Investigating the potential of Juglans regia phytoconstituents for the treatment of cervical cancer utilizing network biology and molecular docking approach.

The fourth most frequent type of cancer in women and the leading cause of mortality for females worldwide is cervical cancer. Traditionally, medicinal plants have been utilized to treat various illnesses and ailments. The molecular docking method is used in the current study to look into the phytoconstituents of Juglans regia's possible anticancer effects on cervical cancer target proteins. This work uses the microarray dataset analysis of GSE63678 from the NCBI Gene Expression Omnibus database to find differentially expressed genes. Furthermore, protein-protein interactions of differentially expressed genes were constructed using network biology techniques. The top five hub genes (IGF1, FGF2, ESR1, MYL9, and MYH11) are then determined by computing topological parameters with Cytohubba. In addition, molecular docking research was performed on Juglans regia phytocompounds that were extracted from the IMPPAT database versus hub genes that had been identified. Utilizing molecular dynamics, simulation confirmed that prioritized docked complexes with low binding energies were stable.

Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer.

BACKGROUND: The intriguing connection between selenium and cancer resembles a captivating puzzle that keeps researchers engaged and curious. While selenium has shown promise in reducing cancer risks through supplementation, its interaction with epigenetics in cervical cancer remains a fascinating yet largely unexplored realm. Unraveling the intricacies of selenium's role and its interaction with epigenetic factors could unlock valuable insights in the battle against this complex disease. RESULT: Selenium has shown remarkable inhibitory effects on cervical cancer cells in various ways. In in vitro studies, it effectively inhibits the proliferation, migration, and invasion of cervical cancer cells, while promoting apoptosis. Selenium also demonstrates significant inhibitory effects on human cervical cancer-derived organoids. Furthermore, in an in vivo study, the administration of selenium dioxide solution effectively suppresses the growth of cervical cancer tumors in mice. One of the mechanisms behind selenium's inhibitory effects is its ability to inhibit histone demethylases, specifically JMJD3 and UTX. This inhibition is observed both in vitro and in vivo. Notably, when JMJD3 and UTX are inhibited with GSK-J4, similar biological effects are observed in both in vitro and in vivo models, effectively inhibiting organoid models derived from cervical cancer patients. Inhibiting JMJD3 and UTX also induces G2/M phase arrest, promotes cellular apoptosis, and reverses epithelial-mesenchymal transition (EMT). ChIP-qPCR analysis confirms that JMJD3 and UTX inhibition increases the recruitment of a specific histone modification, H3K27me3, to the transcription start sites (TSS) of target genes in cervical cancer cells (HeLa and SiHa cells). Furthermore, the expressions of JMJD3 and UTX are found to be significantly higher in cervical cancer tissues compared to adjacent normal cervical tissues, suggesting their potential as therapeutic targets. CONCLUSIONS: Our study highlights the significant inhibitory effects of selenium on the growth, migration, and invasion of cervical cancer cells, promoting apoptosis and displaying promising potential as a therapeutic agent. We identified the histone demethylases JMJD3 and UTX as specific targets of selenium, and their inhibition replicates the observed effects on cancer cell behavior. These findings suggest that JMJD3 and UTX could be valuable targets for selenium-based treatments of cervical cancer.

The potential mechanism of Guizhi Fuling Wan effect in the treatment of cervical squamous cell carcinoma: A bioinformatics analysis investigation.

As a global malignancy with high mortality rate, targeted drug development for Uterine Cervical Neoplasms is an important direction. The traditional formula Guizhi Fuling Wan (GFW) is widely used in gynecological diseases. However, its potential mechanism of action remains to be discovered. We retrieved GFW and cervical squamous cell carcinoma (CSCC) targets from public databases. The protein-protein interaction network was obtained by string computational analysis and imported Cytoscape_v3.9.0 to obtain the core network and the top 10 Hub genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for enrichment analysis of the core network, and then molecular docking to verify whether the selected signaling pathway binds well to the core node. Finally, clinical prognostic analysis and expression differences of Hub genes were validated using the Cancer Genome Atlas database and R language. Our search yielded 152 common targets for GFW and CSCC. The interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and Toll-like signaling pathway were then selected for further molecular docking from the hub genes enrichment analysis results, which showed good binding. Among the Hub genes, JUN, VEGFA, IL1B, and EGF had a poor prognosis for CSCC. In conclusion, this study illustrates that GFW can have adjuvant therapeutic effects on CSCC through multiple targets and multiple pathways, providing a basis for further research.

miR-638 suppresses cervical cancer progression by inhibiting NCAPG2 under the treatment of Tetrandrine.

