Treatment Strategy For Cervical Cancer Research Articles

PO-1355 The treatment strategy for cervical cancer; image-guided HDR-ICBT and IMRT using central shielding

PO-1355 The treatment strategy for cervical cancer; image-guided HDR-ICBT and IMRT using central shielding

SND1 Promotes Radioresistance in Cervical Cancer Cells by Targeting the DNA Damage Response.

Background: Radiotherapy is one of the most effective therapeutic strategies for cervical cancer patients, although radioresistance-mediated residual and recurrent tumors are the main cause of treatment failure. However, the mechanism of tumor radioresistance is still elusive. DNA damage response pathways are key determinants of radioresistance. The purpose of this study was to investigate the role and mechanism of SND1 in radioresistance of cervical cancer. Methods: A stable HeLa cell line with SND1 knockout (HeLa-KO) was generated through a modified CRISPR/Cas9 double-nicking gene editing system. The stable CaSki cell lines with SND1 knockdown (CaSki-Ctrl, CaSki-SND1-sh-1, CaSki-SND1-sh-2) were constructed through lentivirus transfection with the pSil-SND1-sh-1 and pSil-SND1-sh-2 plasmids. Results: It was observed that SND1 deficiency significantly increased the radiosensitivity of cervical cancer cells. It was also found that silencing SND1 promotes radiation-induced apoptosis. Significantly, the cells with a loss of SND1 function exhibited inefficient ataxia telangiectasia mutated pathway activation, subsequently impairing DNA repair and G2/M checkpoint arrest. In addition, threonine 103 is an important phosphorylation site of SND1 under DNA damaging stress. Conclusion: Collectively, the results of this study reveal a potent radiosensitizing effect of silencing SND1 or T103 mutation on cervical cancer cells, providing novel insights into potential therapeutic strategies for cervical cancer treatment.

Downregulation of NCL attenuates tumor formation and growth in HeLa cells by targeting the PI3K/AKT pathway.

BackgroundNucleolin (NCL, C23) is a multifunctional phosphoprotein that plays a vital role in modulating the survival, proliferationand apoptosis of cancer cells. However, the effects of NCL on cervical cancer and the underlying mechanisms behind this are poorly understood.MethodsLentiviral transfection technology was used to construct NCL knockdown cell lines. MTT, colony formation assays, and tumorigenic assays in vivo were performed to observe cell proliferation. HOECHST 33342 staining, flow cytometry, and caspase activity assay were used to test cell apoptosis. RNA‐Seq, Western blotting, and RT‐PCR were conducted to investigate the specific molecular mechanism.ResultsNCL knockdown inhibited cell proliferation and promoted apoptosis both in vivo and in vitro. Mechanistic studies revealed that NCL knockdown inhibited the PI3K/AKT pathway by upregulating FGF, ITGA, TNXB, VEGF, Caspase 3, and Bax, as well as by downregulating AKT, GNB4, CDK6, IL6R, LAMA, PDGFD, PPP2RSA and BCL‐2. In addition, the expression levels of apoptosis‐related genes after using a PI3K inhibitor LY294002 were consistent with shRNA studies, while treatment with a 740Y‐P agonist showed the opposite effect.ConclusionsOur findings indicate that downregulation of NCL may be a novel treatment strategy forcervical cancer.

P22077 enhances the antitumor efficacy of Cisplatin and its mechanism

Activation of DNA damage repair pathways in tumor cells may reduce the treatment efficacy of platinum-based chemotherapeutic agents. Ubiquitin-specific protease 7 (USP7) is one of the deubiquitinating enzymes that can remove the ubiquitin from target proteins and protect substrate proteins from degradation. Although ubiquitin-specific protease 7(USP7) is highly expressed in cervical cancer tissues and plays an important role in DNA damage repair, the role of USP7 inhibition in the antitumor efficacy of cisplatin remains unknown. This study explored the effects and mechanisms of a USP7 inhibitor P22077 on the anti-cervical cancer efficacy of cisplatin. In in vitro studies, P22077 and cisplatin both significantly reduced HeLa cell proliferation and colony formation, and the combination produced preferable effects. In in vivo xenograft tumor model, P22077 and cisplatin both demonstrated significant antitumor efficacy. The drug combination produced greater antitumor activity than the individual drug alone. Cisplatin evoked DNA damage repair-related molecules and P22077 tended to prevent this change. The drug combination produced higher cell death rate than the individual drug alone. Collectively, These results suggest that the USP7 inhibitor P22077 alone has significant antitumor efficacy and also can enhance the antitumor effects of cisplatin. The USP7 inhibitor P22077 combined with cisplatin may be an effective treatment strategy for cervical cancer.

