Synergistic effect of human uterine cervical mesenchymal stem cell secretome and paclitaxel on triple negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer and, despite its adverse effects, chemotherapy is the standard systemic treatment option for TNBC. Since, it is of utmost importance to consider the combination of different agents to achieve greater efficacy and curability potential, MSC secretome is a possible innovative alternative. METHODS: In the present study, we proposed to investigate the anti-tumor effect of the combination of a chemical agent (paclitaxel) with a complex biological product, secretome derived from human Uterine Cervical Stem cells (CM-hUCESC) in TNBC. RESULTS: The combination of paclitaxel and CM-hUCESC decreased cell proliferation and invasiveness of tumor cells and induced apoptosis in vitro (MDA-MB-231 and/or primary tumor cells). The anti-tumor effect was confirmed in a mouse tumor xenograft model showing that the combination of both products has a significant effect in reducing tumor growth. Also, pre-conditioning hUCESC with a sub-lethal dose of paclitaxel enhances the effect of its secretome and in combination with paclitaxel reduced significantly tumor growth and even allows to diminish the dose of paclitaxel in vivo. This effect is in part due to the action of extracellular vesicles (EVs) derived from CM-hUCESC and soluble factors, such as TIMP-1 and - 2. CONCLUSIONS: In conclusion, our data demonstrate the synergistic effect of the combination of CM-hUCESC with paclitaxel on TNBC and opens an opportunity to reduce the dose of the chemotherapeutic agents, which may decrease chemotherapy-related toxicity.

Expression of E-Cadherin and N-Cadherin in the Endocervix as a Predictive Factor in Patients with Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecological malignancy. This study aimed to evaluate the expression of E-cadherin and N-cadherin in primary endometrial lesions and the endocervix in patients with EC to identify noninvasive predictive factors. In this single-center retrospective study, data on 101 patients who underwent surgery for EC were collected. The immunohistochemical expression of E-cadherin and N-cadherin was assessed depending on the tumor grade, location, and cell differentiation. Correlations between E-cadherin and N-cadherin levels in the endocervix and the primary tumor were determined. The degree of histological tumor differentiation significantly affected E-cadherin expression (p = 0.04) but had no impact on N-cadherin levels. In type II EC, the expression of both cadherins in the tumor tissue differed from their endocervical levels. The expression of E-cadherin differed significantly between the endocervix (p < 0.001) and the tumor (p = 0.001), depending on the type of EC. The expression of E-cadherin was related to the N-cadherin level only in the endocervix in patients with type II EC (p = 0.02). E-cadherin and N-cadherin were expressed in the endocervix in patients with EC. The expression of cadherins, determined during cervical cytology, may be a valuable clinical marker of EC.

Immunohistochemical characterization of integrin alfa 6 in uterus and cervix of the cynomolgus monkeys (Macaca fascicularis) with MfPV3 infection.

BACKGROUND: Cervical cancer is an abnormal growth of cervical tissue epithelial cells due to persistent human papilloma virus (HPV) infection. Cynomolgus monkeys (Macaca fascicularis) can be naturally and spontaneously infected with M. fascicularis Papillomavirus Type 3 (MfPV3), a virus that is phylogenetically closely related to human oncogenic HPV (HPV-16 and HPV-34), and therefore a potentially beneficial for modeling HPV disease. This study aims to evaluate the expression of the integrin alpha 6 (ITGα6) receptor in cynomolgus monkeys spontaneously infected with MfPV3, which this receptor also found in human infected with HPV. METHODS: The study was done on archived Formalin-fixed Paraffin-Embedded (FFPE) samples of uterine and cervix tissue of cynomolgus monkeys. Immunohistochemistry was also performed to quantify the expression levels of ITGα6. RESULTS: The results showed 80% of the samples positive Cervical Intraepithelial Neoplasia (CIN) and increased expression of ITGα6 significantly in Positive-MfPV3 group than negative-MfPV3 group. CONCLUSIONS: This indicated the potential of cynomolgus monkeys as a spontaneous oncogenesis model of PV infection type.