BACKGROUND: The interaction of microRNA with Chinese herbal medicines is a promising therapeutic approach for prevention of cervical cancer. METHODS: Western blotting or qRT-PCR were carried out to identify the expression of NCAPG2 and miR-638. A tetrandrine (TET) cell model was used to explore the effects of miR-638 and its target gene NCAPG2 using CCK-8, transwell, wound healing, and western blot assays. Furthermore, luciferase activity assay was conducted to measure the interaction among TET, NCAPG2 and miR-638. RESULTS: Under TET treatment, Hela and SiHa cells exhibited repressed cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT), and these effects were further enhanced by high expression of miR-638. In contrast, NCAPG2 expression was low in TET-treated cells and had an opposite effect to that of miR-638. CONCLUSION: We highlighted that miR-638 suppresses cervical cancer progression by inhibiting NCAPG2 under tetrandrine treatment.

SLC5A3 is important for cervical cancer cell growth.

Novel molecular targets for cervical cancer must be identified. This study examined the role of SLC5A3, a myo-inositol transporter, in the pathogenesis of cervical cancer. Through boinformatics analysis, we showed that the SLC5A3 mRNA levels were upregulated in cervical cancer tissues. The upregulated SLC5A3 mRNA levels were negatively correlated with survival and progression-free interval. Genes co-expressed with SLC5A3 were enriched in multiple signaling cascades involved in cancer progression. In primary/established cervical cancer cells, SLC5A3 shRNA/knockout (KO) exerted growth-inhibitory effects and promoted cell death/apoptosis. Furthermore, SLC5A3 knockdown or KO downregulated myo-inositol levels, induced oxidative injury, and decreased Akt-mTOR activation in cervical cancer cells. In contrast, supplementation of myo-inositol or n-acetyl-L-cysteine or transduction of a constitutively active Akt1 construct mitigated SLC5A3 KO-induced cytotoxicity in cervical cancer cells. Lentiviral SLC5A3 overexpression construct transduction upregulated the cellular myo-inositol level and promoted Akt-mTOR activation, enhancing cervical cancer cell proliferation and migration. The binding of TonEBP to the SLC5A3 promoter was upregulated in cervical cancer. In vivo studies showed that intratumoral injection of SLC5A3 shRNA-expressing virus arrested cervical cancer xenograft growth in mice. SLC5A3 KO also inhibited pCCa-1 cervical cancer xenograft growth. The SLC5A3-depleted xenograft tissues exhibited myo-inositol downregulation, Akt-mTOR inactivation, and oxidative injury. Transduction of sh-TonEBP AAV construct downregulated SLC5A3 expression and inhibited pCCa-1 cervical cancer xenograft growth. Together, overexpressed SLC5A3 promotes growth of cervical cancer cells, representing as a novel therapeutic oncotarget for the devastating disease.

Microwave hyperthermia represses human papillomavirus oncoprotein activity and induces cell death due to cell stress in 3D tissue models of anogenital precancers and cancers.