Silent Information Regulator 1 Promotes Proliferation, Migration, and Invasion of Cervical Cancer Cells and Is Upregulated by Human Papillomavirus 16 E7 Oncoprotein

Objective: Silent information regulator 1 (SIRT1), an NAD+-dependent III class histone deacetylase, plays crucial roles in cell proliferation, apoptosis, senescence, metabolism, and stress responses. Nevertheless, the role of SIRT1 in tumorigenesis remains unclear. Methods: In the present study, we measured expression levels of SIRT1 and HPV16 E7 protein in cervical cancer (CC) tissue and calculated their correlations. We measured the effect of silencing SIRT1 on the proliferation, migration, invasion, and apoptosis in human CC SiHa cells. Results: Immunohistochemistry results revealed that the expression of SIRT1 was upregulated with progression from CIN II–III to CC, but was not expressed in normal cervical tissues and CIN I. There was a positive correlation between SIRT1 expression and HPV16 E7 expression in CC tissues, and silencing of HPV16 E7 downregulated the expression of SIRT1. Depletion of SIRT1 downregulated SIRT1 expression, and inhibited proliferation, migration, and invasion of SiHa cells, inducing apoptosis. Conclusions: Taken together, the data suggest that SIRT1 promotes CC carcinogenesis. SIRT1 inhibition is a potential treatment strategy for CC.

Knockdown of p62/sequestosome enhances ginsenoside Rh2-induced apoptosis in cervical cancer HeLa cells with no effect on autophagy.

p62/sequestosome is a multifunctional adaptor protein that participates in a wide variety of cellular processes. 20(S)-Ginsenoside Rh2 (G-Rh2) has various biological effects, including anticancer activity. We found that G-Rh2 can induce apoptosis and autophagy in HeLa cells. G-Rh2 significantly enhanced the transcriptional level of p62. A siRNA was constructed to knock down p62 and assess its effect on apoptosis induced by G-Rh2. p62 protein levels were successfully downregulated in cells transfected with the p62-specific siRNA. Silencing of p62 further decreased cell viability while also enhancing cell apoptosis, reactive oxygen species generation, the ratio of Bax to Bcl-2, and the cleavage of PARP. p62 knockdown decreased expression levels of Nrf2. Moreover, silencing of p62 had no significant effect on autophagy induced by G-Rh2. These results suggest that combining G-Rh2 treatment with inhibition of p62 may be a potential treatment strategy for cervical cancer.

Acetylation-stabilized chloride intracellular channel 1 exerts a tumor-promoting effect on cervical cancer cells by activating NF-κB.

Cervical cancer remains a major cause of cancer-related death in women, especially in developing countries. Previously, we found that the acetylation levels of chloride intracellular channel 1 (CLIC1) at lysine 131 were increased in cervical cancer tissues using a label-free proteomics approach. The aim of this study was to further determine the role of CLIC1 expression and its acetylation in cervical cancer. CLIC1 expression and its implications for the prognosis of cervical cancer were analyzed using primary patient samples and cells, and the Gene Expression Profiling Interactive Analysis (GEPIA) database (gepia.cancer-pku.cn). The effect of CLIC1 on cervical cancer cells was evaluated using Cell Counting Kit (CCK)-8, flow cytometry, scratch wound healing, transwell, Western blotting and co-immunoprecipitation (Co-IP) assays. In vivo tumor growth was assessed using mouse xenograft models. We found that CLIC1 expression was increased in cervical cancer tissues and cells and that patients with a high CLIC1 expression tended to havea shorter overall survival time. Knockdown of CLIC1 significantly reduced in vitro cervical cancer cell proliferation, migration and invasion, and in vivo tumorigenesis. At the molecular level, we found that nuclear factor kappa B (NF-κB) activity was positively regulated by CLIC1. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, attenuated the tumor-promoting effect of CLIC1. Moreover, we found that CLIC1 acetylation at K131 was upregulated in cervical cancer cells, which stabilized CLIC1 by inhibiting its ubiquitynation. Substitution of K131 inhibited CLIC1 ubiquitynation and promoted in vitro cervical cancer cell proliferation, migration and invasion, and in vivo tumor growth. In addition, we found that acetyltransferase HAT1 was responsible for CLIC1 acetylation at K131. Our data indicate that CLIC1 acts as a tumor promoter in cervical cancer, suggesting a potential treatment strategy for cervical cancer by regulating CLIC1 expression and/or acetylation.