Effects of commonly used carbamates (carbaryl and thiram) on the regulatory, secretory and motor functions of bovine cervixes in vitro.

Previously studied classes of pesticides, including organochlorines, organophosphates and pyrethroids disturb the mechanism that causes bovine myometrial contractions. Hence, the aim of this study was to investigate the effects of carbaryl and thiram, which are representative carbamate pesticides commonly used in global agriculture, on the motor and secretory functions of bovine cervixes. Additionally, the impacts of these pesticides on intra- and intercellular signaling in vitro were estimated. In this study, cervical cells or strips were obtained from cows at days 18-20 of the estrous cycle and were treated with carbaryl or thiram. Neither carbamate (10 or 100 ng/ml) exerted cytotoxic effects. Carbaryl increased the level of mRNA (at a dose of 0.1 ng/ml) and protein (at both doses, 1 and 10 ng/ml) expression for the oxytocin receptor (OXTR), while thiram (at 0.1 and 10 ng/ml or 0.1-10 ng/ml, respectively) caused the opposite effects. Moreover, the level of the second messenger inositol-trisphosphate (IP3) was decreased by carbaryl (10 ng/ml) but increased by thiram (10 ng/ml). Only thiram decreased prostaglandin-endoperoxide synthase 2 (PTGS2; 0.1 ng/ml) and aldo-keto reductase family 1, member B1 (AKR1B1; 0.1 ng/ml), and prostaglandin E synthase 2 (PTGES2; 0.1-10 ng/ml) mRNA expression, while thiram (0.1-10 ng/ml) and carbaryl (0.1 and 10 ng/ml) both decreased the release of PGF2α. Carbaryl (10 ng/ml) and thiram (10 ng/ml) also decreased the level of a gap junction protein (GAP). Moreover, carbaryl (10 ng/ml) decreased the level of myosin light chain kinase (MLCK). However, the strength of cervical contractions was increased by thiram (1 and 10 ng/ml) but decreased by carbaryl (1 and 10 ng/ml). Carbaryl increased the receptivity of cervical cells to oxytocin (OXT), but inhibited further transduction (IP3) of this signal. Hence, direct inhibition of cervical strip contraction may occur. In contrast, thiram mostly decreased the receptivity of cervical cells to OXT, while it stimulated the contraction of cervical strips. Moreover, compared to carbaryl, thiram more greatly affected the synthesis and release of prostaglandins. These results suggest that carbaryl and thiram disturb OXT signaling, PG secretion and cervical contraction in vitro.

Clonal Origin and Lineage Ambiguity in Mixed Neuroendocrine Carcinoma of the Uterine Cervix.

Small-cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare disease characterized by a high incidence of mixed tumors with other types of cancer. The mechanism underlying this mixed phenotype is not well understood. This study established a panel of organoid lines from patients with SCNEC of the cervix and ultimately focused on one line, which retained a mixed tumor phenotype, both in vitro and in vivo. Histologically, both organoids and xenograft tumors showed distinct differentiation into either SCNEC or adenocarcinoma in some regions and ambiguous differentiation in others. Tracking single cells indicated the existence of cells with bipotential differentiation toward SCNEC and adenocarcinomas. Single-cell transcriptional analysis identified three distinct clusters: SCNEC-like, adenocarcinoma-like, and a cluster lacking specific differentiation markers. The expression of neuroendocrine markers was enriched in the SCNEC-like cluster but not exclusively. Human papillomavirus 18 E6 was enriched in the SCNEC-like cluster, which showed higher proliferation and lower levels of the p53 pathway. After treatment with anticancer drugs, the expression of adenocarcinoma markers increased, whereas that of SCNEC decreased. Using a reporter system for keratin 19 expression, changes in the differentiation of each cell were shown to be associated with the shift in differentiation induced by drug treatment. These data suggest that mixed SCNEC/cervical tumors have a clonal origin and are characterized by an ambiguous and flexible differentiation state.

γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids.

Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αß T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids. To identify the underlying pathways involved in this observed cytotoxicity, we performed bulk-RNA sequencing on the organoid lines, revealing differences in DNA-damage and cell cycle checkpoint pathways, as well as transcription of potential γδ T cell ligands. We validated these results using immunoblotting and flow cytometry. We also demonstrated the involvement of BTN3A1 and BTN2A1, crucial molecules for γδ T cell activation, as well as differential expression of PDL1/CD274 in cancer, E6/E7+ and healthy organoids. Interestingly, we observed a significant reduction in cytotoxicity upon blocking MSH2, a protein involved in DNA mismatch-repair. In summary, we established a co-culture system of γδ T cells with cervical cancer organoids, providing a novel in vitro model to optimize innovative patient-specific immunotherapies for cervical cancer.

Novel Complex of Zinc (II) Dichloroethylenediamine: Synthesis, Characterization, In-silico, and In-vitro Evaluation against Cervical Cancer Cells.

OBJECTIVE: Cervical cancer is a malignancy originating from the cervix and often caused by oncogenic Human Papilloma Virus (HPV), specifically subtypes 16 and 18. Anticancer drugs are chemotherapeutic compounds used for cancer treatment. Therefore, this research aims to synthesize and characterize Zinc (II) dichloroethylenediamine (Zn(en)Cl2) complex, as well as determine its antiproliferative activity against HeLa cells. The Zn(en)Cl2 complex was successfully synthesized, and the antiproliferative activity was tested. METHODS: The synthesis involved reacting ethylenediamine and KCl with Zn metal. The complex formed was characterized using a conductometer, UV-Vis spectroscopy, FT-IR spectroscopy, and XRD, while the activity was measured against HeLa cells. RESULT: The synthesis yielded a 56.12% conversion with a melting point of 198-200 oC and a conductivity value of 2.02 mS/cm. The Zn(en)Cl2 complex showed potential activity against HeLa cells with an IC50 value of 898.35 µg/mL, which was evidenced by changes in the morphological structure of HeLa cells. Its interaction with DNA targets was investigated by employing molecular docking. CONCLUSION: The observed data indicated that the Zn(en)Cl2 complex bound to DNA at the nitrogenous base Guanine (DG) by coordinate covalent bonds. Interestingly, DG maintained interaction with the complex until the end of the docking simulation. Additionally, molecular dynamics (MD) simulation was conducted, and the results showed that Zn(en)Cl2 remained bound to the DNA binding pocket all through the process.

Increased Gene Expression of C1orf74 Is Associated with Poor Prognosis in Cervical Cancer.

C1orf74, also known as URCL4, has been reported to have higher expression and be associated with poor prognosis in lung adenocarcinoma patients, and its role in regulation of the EGFR/AKT/mTORC1 pathway has been recently elucidated. In the current study, we used publicly available data and experimental validation of C1orf74 gene expression and its association with prognosis in cervical cancer patients. qRT-PCR was performed using RNA from cervical cancer cell lines and twenty-five cervical cancer patients. Data from TNMplot revealed that mRNA expression of the C1orf74 gene in primary tumor tissues, as well as metastatic tissues from cervical cancer patients, was significantly higher compared to normal cervical tissues. HPV-positive tumors had higher expression of this gene compared to HPV-negative tumors. qPCR analysis also demonstrated higher expression of C1orf74 in HPV-positive cervical cancer cell lines and most cervical cancer patients. The promoter methylation levels of the C1orf74 gene in cervical cancer tissues were lower compared to normal cervical tissues (p < 0.05). Collectively, our study indicates that higher expression of the C1orf74 gene caused by hypomethylation of its promoter is associated with poor overall survival in cervical cancer patients. Thus, C1orf74 is a novel prognostic marker in cervical cancer.

Evaluation of changes of apelin and apelin receptor (APJ) expression in cervix-uterus and placental axis in an LPS-induced preterm labor model.

