Human Cervical Cancer Progression Research Articles

Ang-1 promotes tumorigenesis and mediates the anti-cancer effects of Artesunate on Choroidal melanoma via the regulation of Akt/mTOR signaling pathway

The impact of Ang-1 on tumors remains a subject of contention, with its mechanism of action exhibiting complexity in the progression of diverse tumor types. Ang-1 has been shown to promote the progression of glioma, glioma, esophageal and human cervical cancer, whereas it exerts inhibitory effects on the growth of breast and colon cancer. However, the specific function of Ang-1 in CM has not been clarified. This research aims to explore the function of Ang-1 on CM and the underlying mechanism. WB and qPCR were utilized to measure the expression levels of different factors in CM cells. Clonogenic, CCK-8 and Transwell migration assay were used to probe CM cells’ proliferation and migration ability. Xenograft tumor model was used to testify the effect of Ang-1 and Artesunate (ART) on the growth of CM in vivo. We found Ang-1 promoted CM proliferation and migration, while it was inhibited by ART in vitro. Moreover, both ART treatment and Ang-1 knockdown had the effect of suppressing tumor growth in CM xenograft model. Mechanically, Ang-1 activated Akt/mTOR pathway and induced epithelial-mesenchymal transition (EMT) in CM cells. Furthermore, ART regulated Akt/mTOR pathway by decreasing the expression of Ang-1 in CM cells. Ang-1 promotes tumorigenesis of CM by regulating Akt/mTOR pathway, which can be inhibited by ART.

Analysis of the correlation between cervical HPV infection, cervical lesions and vaginal microecology.

Vaginal microbiota is involved in human papillomavirus (HPV) infection and cervical cancer (CC) progression, and the specific changes in vaginal microbial composition during this process remains uncertain. This study aimed to observe the changes in the specific composition of vaginal microorganisms in different cervical lesions and identify biomarkers at different stages of lesions. In this study we used the illumina high-throughput gene sequencing technology to determine the V4 region of 16SrRNA and observed the vaginal microbial composition in different cervical lesions. The vaginal microbiota of patients with high-risk HPV infection and cervical lesions is significantly different from that of the normal population, but there is no significant difference in the richness of vaginal microbes. The diversity of vaginal species in CC patients is higher than that in high-risk HPV infection or CIN patients. The main manifestation is an increase in the diversity of vaginal microbes, a decrease in the relative abundance of cyanobacteria and Lactobacillus, and an increase in the relative abundance of dialister, peptonephila and other miscellaneous bacteria. There are characteristic vaginal biomarker in normal women, high risk HPV patients and CC patients. In detail, the biomarker in the normal group was varibaculum, the biomarker in the high-risk HPV group was saccharopolyspora, the biomarker of the CC group was the Proteobacteria, Corynebacterium, Coprococcus, Peptococcus and Ruminococcus. The study indicated that the compositions of vaginal microbes in different cervical lesions is different. The vaginal microbial composition has a certain diagnostic effect on healthy women, patients with high-risk HPV infection and cervical lesions. These microbes may serve as potential biomarkers for CC. It also provided an effective way for the treatment of HPV infections and cervical lesions.

E6/E7 Oncogenes Mutation of Human Papillomavirus Type 16 Associated with P16 Protein Expression in Cervical Cancer

The genetic composition of the E6 and E7 oncogenes is very susceptible to mutation. Mutations occur due to interactions between the viral genome and the host. Changes in one nucleotide oncogenes E6 and E7 can affect the function of these oncogenes so that they can trigger the persistence of Human Papilloma Virus (HPV) infection and cervical cancer progression in several intratypic variants of HPV type 16 and alteration p16 expression in cervical cancer cases. This study was conducted on cervical cancer women first diagnosed from May 2021 to November 2021 who had not received surgery, chemotherapy, or radiation therapy. Willing to participate in the study after signing the informed consent. Cervical tissue samples with a positive test result for HPV 16 were then grouped based on the mutation sequencing of E6 and E7 into a wild-type group and a mutant group. Furthermore, the immunohistochemical examination was carried out to assess the expression of p16 protein in paraffin blocks. The results of this study showed that there was no association between mutations in the E6 and E7 oncogenes of HPV Type 16 with p16 expression (c= 0.048 and p value 0.78). The expression of p16 was stronger in the mutant group with the median percentage of cells from p16 immunohistochemistry staining which was 60.5% (range 3-73%) in the mutant group and 53% (range 2-65%) in the wild type of group. However, the correlation coefficient interval between HPV type 16 and E6 oncogene mutations with p16 protein expression is very weak.