Erb‑B2 Receptor Tyrosine Kinase 2 is negatively regulated by the p53‑responsive microRNA‑3184‑5p in cervical cancer cells.

The oncogenic role of Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) has been identified in several types of cancer, but less is known on its function and mechanism of action in cervical cancer cells. The present study employed a multipronged approach to investigate the role of ERBB2 in cervical cancer. ERBB2 and microRNA (miR)-3184-5p expression was assessed in patient-derived cervical cancer biopsy tissues, revealing that higher levels of ERBB2 and lower levels of miR-3184-5p were associated with clinicopathological indicators of cervical cancer progression. Furthermore, ERBB2 stimulated proliferation, migration and sphere-formation of cervical cancer cells in vitro. This effect was mediated by enhanced phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α activity. Additionally, it was revealed that miR-3184-5p directly suppressed ERBB2 in cervical cancer cells. The p53 activator Mithramycin A stimulated p53 and miR-3184-5p expression, thereby lowering the levels of ERBB2 and attenuating proliferation, migration and sphere-formation of cervical cancer cells. In conclusion, the findings of the present study suggested ERBB2 as an oncogenic protein that may promote invasiveness in cervical cancer cells. Treatment of cervical cancer cells with the p53 activator Mithramycin A restored the levels of the endogenous ERBB2 inhibitor miR-3184-5p and may represent a novel treatment strategy for cervical cancer.

Effect of berberine associated with photodynamic therapy in cell lines.

Cervical cancer is a serious worldwide health problem. In view of the potentially harmful effects of current conventional therapies, photodynamic therapy may be an option as it is a minimally invasive therapy and can promote selective cytotoxic activity for neoplastic cells in the target tissue., Berberine (BBR) as an isolated molecule is a natural compound that has antineoplastic properties and potential action as a photosensitizer agent. The purpose of this study was to evaluate the use of berberine as a photosensitizer in photodynamic therapy (PDT) protocols and observe the effects produced by this association in cervical carcinoma cells and in immortalized keratinocytes. Incubation with 2.5 μM berberine promoted less than 10 % of cellular death in both cell lines studied. In addition, by fluorescence microscopy, we demonstrated that berberine was internalized by the cells, and after a period of 48 h, it was still present in the intracellular environment preferentially localized in the cytoplasm. After photodynamic therapy using berberine as a photosensitizer and visible light activation at 447 (±10) nm, we observed a phototoxic effect, which resulted in 19.84 % cell viability for Caski cells and 47.22 % cell viability for HaCaT. Treatment with berberine associated with photodynamic therapy promoted an increase in the production of reactive species of oxygen (ROS) and caspase-3 activity, indicating a preferential cell death mechanism by caspase-dependent apoptosis. Therefore, we demonstrated that berberine is an efficient photosensitizer and that its association with photodynamic therapy may be a potential anticancer treatment strategy for cervical cancer.