BACKGROUND: Hyperthermia is a well-accepted cancer therapy. Microwaves provide a very precise, targeted means of hyperthermia and are currently used to treat plantar warts caused by cutaneous-infective human papillomaviruses (HPVs). Other HPV genotypes infecting the anogenital mucosa cause genital warts or preneoplastic lesions or cervical cancer. Effective, non-ablative therapies for these morbid HPV-associated lesions are lacking. METHODS: The molecular consequences of microwave treatment were investigated in in vitro cultured three-dimensional HPV-positive cervical tumour tissues, and tissues formed from HPV-infected normal immortalised keratinocytes. Microwave energy delivery to tissues was quantified. Quantitative reverse transcriptase PCR was used to quantify mRNA expression. Immunohistochemistry and fluorescence immunostaining was used to assess protein expression. FINDINGS: Microwave energy deposition induced sustained, localised cell death at the treatment site. There was a downregulation in levels of HPV oncoproteins E6 and E7 alongside a reduction in cellular growth/proliferation and induction of apoptosis/autophagy. HSP70 expression confirmed hyperthermia, concomitant with induction of translational stress. INTERPRETATION: The data suggest that microwave treatment inhibits tumour cell proliferation and allows the natural apoptosis of HPV-infected cells to resume. Precision microwave delivery presents a potential new treatment for treating HPV-positive anogenital precancerous lesions and cancers. FUNDING: Funding was through an Innovate UK Biomedical Catalyst grant (ID# 92138-556187), a Chief Scientist Office grant (TCS/19/11) and core support from Medical Research Council (MC_ UU_12014) core funding for the MRC-University of Glasgow Centre for Virus Research.

Integrating network pharmacology approaches for the investigation of multi-target pharmacological mechanism of 6-shogaol against cervical cancer.

Traditional treatment of cancer has been plagued by a number of obstacles, such as multiple drug resistance, toxicity and financial constraints. In contrast, phytochemicals that modulate a variety of molecular mechanisms are garnering increasing interest in complementary and alternative medicine. Therefore, an approach based on network pharmacology was used in the present study to explore possible regulatory mechanisms of 6-shogaol as a potential treatment for cervical cancer (CC). A number of public databases were screened to collect information on the target genes of 6-shogaol (SuperPred, Targetnet, Swiss target prediction and PharmMapper), while targets pertaining to CC were taken from disease databases (DisGeNet and Genecards) and gene expression omnibus (GEO) provided expression datasets. With STRING and Cytoscape, protein-protein interactions (PPI) were generated and topology analysis along with CytoNCA were used to identify the Hub genes. The Gene Ontology (GO) database Enrichr was used to annotate the target proteins, while, using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, signaling pathway enrichment analysis was conducted. Molecular docking and survival analysis for the Hub genes revealed four genes (HSP90AA1, HRAS, ESR1 and EGFR) with lowest binding energy and majority of the Hub genes (EGFR, SRC, CASP-3, HSP90AA1, MTOR, MAPK-1, MDM2 and ESR1) were linked with the overall survival of CC patients. In conclusion, the present study provides the scientific evidence which strongly supports the use of 6-shogoal as an inhibitor of cellular proliferation, growth, migration as well as inducer of apoptosis via targeting the hub genes involved in the growth of CC.Communicated by Ramaswamy H. Sarma.

The Phytochemical α-Mangostin Inhibits Cervical Cancer Cell Proliferation and Tumor Growth by Downregulating E6/E7-HPV Oncogenes and KCNH1 Gene Expression.

Cervical cancer is the fourth most common cancer among women worldwide. The main factor associated with the onset and progression of this neoplasia is the human papillomavirus (HPV) infection. The HPV-oncogenes E6 and E7 are critical drivers of cellular transformation, promoting the expression of oncogenes such as KCNH1. The phytochemical α-mangostin (AM) is a potent antineoplastic and antiviral compound. However, its effects on HPV oncogenes and KCNH1 gene expression remain unknown. This study evaluated the effects of AM on cell proliferation, cell cycle distribution and gene expression, including its effects on tumor growth in xenografted mice. AM inhibited cell proliferation in a concentration-dependent manner, being the most sensitive cell lines those with the highest number of HPV16 copies. In addition, AM promoted G1-cell cycle arrest in CaSki cells, while led to cell death in SiHa and HeLa cells. Of interest was the finding of an AM-dependent decreased gene expression of E6, E7 and KCNH1 both in vitro and in vivo, as well as the modulation of cytokine expression, Ki-67, and tumor growth inhibition. On these bases, we suggest that AM represents a good option as an adjuvant for the treatment and prevention of cervical cancer.

