TFEB/LAMP2 contributes to PM0.2-induced autophagy-lysosome dysfunction and alpha-synuclein dysregulation in astrocytes.

Atmospheric particulate matter (PM) exacerbates the risk factor for Alzheimer's and Parkinson's diseases (PD) by promoting the alpha-synuclein (α-syn) pathology in the brain. However, the molecular mechanisms of astrocytes involvement in α-syn pathology underlying the process remain unclear. This study investigated PM with particle size <200 nm (PM0.2) exposure-induced α-syn pathology in ICR mice and primary astrocytes, then assessed the effects of mammalian target of rapamycin inhibitor (PP242) in vitro studies. We observed the α-syn pathology in the brains of exposed mice. Meanwhile, PM0.2-exposed mice also exhibited the activation of glial cell and the inhibition of autophagy. In vitro study, PM0.2 (3, 10 and 30 µg/mL) induced inflammatory response and the disorders of α-syn degradation in primary astrocytes, and lysosomal-associated membrane protein 2 (LAMP2)-mediated autophagy underlies α-syn pathology. The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3 (LC3II), cathepsin B (CTSB) and lysosomal abundance increased first and then decreased, which might both be a compensatory mechanism to toxic α-syn accumulation induced by PM0.2. Moreover, with the transcription factor EB (TFEB) subcellular localization and the increase in LC3II, LAMP2, CTSB, and cathepsin D proteins were identified, leading to the restoration of the degradation of α-syn after the intervention of PP242. Our results identified that PM0.2 exposure could promote the α-syn pathological dysregulation in astrocytes, providing mechanistic insights into how PM0.2 increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM0.2 toxicity.

Development and clinical validation of a seven-gene signature based on tumor stem cell-related genes to predict ovarian cancer prognosis.

OBJECTIVE: Tumors are highly heterogeneous, and within their parenchyma, a small population of tumor-stem cells possessing differentiation potential, high oncogenicity, and self-renewal capabilities exists. These cells are pivotal in mediating tumor development, chemotherapy resistance, and recurrence. Ovarian cancer shares characteristics with tumor stem cells, making it imperative to investigate molecular markers associated with these cells. METHODS: Stem cell-related genes were collected, and molecular subtypes were established based on gene expression profiles from The Cancer Genome Atlas using the R package tool "ConsensusClusterPlus." Multi-gene prognostic markers were identified using LASSO regression analysis. Gene set enrichment analysis was employed to gain insights into the potential molecular mechanisms of these identified markers. The robustness of these prognostic markers was analyzed across different cohorts, and their clinical independence was determined through multivariate Cox analysis. A nomogram was constructed to assess the model's clinical applicability. Immunohistochemistry was performed to validate the expression of hub genes. RESULTS: Utilizing 49 tumor stem cell-related genes associated with prognosis, 362 ovarian cancer samples were divided into two distinct clusters, revealing significant prognostic disparities. A seven-gene signature (GALP, CACNA1C, COL16A1, PENK, C4BPA, PSMA2, and CXCL9), identified through LASSO regression, exhibited stability and robustness across various platforms. Multivariate Cox regression analysis confirmed the signature's independence in predicting survival in patients with ovarian cancer. Furthermore, a nomogram combining the gene signature demonstrated strong predictive abilities. Immunohistochemistry results indicated significantly elevated GALP, CACNA1C, COL16A1, PENK, C4BPA, PSMA2, and CXCL9 expression in cancer tissues. CONCLUSION: The seven-gene signature holds promise as a valuable tool for decision-making and prognosis prediction in patients with ovarian cancer.

Association of urinary metal levels with metabolic syndrome in coal workers.

Studies have indicated that metal exposure is associated with an increased risk of metabolic syndrome (MetS). However, it is unclear whether overexposure to heavy metals occurs in miners and is associated with MetS risk remains unclear. In a cross-sectional study, analysis for metal exposure levels of 3428 participants from three types of workplaces was conducted. Relationships between metals in urine and MetS were characterized using a multivariate binary logistic regression model and restricted cubic spline analysis. The association between urinary metals and workplaces with respect to MetS was studied via mediation analysis and multiplicative interaction analysis. And a sensitivity analysis was performed to assess the robustness of the association between MetS and urinary metals in participants without obesity (n = 2811). Zn, Cu, Fe, Co, and Ni were found to be associated with MetS in the single-metal models, whereas only Zn and Cu showed considerable associations in the multimetal model. The odds ratios (95% CI) for MetS in the highest quartiles were 2.089 (1.611, 2.707) for urinary Zn and 1.394 (1.084, 1.794) for urinary Cu (both false discovery rate for both was < 0.05). Urinary Zn and Cu were positively associated with hypertriglyceridemia. In addition, higher Zn exposure was confirmed in underground workers than ground workers and office workers, and there was a significant association between urinary metal exposure and workplace, which together influenced the occurrence of MetS. These results provided scientific evidence for the relationship between Zn, Cu, workplaces, and MetS in coal workers and indicated that it is critical to reduce occupational metal exposure, especially in underground workers.