HPV-induced Nurr1 promotes cancer aggressiveness, self-renewal, and radioresistance via ERK and AKT signaling in cervical cancer

Human papillomavirus (HPV) is the etiological agent of cervical cancer; however, the mechanisms underlying HPV-mediated carcinogenesis remain poorly understood. Here, we showed that nuclear receptor related-1 protein (Nurr1) was upregulated in primary cervical cancer tissue-derived spheroid cells and HPV-positive cell lines, and Nurr1 upregulation was correlated with cancer grade. Nurr1 promoted cell proliferation, migration, invasion, and anchorage-independent cell growth. In addition to its effect on cancer aggressiveness, Nurr1 enhanced the self-renewal ability of cells in vitro and in vivo, underscoring the importance of Nurr1 in maintaining the stemness of cancer stem-like cells (CSLCs). Mechanistically, Nurr1 independently activated the MEK/ERK and PI3K/Akt/mTOR signaling cascades. The MEK inhibitor trametinib (GSK) and PI3K/mTOR dual inhibitor dactolisib (BEZ) were shown to abrogate Nurr1-augmented tumorigenesis by upregulating p21 and p27 expression and by suppressing MMP9 and KLF4 expression. We provided further evidence that BEZ, but not GSK, could abolish Nurr1-enhanced radioresistance, suggesting its potential value for radiosensitizing CSLCs in the clinical setting. This study highlights the unprecedented roles of Nurr1 and elucidates mechanisms by which Nurr1 promotes tumor progression and radioresistance, providing a novel therapeutic strategy for cervical cancer treatment.

Cascade-Targeting of Charge-Reversal and Disulfide Bonds Shielding for Efficient DOX Delivery of Multistage Sensitive MSNs-COS-SS-CMC.

BackgroundAlthough pH and redox sensitiveness have been extensively investigated to improve therapeutic efficiency, the effect of disulfide bonds location and pH-triggered charge-reversal on cascade-targeting still need to be further evaluated in cancer treatment with multi-responsive nanoparticles.PurposeThe aim of this study was to design multi-responsive DOX@MSNs-COS-NN-CMC, DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS and systematically investigate the effects of disulfide bonds location and charge-reversal on the cancer cell specificity, endocytosis mechanisms and antitumor efficiency.ResultsIn vitro drug release rate of DOX@MSNs-COS-SS-CMC in tumor environments was 7-fold higher than that under normal physiological conditions after 200 h. Furthermore, the fluorescence intensity of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS was 1.9-fold and 1.3-fold higher than free DOX at pH 6.5 and 10 mM GSH. In addition, vesicular transport might be a factor that affects the uptake efficiency of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS. The clathrin-mediated endocytosis and endosomal escape of DOX@MSNs-COS-SS-CMC enhanced cellular internalization and preserved highly controllable drug release into the perinuclear of HeLa cells. DOX@MSNs-COS-SS-CMC exhibited a synergistic chemotherapy in preeminent tumor inhibition and less side effects of cardiotoxicity.ConclusionThe cascade-targeting of charge-reversal and disulfide bonds shielding would be a highly personalized strategy for cervical cancer treatment.

Integrative Bioinformatics Approaches to Screen Potential Prognostic Immune-Related Genes and Drugs in the Cervical Cancer Microenvironment

In developing countries, cervical cancer is still the major cause of cancer-related death among women. To better understand the correlation between tumor microenvironment (TME) and prognosis of cervical cancer, we screened 1367 differentially expressed genes (DEGs) of cervical cancer samples in The Cancer Genome Atlas (TCGA) database using Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm-derived immune scores. Then, we extracted 401 tumor immune microenvironment (TIME)-related DEGs that related to patients’ survival outcomes. Protein-protein interaction (PPI) network and functional enrichment analysis revealed that the prognostic genes mainly participated in myeloid leukocyte activation, adaptive immune response regulation, and receptor signaling pathways. A total of 79 key prognostic DEGs were obtained through PPI network. A TF-lncRNA-miRNA-mRNA regulatory network was constructed to explore the potential regulatory mechanism. 4 genes (CCR7, PD-1, ZAP70, and CD28) were validated in another independent cohort of cervical cancer from the Gene Expression Omnibus (GEO) database. Finally, potential drugs for key prognostics DEGs were predicted using DrugBank. In conclusion, we obtained a list of potential prognostic TIME-related genes and potential predicted drugs by integrative bioinformatics approaches. A comprehensive understanding of prognostic genes within the TIME may provide new strategies for cervical cancer treatment.

Predictive value of S100A9 for lymph node metastasis in cervical cancer.