PLAU is associated with cell migration and invasion and is regulated by transcription factor YY1 in cervical cancer.

Cervical cancer, one of the most common malignancies, has a poor survival rate. The identification of more biomarkers for cervical cancer diagnosis and therapy is urgently needed. Plasminogen activator urokinase (PLAU) exerts multiple biological effects in various physiological and pathological processes; however the role of PLAU in cervical cancer progression is not fully understood. In the present study, the involvement and transcriptional regulation of PLAU in cervical cancer were explored. The expression of PLAU in cervical cancer was first analyzed, and PLAU was found to be overexpressed. In vitro experiments demonstrated that the migration and invasion of HeLa and HT3 cells were significantly suppressed by PLAU knockdown. Additionally, the core promoter of PLAU was confirmed, and the transcription factor YinYang 1 (YY1) was found to regulate PLAU mRNA expression. Overall, the present study elucidated the direct association between PLAU and cervical cancer, suggesting the YY1/PLAU axis as a potential novel therapeutic target for cervical cancer.

New light on treatment of cervical cancer: Chinese medicine monomers can be effective for cervical cancer by inhibiting the PI3K/Akt signaling pathway.

Cervical cancer (CC), as the most common malignant tumor of the female reproductive system, is infamous for its high morbidity and mortality rates. Its development and metastasis are intricate because numerous signaling pathways are involved. Since the cancer and the PI3K/Akt signaling pathway are closely intertwined, direct inhibition of either the PI3K/Akt pathway or its target genes and molecules may be remarkably constructive for treatment. Albeit remarkable advances in the treatment of CC, existing common anti-cancer medications are not without problems. These problems include myelotoxicity, cardiotoxicity, genotoxicity, and vasospasm, which are the most common and well-recognized toxicities associated with these medications. Therefore, it is necessary and urgent to develop novel, potent, secure, and more reasonably priced anticancer medications that are void of the above problems. Against this backdrop, Chinese medicine monomers have received more attention in recent years owing to their safety, low toxicity, few side effects, and anti-tumor properties. By regulating the PI3K/Akt signaling pathway, Chinese medicine monomers are effective not only in inhibiting CC growth, proliferation, apoptosis, invasion, migration, and reversing drug resistance but also in a variety of targets. Most previous earlier studies focused on the use of a single traditional Chinese medicine monomer to treat CC by regulating the PI3K/Akt signaling pathway rather than a combination of several such monomers. More importantly, to our knowledge, there has hardly been any study providing an exhaustive and comprehensive review of all the Chinese medicine monomers at CC. In response to this scarcity, we attempt in this paper to provide a comprehensive review of all the literature to date on traditional Chinese medicine monomers at cervical cancer, highlight the mechanisms and future prospects for their use in the prevention and treatment of cervical cancer.

Methanolic neem (Azadirachta indica) stem bark extract induces cell cycle arrest, apoptosis and inhibits the migration of cervical cancer cells in vitro.

BACKGROUND: Cervical cancer remains one of the significant causes of mortality in women due to the limitations of current treatment strategies and their associated side effects. Investigation of alternative medicine, including phytomedicine, has shown effective anti-cancer potential with fewer side effects. Azadirachta indica (commonly known as neem) is known for its medicinal properties. The present study investigated the anti-cancer potential of methanolic neem stem bark extract (MNBE) against cervical cancer using HeLa, SiHa, and ME-180 cell lines. METHODS: Cytotoxic effect of MNBE on cultured cell lines was evaluated by MTT and clonogenic assay. The growth-inhibiting effect of MNBE was further confirmed by performing cell cycle analysis and apoptosis assay using flow cytometry. The anti-migratory effect of MNBE was evaluated by using wound healing and Boyden chamber assay. Real-time PCR was used to determine the mRNA expression, and western blot and flow cytometry was used to determine the protein levels of growth and migration-related genes. RESULTS: MNBE significantly suppressed the growth and survival of cervical cancer cells in a dose-dependent manner by inducing cell cycle arrest and apoptosis. In addition, the growth inhibitory effect of MNBE was specific to cervical cancer cells than normal cells. Cell cycle arrest was correlated to transcriptional downregulation of cyclin dependent kinase 1 (CDK1), cyclin A, and cyclin B. Additionally, MNBE treatment resulted in the upregulation of active caspase-3 protein and downregulation of prosurvival genes, Bcl2, and survivin at mRNA level and NFkB-p65 at the protein level. Furthermore, MNBE inhibited the migration of cervical cancer cells accompanied by modulation of migration-related genes, including zona occludens-1 (ZO-1), matrix metalloproteinase 2 (MMP2), focal adhesion kinase (FAK), N-cadherin, snail, and E-cadherin. CONCLUSION: In summary, the present study provides the first evidence of MNBE in restricting cervical cancer cell growth and migration, which warrants further investigation for developing novel anti-cancer drugs.