The role of reactive astrocytes in neurotoxicity induced by ultrafine particulate matter.

Epidemiological studies have shown that ambient fine particulate matter (PM) can cause various neurodegenerative diseases, including Alzheimer's disease. Reactive astrocytes are strongly induced by ambient fine PM, although their role is poorly understood. Herein, we show that A1 reactive astrocytes (A1s) were induced by neuroinflammatory microglia activated by PM with an aerodynamic diameter ≤ 0.2 µm (PM0.2). The activated-microglia induced A1s by secreting interleukin-1α, tumor necrosis factor-α, and complement 1q, and these cytokines acting together were necessary and sufficient to induce A1s. PM0.2-induced A1s could promote synaptic damage in neurons by secreting complement 3 (C3). SB 290157, a highly selective C3aR nonpeptide antagonist, partially ameliorated glial conditioned medium-induced synaptic injury. In vitro synaptic damage was partially prevented when A1 formation was blocked by minocycline. Finally, this study showed that N-acetyl-L-cysteine ameliorated PM0.2-induced neural damage independent of A1 differentiation. Collectively, these findings explain why central nervous system neurons suffer synaptic damage and neuroinflammation after PM0.2 exposure and suggest that this exposure induces A1s to contribute to synaptic damage of neurons. This study indicates a potential approach for developing improved treatment of these diseases induced by particulate exposure. SYNOPSIS: PM0.2-activated neuroinflammatory microglia induced A1 reactive astrocytes (A1s) by secreting IL-1α, TNF-α, and C1q. PM0.2-induced A1s could promote synaptic damage of neuron by secreting complement 3.

Mitigation of tobacco bacteria wilt with microbial degradation of phenolic allelochemicals.

Long-term continuous monoculture cropping of tobacco leads to high incidence of tobacco bacterial wilt (TBW) caused by Ralstonia solanacearum, which threatening world tobacco production and causing great economy loss. In this study, a safe and effective way to control TBW by microbial degradation of phenolic allelochemicals (PAs) was explored. Eleven kinds of PAs were identified from continuous tobacco cropping soil. These PAs exhibited various effects on the growth, chemotaxis and biofilm formation of R. solanacearum. Then we isolated eight strains of Bacillus, one strain of Brucella, one strain of Enterobacter and one strain of Stenotrophomonas capable of degrading these PAs. The results of degradation assay showed that these isolated strains could degrade PAs both in culture solutions and soil. Besides, the incidence of TBW caused by R. solanacearum and deteriorated by PAs were significantly decreased by treating with these degrading strains. Furthermore, six out of eleven isolated strains were combined to degrade all the identified PAs and ultimately sharply reduced the incidence of TBW by 61.44% in pot experiment. In addition, the combined degrading bacteria could promote the plant growth and defense response. This study will provide a promising strategy for TBW control in tobacco production.

Large-cell neuroendocrine carcinoma of the gynecologic tract: Prevalence, survival outcomes, and associated factors.

Background: We aimed to assess the clinical behavior of gynecologic large-cell neuroendocrine carcinoma (LCNEC) via a retrospective analysis of data from 469 patients. Methods: Patients diagnosed with gynecologic LCNEC from 1988 to 2015 were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox hazard regression analyses were performed to assess independent predictors of overall survival (OS) and cancer-specific survival (CSS). OS and CSS were also evaluated using the Kaplan-Meier method, and the effects of different treatment regimens on prognosis were compared according to disease stage. Results: Cervical, ovarian, and endometrial LCNEC were observed in 169, 219, and 79 patients, respectively. The 5-year OS rates for patients with cervical, ovarian, and endometrial LCNEC were 35.98%, 17.84%, and 23.21%, respectively, and the median duration of overall survival was 26, 11, and 11 months in each group. The 5-year CSS rates for the three groups were 45.23%, 19.23%, and 31.39%, respectively, and the median duration of CSS was 41, 12, and 11 months in each group. Multivariate analysis revealed that American Joint Committee on Cancer stage, lymph node metastasis, and chemotherapy were independent prognostic factors for OS and CSS in patients with cervical LCNEC. Lymph node metastasis, surgery, and chemotherapy were independent prognostic factors for OS and CSS in the ovarian group and for OS in the endometrial group. Lymph node metastasis and surgery were also independent prognostic factors for CSS in the endometrial group. Conclusion: Surgery alone may help to improve overall survival and CSS in patients with early-stage cervical LCNEC. In contrast, surgery+chemotherapy and surgery+radiotherapy may help to improve survival in those with early-stage ovarian and endometrial LCNEC, respectively. Regardless of subtype, comprehensive treatment involving surgery, CTX, and RT should be considered to improve prognosis in patients with advanced-stage gynecologic LCNEC.