Although preterm birth is among the preventable causes of maternal and infant death, its mechanism has not yet been clarified. When evaluated in terms of the results, the psycho-social burden of mother-infant losses and the costs of rehabilitation, care, and treatment for postpartum sequelae are high. When evaluated in terms of its causes, infection/inflammation has an important place. Therefore, it is essential to understand the role of pro- and anti-inflammatory proteins in the process. In our study, apelin and apelin receptor (APJ) expression in the cervix-uterus and placental axis were evaluated at tissue and protein levels in pregnant and non-pregnant control, sham, PBS, and LPS groups in the infection model in which LPS induction was performed by midline laparotomy, in CD-1 mice. The evaluation of this axis regarding apelin and apelin receptor in the preterm birth model is new in the literature. Apelin is expressed more intensely in uterine epithelial cells than in the cervix. In the placenta, expression is more intense in the junctional zone compared to other zones. Apelin protein levels decrease significantly in the cervix and placenta whereas it increases in the uterus. While no change was observed in the expression of the apelin receptor at the tissue and protein level in the cervix and uterus, it increased in both aspects in the placenta in the invasive procedure groups. We propose that the decrease in apelin protein due to LPS in the preterm delivery model may be related to the effort to compensate for the balance deteriorated in the pro-inflammatory direction with post-transitional modification at the tissue level. The tendency of apelin to increase with pregnancy has led to the conclusion that it is necessary for a healthy pregnancy. Although the apelin receptor does not change with inflammation, it is necessary to investigate the mechanisms associated with its stress and trauma-induced increase, since it increases in the invasive procedure group.

Impact of bisphenol A on cell viability and inflammatory cytokine production in human cervical epithelial cells.

PROBLEM: An intact cervix is a barrier that prevents pathogenic bacteria from invading the uterine and amniotic cavity during pregnancy. Its disruption is associated with ascending infection and adverse pregnancy outcomes. This study analyzed the effects of bisphenol A (BPA), a chemical used in plastics manufacturing, on cell death and inflammation in cervical epithelial cells. METHODS: Ectocervical epithelial (ecto) and endocervical epithelial (endo) cells were treated with 100 ng/mL and 300 ng/mL of BPA for 48 h. The cells were subjected to flow cytometry using annexin V and propidium iodide to determine apoptosis and necrosis, cell cycle analysis, and ELISA to determine the levels of inflammatory cytokines (IL-6, IL-8, and IL-10). RESULTS: Low-dose and high-dose BPA significantly increased the live ecto cell population dose-dependently. BPA did not have any noticeable effect on cell cycle progression in either cell type. BPA treatment also decreased the apoptotic ecto and endo cell population dose-dependently. Lastly, high dose BPA significantly increased IL-6 in ecto and endo cells. However, IL-8 and IL-10 were not affected by BPA treatments. CONCLUSION: Chemical exposure damage to the cervix can lead to adverse pregnancy outcomes. Our study showed that the BPA concentrations reported in pregnant subjects do not induce cervical cell toxicity . The decrease in apoptosis and increase in live cells may be a compensatory mechanism to preserve the integrity of the cervical epithelial layer.

Expression of Stemness Markers in the Cervical Smear of Patients with Cervical Insufficiency.

The presence of stem cells has been previously described in human precancerous and malignant cervical cultures. Previous studies have shown a direct interplay of the stem cell niche, which is present in practically every tissue with the extracellular matrix. In the present study, we sought to determine the expression of stemness markers in cytological specimens collected from the ectocervix among women with cervical insufficiency during the second trimester of pregnancy and women with normal cervical length. A prospective cohort of 59 women was enrolled of whom 41 were diagnosed with cervical insufficiency. The expression of OCT-4 and NANOG was higher in the cervical insufficiency group compared to the control group (-5.03 (-6.27, -3.72) vs. -5.81 (-7.67, -5.02) p = 0.040 for OCT4) and (-7.47 (-8.78, -6.27) vs. -8.5 (-10.75, -7.14), p = 0.035 for NANOG. Differences in the DAZL gene were not significantly different (5.94 (4.82, 7.14) vs. 6.98 (5.87, 7.43) p = 0.097). Pearson correlation analysis indicated the existence of a moderate correlation of OCT-4 and Nanog with cervical length. Considering this information, the enhanced activity of stemness biomarkers among pregnant women diagnosed with cervical insufficiency may be predisposed to cervical insufficiency, and its predictive accuracy remains to be noted in larger population sizes.

