P<0.01, P<0.05). At 10 weeks after the endometriosis models were established, the levels of EGF protein in castration group and control group were both 0.620±0.020, the levels of EGFR protein were both 0.610±0.020, and the level of p-ERK1/2 protein were 0.590±0.010 and 0.600±0.020. No statistical difference (P>0.05) was found between those two groups (P>0.05). CONCLUSIONS: EGF could stimulate the proliferation of ectopic endometrial cells by activating the ERK pathway under estrogen deprivation conditions. The inhibition of EGF signaling system in ectopic lesions was alleviated along with the prolongation of the period of estrogen deprivation.

MicroRNA-182 promotes cell growth, invasion, and chemoresistance by targeting programmed cell death 4 (PDCD4) in human ovarian carcinomas.

As an important tumor suppressor, programmed cell death 4 (PDCD4) influences transcription and translation of multiple genes, and modulates different signal transduction pathways. However, the upstream regulation of this gene is largely unknown. In this study, we found that microRNA-182 (miRNA-182, miR-182) was upregulated, whereas PDCD4 was downregulated in ovarian cancer tissues and cell lines. Blocking or increase of miR-182 in ovarian cancer cell lines led to an opposite alteration of endogenous PDCD4 protein level. Using fluorescent reporter assay, we confirmed the direct and negative regulation of PDCD4 by miR-182, which was dependent on the predicted miR-182 binding site within PDCD4 3' untranslated region (3' UTR). MTT and colony formation assays suggested that miR-182 blockage suppressed, whereas miR-182 mimics enhanced viability and colony formation of ovarian cancer cells. These effects may partly be attributed to the cell cycle promotion activity of miR-182. miR-182 also contributed to migration and invasion activities of ovarian cancer cells. Furthermore, miR-182 reduced the chemosensitivity of ovarian cancer cells to CDDP and Taxol, possibly by its anti-apoptosis activity. Importantly, all the alterations of the above cellular phenotypes by blocking or enhancing of miR-182 could be alleviated by subsequent suppression or ectopic expression of its target PDCD4, respectively. We conclude that in ovarian cancer cells, miR-182 acts as an oncogenic miRNA by directly and negatively regulating PDCD4.