Multiple Biomarker Simultaneous Detection in Serum via a Nanomaterial-Functionalized Biosensor for Ovarian Tumor/Cancer Diagnosis.

Ovarian tumors/cancers are threatening women's health worldwide, which demands high-performance detection methods and accurate strategies to effectively detect, diagnose and treat them. Here, we report a nanographene oxide particle-functionalized microfluidic fluorescence biosensor to simultaneously detect four biomarkers, CA125, HE4, CEA and APF, for ovarian tumor/cancer diagnosis. The developed biosensor exhibits good selectivity and a large biomarker detection range with a limit of detection of 0.01 U/mL for CA125 and ~1 pg/mL for HE4, CEA and APF. The current results indicate that (1) the proposed biosensor is a promising tool for the simultaneous detection of multiple biomarkers in ovarian tumors/cancer and (2) CA125 and HE4 are strong indicators, AFP may be helpful, and CEA is a weak biomarker for ovarian tumor/cancer diagnosis. The proposed biosensor would be a potential tool, and an analytical approach for the simultaneous detection of multiple biomarkers will provide a new strategy for the early screening, diagnosis and treatment of ovarian tumors/cancers, as well as other cancers.

Environmental enrichment holds promise as a novel treatment for anesthesia-induced neurocognitive disorders.

In recent years, since the need for anesthetic interventions in pregnant women, newborns, and older patients has been increasing, the anesthesia-induced cognitive impairment has received widespread attention and highlighted the urgent requirement for preventive and therapeutic measures with low risk of side effects. Environmental enrichment (EE), a novel and easy-to-implement rehabilitation treatment strategy, exerts its protective potential on the cognitive abilities of developing and aging brains after anesthetic exposure. This review summarizes the improvement of cognition by EE described in recent studies and explores the molecular mechanisms by which EE exerts neuroprotective effects. The literature indicates that the intervention mode, timing, and duration of EE are vital to its effect.

Comparison of Five Prophylactically Intravenous Drugs in Preventing Opioid-Induced Cough: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.

Background: Due to the absence of direct comparisons of different therapeutic drugs in preventing opioid-induced cough (OIC) during the induction of general anesthesia, clinicians often faced difficulties in choosing the optimal drug for these patients. Hence, this network meta-analysis was conducted to solve this problem. Methods: Online databases, including Pubmed, Embase, Web of Science, Cochrane, and Google Scholar, were searched comprehensively to identify eligible randomized controlled trials (RCTs), up to March 15th, 2021. Within a Bayesian framework, network meta-analysis was performed by the "gemtc" version 0.8.2 package of R-3.4.0 software, and a pooled risk ratio (RR) associated with 95% credible interval (CrI) was calculated. Results: A total of 20 RCTs were finally enrolled, and the overall heterogeneity for this study was low to moderate. Traditional pair-wise meta-analysis results indicated that all of the five drugs, namely, lidocaine, ketamine, dezocine, butorphanol, and dexmedetomidine could prevent OIC for four clinical outcomes, compared with the placebo (all p-values < 0.05). Moreover, dezocine had the best effect, compared with that of the other drugs (all p-values < 0.05). Network meta-analysis results suggested that the top three rank probabilities for four clinical outcomes from best to worst were dezocine, butorphanol, and ketamine based on individual/cumulative rank plots and surface under the cumulative ranking curve (SUCRA) probabilities. The node-splitting method indicated the consistency of the direct and indirect evidence. Conclusions: Our results indicated that all of these five drugs could prevent OIC compared with the placebo. Moreover, the top three rank probabilities for four clinical outcomes from best to worst were dezocine, butorphanol, and ketamine. Our results were anticipated to provide references for guiding clinical research, and further high-quality RCTs were required to verify our findings. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021243358].