Lymph node metastasis affects the initial treatment strategy for cervical cancer and is hard to be diagnosed in clinical practice.This paper aims to explore the relationship between calcium-binding A9 (S100A9) and lymph node metastasis (LNM) in cervical cancer, and to determine the predictive value of S100A9 for LNM in cervical cancer. We performed a retrospective cohort study and collected the pathological data, follow-up data, and paraffin tissue samples of 99 patients with cervical cancer who underwent modified extensive or extensive hysterectomy plus pelvic lymphadenectomy at the Department of Gynecology, Xiangya Hospital, Central South University from January 2013 to December 2018. Immunohistochemistry was used to detect the expression of S100A9 in cervical cancer tissues, and the correlation between S100A9 expression and LNM of cervical cancer, or clinicopathological characteristics were analyzed. The receiver operating characteristic (ROC) curve was used to establish a predictive model for LNM of cervical cancer, and Chi-square test of four-grid table was used to evaluate the diagnostic value of S100A9 for LNM in cervical cancer. The expression of S100A9 was significantly correlated with LNM. The S100A9 immunohistochemical semi-quantitative score of the LNM group was significantly higher than that in the non-lymph node metastasis group (P<0.001). Moreover, the expression of S100A9 was significantly correlated with histological type, stromal invasion, lymphatic vessel invasion, or LNM (P<0.05). The cut-off of the ROC curve for predicting LNM was 5, with the Youden index of 0.649 and the area under the ROC curve of 0.863. The disease-free survival and overall survival in the S100A9 positive group were significantly shorter than those in the negative group (P<0.05). S100A9 alone had a sensitivity of 71.4%, a specificity of 91.5%, and an accuracy of 85.1% for diagnosing LNM. Imaging had a sensitivity of 32.1%, a specificity of 74.6%, and an accuracy of 60.9%. Combination of S100A9 with image examination in parallel test had a sensitivity of 85.7%, a specificity of 71.2%, and an accuracy of 75.9%, while combination of S100A9 and image examination in serial test had a sensitivity of 17.9%, a specificity of 98.3%, and an accuracy of 72.4%. S100A9 may be associated with LNM in cervical cancer. S100A9 shows a promising perspective in predicting LNM in cervical cancer. Combination of S100A9 and image examination in serial test has a high specificity for LNM.

MicroRNA-362-3p Inhibits Migration and Invasion via Targeting BCAP31 in Cervical Cancer.

Cervical cancer (CC) is the most common malignant tumor in gynecology, and metastasis is an important cause of patient death. MiRNAs (microRNAs) have been found to play key roles in cervical cancer metastasis, but the effect of miR-362-3p in CC is unclear. This study aimed to investigate the role of miR-362-3p in cervical cancer migration and invasion. We compared the expression levels of miR-362-3p in cervical cancer tissues and adjacent normal cervical tissues. In CC tissues, miR-362-3p expression was significantly down-regulated, which is related to the cancer stage and patient survival. MiR-362-3p can effectively inhibit the migration and invasion of cervical cancer cells. The dual-luciferase reporter assay results showed that BCAP31 (B cell receptor associated protein 31) is a direct target protein of miR-362-3p. The results of the immunohistochemical examination of clinical tissue samples showed that BCAP31 was abnormally highly expressed in cervical cancer, which was positively correlated with the clinical stage. BCAP31 knockdown exerted similar effects as miR-362-3p overexpression. Further GSEA analysis showed that BCAP31 may participate in multiple biological processes, such as protein transport, metabolism, and organelle organization. Our results suggest that miR-362-3p inhibits migration and invasion via directly targeting BCAP31 in cervical cancer, and restoring miR-362-3p levels may be a new treatment strategy for cervical cancer in the future.

ALOX12B promotes carcinogenesis in cervical cancer by regulating the PI3K/ERK1 signaling pathway.