Quantitative cervicovaginal fetal fibronectin as a predictor of cervical ripening and induced labour duration in late-term pregnancy.

We evaluated quantitative cervicovaginal foetal-fibronectin as a predictor of cervical ripening and labour duration in late-term pregnant women with an unfavourable cervix. This was an analytical cross-sectional study wherein 152 women, with late-term pregnancy and unfavourable cervix, at 41weeks3days gestational age, had pre-induction quantitative cervicovaginal foetal-fibronectin determined using ELISA. Data were compared in nulliparas and multiparas at a significance level < 0.05. The mean age of late-term pregnant women was 30.4 ± 4.3 years. Median cervicovaginal foetal-fibronectin levels in nulliparous and multiparous women were 45.35 ng/ml and 46.93 ng/ml respectively(p = 0.289). The correlation between foetal-fibronectin levels and cervical ripening duration was poor in nulliparous(r = 0.014) and multiparous(r = 0.024) women. The Youden's foetal-fibronectin cut-off level had a sensitivity of 53.5% and specificity of 71.6% in predicting cervical ripening duration of > 12 hours in late-term pregnancy with an area under the ROC curve of 0.634. Quantitative cervicovaginal foetal-fibronectin is a poor correlate and predictor of cervical ripening and induced labour duration in late-term pregnancy.IMPACT STATEMENTWhat is already known on this subject? Cervicovaginal foetal fibronectin is useful in the prediction of preterm delivery but its role in prolonged pregnancy is unclear.What the results of this study add? Cervicovaginal foetal fibronectin is a poor correlate and predictor of cervical ripening and induced labour duration in late-term pregnancyWhat the implications are of these findings for clinical practice and/or further research? Cervicovaginal fibronectin should not be used to predict ease and success of cervical ripening and induction of labour in women with late-term pregnancy.

Hormonal regulation of non-cystic fibrosis transmembrane conductance regulator ion channels in the endocervix.

OBJECTIVE: To characterize ion channel expression and localization in the endocervix under different hormonal conditions using a nonhuman primate primary endocervical epithelial cell model. DESIGN: Experimental. SETTING: University-based, translational science laboratory. INTERVENTIONS: We cultured and treated conditionally reprogrammed primary rhesus macaque endocervix cells with estradiol and progesterone and measured gene expression changes for several known ion channel and ion channel regulators of mucus secreting epithelia. Using both rhesus macaque endocervical samples and human samples, we localized channels in the endocervix using immunohistochemistry. MAIN OUTCOME MEASURES: The relative abundance of transcripts was evaluated using real-time polymerase chain reaction. Immunostaining results were evaluated qualitatively. RESULTS: Compared with controls, we found that estradiol increased gene expression for ANO6, NKCC1, CLCA1, and PDE4D. Progesterone down-regulated gene expression for ANO6, SCNN1A, SCNN1B, NKCC1, and PDE4D (P≤.05). Immunohistochemistry confirmed endocervical cell membrane localization of ANO1, ANO6, KCNN4, LRR8CA, and NKCC1. CONCLUSIONS: We found several ion channels and ion channel regulators that are hormonally sensitive in the endocervix. These channels, therefore, may play a role in the cyclic fertility changes in the endocervix and could be further investigated as targets for future fertility and contraceptive studies.

PDHB-AS suppresses cervical cancer progression and cisplatin resistance via inhibition on Wnt/ß-catenin pathway.

Cervical cancer (CC) is the most prevalent gynecological malignancy occurring in the cervix. Long non-coding RNAs (lncRNAs) can act as oncogenes or anti-oncogenes in CC development. Here, we investigated the functional role and detailed mechanism of lncRNA pyruvate dehydrogenase E1 subunit beta antisense (PDHB-AS) in CC. At first, we found that PDHB-AS was significantly down-regulated in CC cells. Besides, overexpression of PDHB-AS repressed CC cell malignant behaviors. HKF-derived exosomes carried miR-4536-5p to CC cells and thereby inhibited PDHB-AS expression. Moreover, PDHB-AS inactivated the Wnt/ß-catenin pathway via impeding the nuclear translocation of ß-catenin in CC cells. In addition, miR-582-5p could bind with both PDHB-AS and Dickkopf-1 (DKK1). PDHB-AS recruited poly(A) binding protein cytoplasmic 1 (PABPC1) to inhibit Wnt7b expression. PDHB-AS interacted with RNA-binding motif protein X-linked (RBMX) to regulate cisplatin resistance in CC. Finally, we conducted in vivo experiments to confirm that HKF promoted CC tumor growth whereas PDHB-AS suppressed CC tumor growth. Collectively, PDHB-AS plays a tumor-suppressive role in the progression of CC, which suggests the therapeutic potential of PDHB-AS for CC.