Resistin Expression in Epithelial Ovarian Cancer promotes the Proliferation and Migration of Ovarian Cancer Cells to Worsen Prognosis.

Background: Epithelial ovarian cancer (EOC) is the most common gynecological cancer in women. Resistin, an inflammatory adipocytokine, is associated with obesity, insulin resistance, and various cancer types. Materials and Methods: We investigated resistin expression in tissues and its association with the clinicopathological characteristics and prognosis of patients with EOC. The SKOV3 and CAOV3 cell lines were treated with exogenous resistin and rapamycin (resistin inhibitor), and the expression of mTOR in SKOV3 and CAOV3 cells was measured. Cell proliferation was measured using the CCK-8 assay. Western blotting analysis was performed to examine the phosphorylation of P70S6K and mTOR. Wound healing and Transwell analyses were conducted to examine the effect of resistin on the migration of SKOV3 and CAOV3 cells. Results: High resistin expression was positively correlated with the pathological grade (P = 0.017) and lymph node metastasis (P = 0.045). However, resistin expression was not correlated with age, FIGO stage, or residual tumor after initial laparotomy (P > 0.05). Cox multivariate analysis showed that resistin expression was an independent factor for determining disease-free survival, whereas lymph node metastasis, resistin expression, and age (≥55 years) were independent factors affecting overall survival. Exogenous resistin induced ovarian cancer cell proliferation, whereas rapamycin had the opposite effect. Resistin promoted the proliferation of ovarian cancer cells via the mTOR signaling pathway and was associated with phosphorylating P70S6K. Furthermore, resistin promoted the migration of ovarian cancer cells. Conclusions: Resistin may promote the occurrence of ovarian cancer and is related to the prognosis of patients. This protein may also affect the proliferation of EOC cells through the mTOR signaling pathway. Therefore, resistin shows potential as a molecular therapeutic target in ovarian cancer.

Study on the Effective Material Basis and Mechanism of Traditional Chinese Medicine Prescription (QJC) Against Stress Diarrhea in Mice.

Stress diarrhea is a major challenge for weaned piglets and restricts pig production efficiency and incurs massive economic losses. A traditional Chinese medicine prescription (QJC) composed of Astragalus propinquus Schischkin (HQ), Zingiber officinale Roscoe (SJ), and Plantago asiatica L. (CQC) has been developed by our laboratory and shows marked anti-stress diarrhea effect. However, the active compounds, potential targets, and mechanism of this effect remain unclear and warrant further investigation. In our study, we verified the bioactive compounds of QJC and relevant mechanisms underlying the anti-stress diarrhea effect through network pharmacology and in vivo experimental studies. After establishing a successful stress-induced diarrhea model, histomorphology of intestinal mucosa was studied, and Quantitative real-time PCR (RT-qPCR) probe was used for the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway to verify the therapeutic effect of QJC on diarrhea. First, using the network pharmacology approach, we identified 35 active components and 130 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in QJC. From among these, we speculated that quercetin, luteolin, kaempferol, scutellarein, and stigmasterol were the main bioactive compounds and assumed that the anti-diarrhea effect of QJC was related to the PI3K-Akt signaling pathway. The RT-qPCR indicated that QJC and its bioactive components increased the expression levels of PI3K and Akt, inhibited the expression of phosphatase and tensin homolog (PTEN), and activated the PI3K-Akt signaling pathway to relieve stress-induced diarrhea. Furthermore, we found that QJC alleviated the pathological condition of small intestine tissue and improved the integrity of the intestinal barrier. Taken together, our study showed that the traditional Chinese medicine QJC, quercetin, luteolin, kaempferol, scutellarein, and stigmasterol alleviated the pathological condition of small intestine tissue and relieved stress-induced diarrhea by increasing the expression levels of PI3K and Akt and inhibiting the expression levels of PTEN.

A peptide CORO1C-47aa encoded by the circular noncoding RNA circ-0000437 functions as a negative regulator in endometrium tumor angiogenesis.