Unraveling the multi-targeted curative potential of bioactive molecules against cervical cancer through integrated omics and systems pharmacology approach.

Molecular level understanding on the role of viral infections causing cervical cancer is highly essential for therapeutic development. In these instances, systems pharmacology along with multi omics approach helps in unraveling the multi-targeted mechanisms of novel biologically active compounds to combat cervical cancer. The immuno-transcriptomic dataset of healthy and infected cervical cancer patients was retrieved from the array express. Further, the phytocompounds from medicinal plants were collected from the literature. Network Analyst 3.0 has been used to identify the immune genes around 384 which are differentially expressed and responsible for cervical cancer. Among the 87 compounds reported in plants for treating cervical cancer, only 79 compounds were targeting the identified immune genes of cervical cancer. The significant genes responsible for the domination in cervical cancer are identified in this study. The virogenomic signatures observed from cervical cancer caused by E7 oncoproteins serve as the potential therapeutic targets whereas, the identified compounds can act as anti-HPV drug deliveries. In future, the exploratory rationale of the acquired results will be useful in optimizing small molecules which can be a viable drug candidate.

Dual Role of YY1 in HPV Life Cycle and Cervical Cancer Development.

Human papillomaviruses (HPVs) are considered to be key etiological agents responsible for the induction and development of cervical cancer. However, it has been suggested that HPV infection alone may not be sufficient to promote cervical carcinogenesis, and other unknown factors might be required to establish the disease. One of the suggested proteins whose deregulation has been linked with oncogenesis is transcription factor Yin Yang 1 (YY1). YY1 is a multifunctional protein that is involved not only in the regulation of gene transcription and protein modification, but can also control important cell signaling pathways, such as cell growth, development, differentiation, and apoptosis. Vital functions of YY1 also indicate that the protein could be involved in tumorigenesis. The overexpression of this protein has been observed in different tumors, and its level has been correlated with poor prognoses of many types of cancers. YY1 can also regulate the transcription of viral genes. It has been documented that YY1 can bind to the HPV long control region and regulate the expression of viral oncogenes E6 and E7; however, its role in the HPV life cycle and cervical cancer development is different. In this review, we explore the role of YY1 in regulating the expression of cellular and viral genes and subsequently investigate how these changes inadvertently contribute toward the development of cervical malignancy.

Period circadian regulator 2 suppresses drug resistance to cisplatin by PI3K/AKT pathway and improves chronochemotherapeutic efficacy in cervical cancer.