Cervix Abscess Mimicking Cervical Cancer Explored With 18 F-FDG PET/CT and MRI.

ABSTRACT: We report the case of a 32-year-old woman gravida 2 para 2 with pelvic pain evolving for 2 months, who underwent imaging examinations, including 18 F-FDG PET/CT and MRI, which showed a tumor-like cervix tissular mass with pathological lymph nodes and pelviperitonitis. An endocervical curettage with conization revealed a bacterial infection with cervical abscess and without neoplastic component. The follow-up 18 F-FDG PET/CT 3 months after starting antibiotherapy confirmed a complete metabolic and morphological response of the cervical abscess.

The immunolocalization of cadherins and beta-catenin in the cervix and vagina of cycling cows.

The adherens junctions (AJs) maintain the epithelial cell layers' structural integrity and barrier function. AJs also play a vital role in various biological and pathological processes. AJs perform these functions through the cadherin-catenin adhesion complex. This study investigated the presence, cell-specific localization, and temporal distribution of AJ components such as classical type I cadherins and beta-catenin in the cow cervix and vagina during the estrous cycle. Immunohistochemistry and Western blot analysis results demonstrated that beta-catenin and epithelial (E)-, neural (N)-, and placental (P)-cadherins are expressed in the cow cervix and vagina during the estrous cycle. These adhesion molecules were localized in the membrane and cytoplasm of the ciliated and non-ciliated cervical cells and the stratified vaginal epithelial cells. Positive immunostaining for P-, N-cadherin, and beta-catenin was also observed in the vascular endothelial cells of the cervical and vaginal stroma. Quantitative immunohistochemistry examinations revealed that in the cervical and vaginal epithelia, P-cadherin's optical density values (ODv) were the highest; in contrast, the N-cadherin ODv were the lowest. The ODv of P-cadherin and beta-catenin in the cervical epithelium and E-cadherin in the vagina were significantly higher in the luteal phase versus the follicular phase of the estrous cycle. Furthermore, the ODv of P-cadherin, N-cadherin, and beta-catenin in the cervix's central and peripheral epithelial regions were different during the estrous cycle. These findings indicate that classical cadherins and beta-catenin in the cervix and vagina exhibit cell- and tissue-specific expression patterns under the influence of estrogen and progesterone hormones during the estrous cycle.

Endometriosis of the Cervix: A Rare Clinical Case with the Possibility of Comparing the Eutopic and Ectopic Endometrium at the Cellular Level.

Endometriosis of the cervix is a rare form of genital endometriosis, which is characterized by the appearance of tissue on the vaginal part of the cervix, similar to the tissue of the mucous membrane of the uterine cavity. We describe a clinical case in which we compared the content of cytoskeletal proteins, H3 histone modifications and DNA methylation (total and 5-hydroxymethylcytosine content) in the eutopic endometrium and in tissue from endometriosis foci on the cervix. The patient had elevated levels of estradiol, interleukin-1ß and interleukin-8. At the cellular level, the content of tubulin and the marker of stable microtubules were reduced in the ectopic endometrium (by 45% and 37%, p < 0.05, respectively), but the alpha-actinin-1 content was increased (by 75%, p < 0.05) with an increase in the expression of its gene. At the same time, the total level of DNA methylation in the endometriotic focus was reduced by more than 2 times with the accumulation of the intermediate product 5-hydroxymethylcytosine (the content increased by more than 3 times), probably due to an increase in the content of tet methylcytosine dioxygenase 1 (more than 4 times).