Circular RNAs (circRNAs) are a novel class of widespread noncoding RNAs that regulate gene expression in mammals. Recent studies demonstrate that functional peptides can be encoded by short open reading frames in noncoding RNAs, including circRNAs. However, the role of circRNAs in various physiological and pathological states, such as cancer, is not well understood. In this study, through deep RNA sequencing on human endometrial cancer (EC) samples and their paired adjacent normal tissues, we uncovered that the circRNA hsa-circ-0000437 is significantly reduced in EC compared with matched paracancerous tissue. The hsa-circ-0000437 contains a short open reading frame encoding a functional peptide termed CORO1C-47aa. Overexpression of CORO1C-47aa is capable of inhibiting angiogenesis at the initiation stage by suppressing endothelial cell proliferation, migration, and differentiation through competition with transcription factor TACC3 to bind to ARNT and suppress VEGF. CORO1C-47aa directly bound to ARNT through the PAS-B domain, and blocking the association between ARNT and TACC3, which led to reduced expression of VEGF, ultimately lead to reduced angiogenesis. The antitumor effects of CORO1C-47aa on EC progression suggest that CORO1C-47aa has potential value in anticarcinoma therapies and warrants further investigation.

CACNA1C is a prognostic predictor for patients with ovarian cancer.

BACKGROUND: CACNA1C, as a type of voltage-dependent calcium ion transmembrane channel, played regulatory roles in the development and progress of multiple tumors. This study was aimed to analyze the roles of CACNA1C in ovarian cancer (OC) of overall survival (OS) and to explore its relationships with immunity. METHODS: Single gene mRNA sequencing data and corresponding clinical information were obtained from The Cancer Genome Atlas Database (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Gene set enrichment analysis (GSEA) was used to identify CACNA1C-related signal pathways. Univariate and multivariate Cox regression analyses were applied to evaluate independent prognostic factors. Besides, associations between CACNA1C and immunity were also explored. RESULTS: CACNA1C had a lower expression in OC tumor tissues than in normal tissues (P < 0.001), with significant OS (P = 0.013) and a low diagnostic efficiency. We further validated the expression levels of CACNA1C in OC by means of the ICGC dataset (P = 0.01), qRT-PCR results (P < 0.001) and the HPA database. Univariate and multivariate Cox hazard regression analyses indicated that CACNA1C could be an independent risk factor of OS for OC patients (both P < 0.001). Five significant CACNA1C-related signaling pathways were identified by means of GSEA. As for genetic alteration analysis, altered CACNA1C groups were significantly associated with OS (P = 0.0169), progression-free survival (P = 0.0404), disease-free survival (P = 0.0417) and disease-specific survival (P = 9.280e-3), compared with unaltered groups in OC. Besides, CACNA1C was dramatically associated with microsatellite instability (MSI) and immunity. CONCLUSIONS: Our results shed light on that CACNA1C could be a prognostic predictor of OS in OC and it was closely related to immunity.

LncRNA SOX2OT affects cervical cancer cell growth, migration and invasion by regulating SOX2.

Long non-coding RNA (lncRNA) SOX2 overlapping transcript (SOX2OT) has been shown to play an oncogenic role in diverse cancers, generating eight transcript variants. SOX2 is located in the third intron of SOX2OT. However, the biological function of SOX2OT in cervical cancer and implication with SOX2 remain to be further explored. In this study, we screened the expression pattern of different SOX2OT transcript variants in cervical cancer cells. Interestingly, both high-expression levels of SOX2OT transcript 7 (SOX2OT-7) and SOX2 were detected in C-33A (HPV-) and SiHa (HPV16+) cells. Thus, C-33A and SiHa cells were conducted to investigate the effects of SOX2OT on cell growth, migration and invasion. Finally, rescue experiments were performed to confirm the role of SOX2 in SOX2OT-mediated regulation of cervical cancer progression. The results showed that knockdown of SOX2OT suppressed cell viability, arrested cell cycle and ameliorated migration and invasion ability of C-33A and SiHa cells. Ectopic expression of SOX2OT-7 exacerbated cervical cancer cell proliferation, migration and invasion. In addition, we found that the expression levels and protein stability of SOX2 were positively regulated by SOX2OT. Inhibition of SOX2 could block the malignant phenotypes of C-33A and SiHa cells by SOX2OT-7. In conclusion, these findings indicate that lncRNA SOX2OT contributes to the growth, migration and invasion of cervical cancer cells by modulating SOX2. Importantly, we demonstrate that the transcript SOX2OT-7 may be a novel and promising biomarker for both HPV- and HPV16+ cervical cancer.

B7-H3, B7-H4, Foxp3 and IL-2 expression in cervical cancer: Associations with patient outcome and clinical significance.