OBJECTIVE: Chronotherapy, a promising therapy, may build up the chemotherapy efficacy through thinking about timing of therapy. Here, we observed the roles of period circadian regulator 2 (PER2) on cervical cancer progression and the therapeutic efficacy of cisplatin (DDP) based on the circadian rhythm of PER2. METHODS: When Hela/DDP and SiHa/DDP transfected with pcDNA3.1-PER2 and/or treated with human epidermal growth factor (hEGF), viability, apoptosis, migration, and nuclear translocation of NF-κB p65 were detected by CCK-8, flow cytometry, transwell, immunofluorescence and western blot. Furthermore, the expression of circadian rhythm regulators, multidrug resistance, and epithelial-mesenchymal transition (EMT) proteins was detected by western blot. Hela/DDP cells-induced tumor formation in nude mice was constructed. The expression of PER2 was measured at different time point by RT-qPCR. Cisplatin was separately injected into mice with cervical cancer at the highest and lowest expression of PER2. After 5 weeks, tumor volume was measured and tumor proliferation was assessed by immunohistochemistry. RESULTS: Overexpression of PER2 significantly reduced proliferative and migrated capacities and nuclear translocation of NF-κB p65 as well as enhanced apoptosis in Hela/DDP and SiHa/DDP cells. Meanwhile, its overexpression elevated the expression of circadian rhythm regulators as well as lowered the expression of multidrug resistance proteins and EMT pathway activation by suppressing PI3K/AKT pathway. PER2 was rhythmically expressed in cervical cancer tissues. Compared to cisplatin treatment at the lowest expression of PER2, tumor growth and proliferation of tumor cells were distinctly suppressed in mice treated with cisplatin at the highest expression of PER2. CONCLUSION: Our findings confirmed the circadian rhythm of PER2 in cervical cancer and its overexpression restrained the resistance to cisplatin in cervical cancer by PI3K/AKT pathway. It may improve cisplatin efficacy through considering the circadian rhythm of PER2.

The effect of Chaihu-shugan-san on cytotoxicity induction and PDGF gene expression in cervical cancer cell line HeLa in the presence of paclitaxel +cisplatin.

Chaihu-shugan-san, as a traditional Chinese herbal formula, is composed of seven different herbs. This medicine can treat cancer due to its antioxidant compounds. In this study, the effect of Chaihu-shugan-san was considered on cytotoxicity induction and PDGF gene expression in cervical cancer cell line HeLa at different concentrations and at different times, by the MTT method. Paclitaxel + cisplatin were used as a control in this study. The expression of the PDGF gene was quantitatively evaluated in treated cells by real-time PCR, and a generalized linear model was used to evaluate the effect of the medicine, and Duncan's multiple range tests were used to evaluate the data. The results of the MTT test showed that Chaihu-shugan-san had antitumor properties in different concentrations, but there was a significant difference between this medicine and paclitaxel +cisplatin. Also, examination of gene expression showed that this medicine reduced the expression of the PDGF gene in the HeLa cancer cell line (P ? 0.04). Therefore, Chaihu-shugan-san could be suggested as an effective factor in preventing the growth of cervical cancer cells and controlling angiogenic factors that play an important role in the metastasis of cancerous tumors.

Long non-coding RNA KCNQ1OT1 facilitates the progression of cervical cancer and tumor growth through modulating miR-296-5p/HYOU1 axis.

Literature reports that lncRNA KCNQ1OT1 is markedly up-regulated in cervical cancer (CC) tissues and cell lines, and KCNQ1OT1 can promote the proliferation and metastasis of CC cells. This current work was designed to investigate the molecular mechanism underlying the participation of KCNQ1OT1 in CC progression. Herein, RT-qPCR was utilized for determining the levels of KCNQ1OT1, miR-296-5p and HYOU1 in clinical tumor tissue specimens and CC cell lines. Then, starBase predicted the complementary binding sites of KCNQ1OT1 and miR-296-5p or miR-296-5p and HYOU1. Dual-luciferase reporter assay/RIP assay validated the interplays among KCNQ1OT1/miR-296-5p/HYOU1. In addition, CCK-8, wound healing and transwell assays were employed to assess the proliferative, migrative and invasive properties of CC cells. Moreover, nude mice xenograft model was established by subcutaneously injection with SiHa cells in order to validate the precise functions of KCNQ1OT1/miR-296-5p/HYOU1 axis in CC in vivo. Besides, Immunohistochemical staining examined Ki-67 expression in xenograft tumors and western blotting analysis detected expressions of MMP2/9 and Wnt/ß-catenin signaling pathway in CC cells and xenograft tumors. Elevated KCNQ1OT1 and HYOU1 as well as reduced miR-296-5p were observed in clinical tumor tissue specimens and CC cell lines. Results revealed that upregulation of miR-296-5p counteracted the enhancing effects of overexpressed KCNQ1OT1 on the proliferative, migrative and invasive abilities of CC cells. Additionally, HYOU1 overexpression abolished the suppressing effects of silenced KCNQ1OT1 on the malignant behaviors of CC cells and tumor growth. To conclude, KCNQ1OT1 could aggravate the malignant behaviors of CC and facilitate tumor growth through modulating miR-296-5p/HYOU1 axis.