KNTC1, regulated by HPV E7, inhibits cervical carcinogenesis partially through Smad2.

Cervical cancer is the second most common malignancy of the female reproductive tract worldwide. Although cervical cancer is caused by human papillomavirus (HPV) infection, its underlying pathogenesis requires further investigation. The present study investigated the role of kinetochore associated protein 1 (KNTC1) in cervical cancer and its association with the key virus oncoprotein, HPV E7. A series of bioinformatic analyses revealed that KNTC1 might be involved in the tumorigenesis of multiple human malignancies, including cervical cancer. Tissue microarray analysis showed that in vivo KNTC1 expression was higher in high-grade squamous intraepithelial lesions (HSILs) than in normal cervix and even higher in cervical cancer. In vitro silencing of KNTC1 increased the proliferation, invasion and migration of cervical cancer cell lines. Although not affecting apoptosis, KNTC1 silencing significantly promoted G1/S phase transition of the cell cycle. High-throughput analysis of mRNA expression showed that KNTC1 could regulate its downstream target protein Smad2 at the transcriptional level. Moreover, as the key oncoprotein of the virus, HPV E7 could inhibit the expression of KNTC1 protein, and decrease Smad2 protein expression with or without the aid of KNTC1. These results indicated that KNTC1 is a novel tumor suppressor that can impede the initiation and progression of cervical carcinoma, providing insight into the molecular mechanism by which HPV induces cervical cancer.

hnRNP K induces HPV16 oncogene expression and promotes cervical cancerization.

PURPOSE: This study aims to explore the expression of hnRNP K in cervical carcinogenesis and to investigate the regulatory role of hnRNP K on HPV16 oncogene expression as well as biological changes in cervical cancer cells. METHODS: In total 1042 subjects, including 573 with the normal cervix and 469 with different grades of cervical lesions were enrolled in this study to explore the association between hnRNP K and HPV16 oncogene expression in cervical carcinogenesis. Additionally, the Gene Omnibus (GEO) database was used to analyze hnRNP K mRNA expression in cervical cancerization. Meanwhile, the effects of hnRNP K on cell biological functions and HPV16 oncogene expression were investigated in Siha cells. Moreover, Function analyses were conducted using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases after ChIP-seq. RESULTS: hnRNP K was highly expressed in cervical cancer and precancerous lesions, and positively correlated with HPV16 E6, but negatively correlated with HPV16 E2 and HPV16 E2/E6 ratio. hnRNP K induced cell proliferation, inhibited apoptosis and caused cell cycle arrest in the S phase, and particularly increased HPV16 E6 protein expression. CONCLUSION: This study revealed that hnRNP K overexpression has important warning significance for the malignant transformation of cervical lesions, and could be used as a potential therapeutic target for inhibiting the carcinogenicity of HPV16 and prevention of cervical carcinogenesis.

Research Progress in the Relationship Between P2X7R and Cervical Cancer.

Cervical cancer is one of the most common and serious tumors in women. Finding new biomarkers and therapeutic targets plays an important role in the diagnosis, prognosis, and treatment of cervical cancer. Purinergic ligand-gated ion channel 7 receptor (P2X7R) is a purine ligand cation channel, activated by adenosine triphosphate (ATP). Studies have shown that P2X7R plays an important role in a variety of diseases and cancers. More and more studies have shown that P2X7R is also closely related to cervical cancer; therefore, the role of P2X7R in the development of cervical cancer deserves further discussion. The expression level of P2X7R in uterine epithelial cancer tissues was lower than that of the corresponding normal tissues. P2X7R plays an important role in the apoptotic process of cervical cancer through various mechanisms of action, and both antagonists and agonists of P2X7R can inhibit the proliferation of cervical cancer cells, while P2X7R is involved in the antitumor effect of Atr-I on cervical cancer cells. This review evaluates the current role of P2X7R in cervical cancer in order to develop more specific therapies for cervical cancer. In conclusion, P2X7R may become a biomarker for cervical cancer screening, and even a new target for clinical treatment of cervical cancer.