The aim of this study was to determine the expression of B7-H3, B7-H4, Foxp3 and IL-2 in cervical cancer tissues, and evaluate the corresponding clinical significance. The expression of B7-H3, B7-H4, Foxp3 and IL-2 in 108 cervical cancer specimens was detected using immunohistochemistry, and their relationship with clinicopathologic parameters was determined. B7-H3, B7-H4 and Foxp3 had high levels of expression in cervical cancer cells (72.22, 80.56, and 91.56%, respectively). B7-H3 levels were only significantly associated with tumor size (P=0.013), while B7-H4, Foxp3 and IL-2 levels were significantly associated with International Federation of Gynecology and Obstetrics (FIGO) stage (P=0.023, 0.014 and 0.036, respectively) and tumor size (P=0.045, 0.010 and 0.021, respectively). Their expression levels were not correlated with age, histologic type, differentiation and lymph node metastasis (all P>0.05). Cox regression multivariate analysis confirmed that B7-H3 or B7-H4 overexpression was an independent prognostic factor. In addition, there were significant positive relationships between the expression of B7-H3 and B7-H4 with Foxp3 (P<0.001). In contrast, the expression of B7-H3 and B7-H4 was negatively correlated with IL-2 (P<0.05). B7-H3, B7-H4 and Foxp3 may be useful biomarkers in patients with cervical cancer for predicting treatment.

A retrospective study of 152 women with vaginal intraepithelial neoplasia.

OBJECTIVE: To analyze the clinical characteristics and treatment of women with vaginal intraepithelial neoplasia (VAIN), as well as HPV prevalence in this population. METHODS: A retrospective review was undertaken of the medical records of women diagnosed with VAIN at a clinic in Shenyang, China, between January 1, 2009, and December 31, 2012. RESULTS: Of the 152 records reviewed, 69 (45.4%) women had low-grade VAIN (VAIN1) and 83 (54.6%) had high-grade VAIN (VAIN2/3). Among 110 patients with an available HPV status, 97 (88.2%) were positive. The predominant HPV types were HPV16, HPV33, HPV81, HPV53, HPV18, HPV58, and HPV66. Previous hysterectomy was documented in 60 (39.5%) patients. Additionally, 80 (52.6%) patients had no history of dysplasia of the lower genital tract. Of patients with VAIN1, 50 (72.5%) were treated by observation only, 31 (62.0%) of whom regressed spontaneously. Of 66 patients with VAIN2, 38 (57.6%) underwent treatment, 14 (36.8%) of whom experienced recurrence or progression. Of 17 patients with VAIN3, 13 (76.5%) underwent treatment, 5 (38.5%) of whom experienced recurrence or progression. CONCLUSION: Evaluation of the entire vagina by colposcopy is warranted in each patient with abnormal cervical screening results. The predominant HPV genotypes among patients with VAIN could be used to establish diagnosis program and develop an HPV vaccine.

Sex-determining region Y-related high mobility group box (SOX)-2 is overexpressed in cervical squamous cell carcinoma and contributes cervical cancer cell migration and invasion in vitro.

Sex-determining region Y-related high mobility group box 2 (SOX-2) is a key pluripotency-associated transcription factor and may be implicated in the pathogenesis of cervical squamous cell carcinoma (SCC). The aim of this study was to explore SOX-2 expression in cervical SCC tissues and to examine whether and how SOX-2 regulates the malignant behaviors of cervical SCC cells in vitro. We here found that SOX-2 expression in the examined cervical SCC tissues was higher than that in the normal cervical and cervical intraepithelial neoplasia (CIN) tissues. Higher protein level of SOX-2 (nuclear positive staining cells ≥50 %) was detected in 34.9 % (29 out of 83 cases) of cervical SCC patients. We also noted that 100 % of well-differentiated and 66.7 % of moderately differentiated cervical SCCs showed lower SOX-2 expression (nuclear positive staining cells <50 %), while 58.8 % of poorly differentiated tumors had higher SOX-2 expression (P < 0.05). Furthermore, the migratory and invasive capabilities of SiHa cervical cancer cells were enhanced when SOX-2 was upregulated whereas suppressed when SOX-2 was downregulated. Also, the phosphorylation levels of protein kinase B (Akt) and extracellular regulated protein kinases (ERK) 1/2 were increased in SOX-2-overexpressed cancer cells but decreased in SOX-2-depleted cells. Additionally, LY294002 (Akt pathway inhibitor) or U0126 (ERK pathway inhibitor) significantly suppressed SOX-2-overexpression-induced migration and invasion in SiHa cells. Our results indicate that differentially expressed SOX-2 is associated with tumor differentiation (P < 0.05) and that SOX-2 contributes to the migratory and invasive behaviors of cervical SCC in vitro.