QKI-Regulated Alternative Splicing Events in Cervical Cancer: Pivotal Mechanism and Potential Therapeutic Strategy.

QKI is a vital regulator in RNA splicing and maturation, but its role in cervical cancer (CC) is little known. In this study, we found that QKI is decreased in human CC, and overexpression of QKI inhibits HeLa cell proliferation and promotes the apoptosis of cancer cells. We identified hundreds of endogenous QKI-regulated alternative splicing events (ASEs) and differentially expressed genes (DEGs) in QKI-overexpressed HeLa cells by RNA-seq and selectively validated their expression by quantitative reverse-transcription polymerase chain reaction. The gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that QKI-regulated ASEs and DEGs were closely related to cancer, apoptosis, and transcriptional regulatory functions. In short, QKI may affect the occurrence and development of CC by regulating gene expression through AS.

The Involvement of Natural Polyphenols in the Chemoprevention of Cervical Cancer.

From all types of cancer, cervical cancer manages to be in top four most frequent types, with a 6.5% rate of occurrence. The infectious vector that induces the disease, the high-risk Human papillomavirus (HPV), which is a sexually transmitted virus, is capable of transforming the host cell by modulating some of the principal signaling pathways responsible for cell cycle arrest, proliferation, and survival. Fortunately, like other cancer types, cervical cancer can be treated by chirurgical interventions or chemoradiotherapy, but these methods are not exactly the lucky clover of modern medicine because of the adverse effects they have. That is the reason why in the last years the emphasis has been on alternative medicine, more specifically on phytochemicals, as a substantial number of studies showed that diet contributes to cancer prevention and treatment. All these studies are trying to find new chemopreventive agents with less toxicity but high effectiveness both in vitro and in vivo. The aim of this review is to evaluate the literature in order to underline the advantages and disadvantages of polyphenols, a class of dietary compounds, as chemopreventive and chemotherapeutic agents. This review also aims to present polyphenols from different perspectives, starting with mechanisms of action and ending with their toxicity. The bigger picture illustrates that polyphenols have great potential in cervical cancer prevention, with strong effects on gene modulation.

Oncogenic HPV promotes the expression of the long noncoding RNA lnc-FANCI-2 through E7 and YY1.

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3' untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.

Picrasma quassioides Extract Elevates the Cervical Cancer Cell Apoptosis Through ROS-Mitochondrial Axis Activated p38 MAPK Signaling Pathway.

BACKGROUND/AIM: Picrasma quassioides (P. quassioides) is used in traditional Asian medicine widely for the treatment of anemopyretic cold, eczema, nausea, loss of appetite, diabetes mellitus, hypertension etc. In this study we aimed to understand the effect of P. quassioides ethanol extract on SiHa cervical cancer cell apoptosis. MATERIALS AND METHODS: The P. quassioides extract-induced apoptosis was analyzed using the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: P. quassioides extract induced cellular apoptosis by increasing the accumulation of cellular and mitochondrial reactive oxygen species (ROS) levels and inhibiting ATP synthesis. Pretreatment with N-Acetylcysteine (NAC), a classic antioxidant, decreased the intracellular ROS production and inhibited apoptosis. In addition, the P38 MAPK signaling pathway is a key in the apoptosis of SiHa cells induced by the P. quassioides extract. CONCLUSION: The P. quassioides extract exerts its anti-cancer properties on SiHa cells through ROS-mitochondria axis and P38 MAPK signaling. Our data provide a new insight for P. quassioides as a therapeutic strategy for cervical cancer treatment.