Cervical cancer is a malignant disease and a threat to women's health worldwide. Surgical resection followed by radiotherapy or chemotherapy is the main treatment strategy for cervical cancer; however, patients with cervical cancer, especially those with late-stage disease, may not benefit from these traditional therapies, which results in poor clinical outcome. ALOX12B is a gene encoding lipoxygenase, and a mutation in ALOX12B was detected in lung and breast cancer. Furthermore, ALOX12B is essential to the proliferation of epidermoid carcinoma cells; however, the role of ALOX12B in cervical cancer has not been studied thus far, to the best of our knowledge. In the present study, the expression levels of ALOX12B were reduced in cervical cancer cells by lentiviral transfection, and it was found that both cell proliferation and clone formation ability were significantly reduced, and the cell cycle was blocked at G1 phase. Tumor growth was also suppressed in vivo in a xenograft tumor model, but the migration of tumor cells was not affected by ALOX12B. Subsequently, using western blotting, it was demonstrated that knockdown of ALOX12B decreased the expression levels of PI3K, MEK1, ERK1, C-fos and cdc25. Meanwhile, overexpression of ALOX12B increased the expression levels of these five molecules. Conclusively, ALOX12B promoted cell proliferation in cervical cancer via regulation of the PI3K/ERK1 signaling pathway. The present study may improve our understanding of the molecular mechanisms underlying the function of ALOX12B in cervical cancer and inform new therapeutic strategies.

Cervical cancer and potential pharmacological treatment with snake venoms.

Cervical cancer is the fourth most common cancer worldwide in women. Apoptosis reactivation has become the main strategy for decreasing cancer proliferation. There is a need to extend the search for new drugs to implement more effective and less toxic strategies for cervical cancer treatment. Research has been carried out to find new drugs that have minimal side effects and that focus on the tumor microenvironment, particularly in the induction of cellular apoptosis and cell migration and the inhibition of angiogenesis. Potent toxins from snake venoms have shown potential as sources for the synthesis of new drugs with such characteristics. The present work aimed to describe cervical cancer characteristics, associated risk factors, current treatments and to highlight the effects of toxins isolated from the venom of snakes of the Viperidae family on cervical cancer cell lines.

A five-mRNA signature associated with post-translational modifications can better predict recurrence and survival in cervical cancer.

High mortality of patients with cervical cancer (CC) stresses the imperative of prognostic biomarkers for CC patients. Additionally, the vital status of post‐translational modifications (PTMs) in the progression of cancers has been reported by numerous researches. Therefore, the purpose of this research was to dig a prognostic signature correlated with PTMs for CC. We built a five‐mRNA (GALNTL6, ARSE, DPAGT1, GANAB and FURIN) prognostic signature associated with PTMs to predict both disease‐free survival (DFS) (hazard ratio [HR] = 3.967, 95% CI = 1.985‐7.927; P < .001) and overall survival (HR = 2.092, 95% CI = 1.138‐3.847; P = .018) for CC using data from The Cancer Genome Atlas database. Then, the robustness of the signature was validated using GSE44001 and the Human Protein Atlas (HPA) database. CIBERSORT algorithm analysis displayed that activated CD4 memory T cell was also an independent indicator for DFS (HR = 0.426, 95% CI = 0.186‐0.978; P = .044) which could add additional prognostic value to the signature. Collectively, the PTM‐related signature and activated CD4 memory T cell can provide new avenues for the prognostic predication of CC. These findings give further insights into effective treatment strategies for CC, providing opportunities for further experimental and clinical validations.

DGUOK-AS1 promotes cell proliferation in cervical cancer via acting as a ceRNA of miR-653-5p.

Cervical cancer (CC) holds the second highest incidence and is the fourth dominating cause of cancer-induced death in women. It has been widely accepted that long noncoding RNAs (lncRNAs) are implicated in pathological and physiological activities of CC. However, the research of lncRNAs is still in the initial stage. The biological function of lncRNA deoxyguanosine kinase antisense RNA 1 (DGUOK-AS1) in human cancers has not been reported yet. We found that DGUOK-AS1 was aberrantly upregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tissues through TCGA database. Real-time quantitative polymerase chain reaction (RT-qPCR) also verified the high expression of DGUOK-AS1 in CC cell lines. Loss-of-function assays indicated that DGUOK-AS1 silence repressed CC cell growth. In addition, dual-luciferase reporter and RNA immunoprecipitation (RIP) experiments validated the binding relation between miR-653-5p and DGUOK-AS1 or EMSY. Results of the rescue assays elucidated that EMSY overexpression or miR-653-5p downregulation reversed the suppressive function of DGUOK-AS1 knockdown on cell growth and DNA repair in CC. To sum up, this research highlighted that DGUOK-AS1 could promote CC cell proliferation via serving as a ceRNA of miR-653-5p to release EMSY, which might inspire us to discover novel strategies for CC treatment. SIGNIFICANCE OF THE STUDY: DGUOK-AS1 knockdown hinders proliferation of CC cells. DGUOK-AS1 sequesters miR-653-5p to elevate EMSY in CC. EMSY is required for DGUOK-AS1 to induce cell proliferation and repress DNA damage in CC.

Long Noncoding RNA FOXD2-AS1 Promotes the Malignancy of Cervical Cancer by Sponging MicroRNA-760 and Upregulating Hepatoma-Derived Growth Factor.

Although the functions of long noncoding RNA (lncRNA) called FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) have been well studied in multiple human cancer types, its expression status and detailed roles in cervical cancer remain unknown and merit investigation. This study was aimed at assessing FOXD2-AS1 expression in cervical cancer and at determining its effects on the aggressive behavior of cervical cancer in vitro and in vivo. Expression of FOXD2-AS1 in cervical cancer tissues and cell lines was determined via reverse-transcription quantitative PCR. The effects of FOXD2-AS1 on cervical cancer cells were examined by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, flow-cytometric analysis, migration and invasion assays, and an in vivo tumorigenicity assay. FOXD2-AS1 was found to be significantly upregulated in cervical cancer tissues and cell lines. High FOXD2-AS1 expression was notably linked with the Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and depth of cervical invasion in patients with cervical cancer. Kaplan–Meier survival analysis revealed significantly shorter overall survival of patients when the tumor expression of FOXD2-AS1 was higher in comparison with those in patients with lower FOXD2-AS1 expression. In vitro functional assays revealed that downregulation of FOXD2-AS1 led to suppression of proliferation, migration, and invasiveness as well as to the induction of apoptosis of cervical cancer cells. In addition, FOXD2-AS1 silencing hindered tumor growth in vivo. Mechanism investigation revealed that FOXD2-AS1 functioned as a molecular sponge of microRNA-760 (miR-760). Furthermore, hepatoma-derived growth factor (HDGF) was validated as a direct target gene of miR-760 in cervical cancer cells. Moreover, an miR-760 knockdown reversed the effects of FOXD2-AS1 silencing on cervical cancer cells. FOXD2-AS1 possesses significant oncogenic activity in cervical cancer progression; this activity is mediated by sponging of miR-760 with consequent upregulation of HDGF. The FOXD2-AS1–miR-760–HDGF axis might harbor promising targets for novel treatment strategies of cervical cancer.

High mobility group box 3 promotes cervical cancer proliferation by regulating Wnt/β-catenin pathway.

ObjectiveHigh mobility group box 3 (HMGB3) plays an important role in the development of various cancer. This study aims to explore whether HMGB3 regulates cervical cancer (CC) progression and elucidate the underlying mechanism.MethodsHMGB3 expression in clinical patients' tumor samples were determined by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot. HMGB3 overexpression/knockdown were used to investigate its function. Cell apoptosis and cycle were detected by Annexin V/PI staining and flow cytometry. In vivo tumor model was made by subcutaneous injection of HeLa cells transfected with shRNAs targeting HMGB3 (sh-HMGB31) into the flank area of nude mice. Western blot was used to detect the levels of β-catenin, c-Myc, and matrix metalloproteinase-7 (MMP-7) in Hela and CaSki cells transfected with sh-HMGB3 or shRNAs targeting β-catenin.ResultsBoth messenger RNA and protein levels of HMGB3 were upregulated in CC tissues from patients. High expression level of HMGB3 had positive correlation with serosal invasion, lymph metastasis, and tumor sizes in CC patient. Functional experiments showed that HMGB3 could promote CC cell proliferation both in vitro and in vivo. The expression levels of c-Myc and MMP-7 were increased, resulting in regulating cell apoptosis, cell cycle, and activating Wnt/β-catenin pathway.ConclusionsOur data indicated that HMGB3 may serve as an oncoprotein. It could be used as a potential prognostic marker and represent a promising therapeutic strategy for CC treatment.