Timosaponin AIII Inhibits Migration and Invasion Abilities in Human Cervical Cancer Cells through Inactivation of p38 MAPK-Mediated uPA Expression In Vitro and In Vivo

Cervical cancer is one of the most common gynecologic cancers globally that require novel approaches. Timosaponin AIII (TSAIII) is a steroidal saponin that displays beneficial effects in antitumor activities. However, the effect of TSAIII on human cervical cancer remains unknown. In this study, we found that TSAIII showed no influence on cell viability, cytotoxicity, cell cycle distribution and apoptosis induction in human cervical cancer cells. TSAIII was revealed to have a significant inhibitory effect on cell migration and invasion through the downregulation of invasion-related uPA expression and p38 MAPK activation in both human cervical cancer cells and cervical cancer stem cells (CCSCs), indicating that the p38 MAPK-uPA axis mediated the TSAIII-inhibited capacity of cellular migration and invasion. In a synergistic inhibition assay, a TSAIII plus p38 siRNA cotreatment revealed a greater inhibition of uPA expression, migration and invasion in human cervical cancer cells. In an immunodeficient mouse model, TSAIII significantly inhibited lung metastases from human cervical cancer SiHa cells without TSAIII-induced toxicity. These findings first revealed the inhibitory effects of TSAIII on the progression of human cervical cancer through its downregulation of p38 MAPK-uPA axis activation. Therefore, TSAIII might provide a potential strategy for auxiliary therapy in human cervical cancer.

Altered vaginal eukaryotic virome is associated with different cervical disease status

Viruses are important components of the human body. Growing evidence suggests that they are engaged in the physiology and disease status of the host. Even though the vaginal microbiome is involved in human papillomavirus (HPV) infection and cervical cancer (CC) progression, little is known about the role of the vaginal virome. In this pilot exploratory study, using unbiased viral metagenomics, we aim to investigate the vaginal eukaryotic virome in women with different levels of cervical lesions, and examine their associations with different cervical disease status. An altered eukaryotic virome was observed in women with different levels of lesions and Lactobacillus profiles. Anelloviruses and papillomaviruses are the most commonly detected eukaryotic viruses of the vaginal virome. Higher abundance and richness of anelloviruses and papillomaviruses were associated with low-grade squamous intraepithelial lesion (LSIL) and CC. Besides, higher anellovirus abundance was also associated with lactobacillus-depleted microbiome profiles and bacterial community state (CST) type IV. Furthermore, increased correlations between Anelloviridae and Papillomaviridae occurred in the women with increased cervical disease severity level from LSIL to CC. These data suggest underlying interactions between different microbes as well as the host physiology. Higher abundance and diversity of both anelloviruses and papillomaviruses shared by LSIL and CC suggest that anellovirus may be used as a potential adjunct biomarker to predict the risk of HPV persistent infection and/or CC. Future studies need to focus on the clinical relevance of anellovirus abundance with cervical disease status, and the evaluation of their potential as a new adjunct biomarker for the prediction and prognoses of CC.

Emodin Exhibits Strong Cytotoxic Effect in Cervical Cancer Cells by Activating Intrinsic Pathway of Apoptosis

Pharmacognosy Research,2022,14,4,499-503.DOI:10.5530/pres.14.4.72Published:October 2022Type:Original ArticleAuthors:Amir Saeed, and Ahmed Alharbi Author(s) affiliations:Amir Saeed1,2, Ahmed Alharbi1 1Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, KSA. 2Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Medical Sciences and Technology, Khartoum, SUDAN. Abstract:Background: Cervical cancer is widely acknowledged as the main cause of mortality and a major obstacle to increasing life expectancy, after breast cancer, in women. Natural products have been proven to be a promising source for the development of potential anticancer drugs. Emodin (1,3,8-trihydroxy-6-methyl-9,10-anthracenedione) is shown to exert wide range of biological effects, including antibacterial, hepatoprotective, anti-inflammatory and anticancer. Aim: The major aim of this study was to evaluate the efficacy of emodin against the progression of human cervical cancer. Materials and Methods: The cytotoxic effect of emodin on cervical cancer HeLa cells was assessed by cell viability assay and phase contrast microscopy. Moreover, DAPI staining was performed to analyze nuclear condensation. H2DCFDA staining was done to evaluate ROS generation. Activation of caspases was determined to ascertain mitochondria-mediated apoptosis in cervical cancer cells. Results: The results revealed that emodin strongly inhibited the HeLa cell growth and proliferation; which was validated by cell viability assay and phase contrast microscopy. Moreover, DAPI staining authenticated nuclear condensation and fragmentation in HeLa cells indicating initiation of apoptosis. We also observed significant ROS generation and caspases activation in emodin-treated cervical cancer cells. Conclusion: Our results suggested strong cytotoxic potential of emodin against cervical cancer cells. Keywords:Apoptosis, Cervical Cancer, DAPI, Emodin, HeLa, ROSView:PDF (807.5 KB)

Building Indian Biomedical Leadership to Bridge the Gap Between Science, Primary Health Care and Public Health.

The Indian biomedical landscape has been characterized by the existence of somewhat polarized institutional structures and professional growth. While some scientific and public health challenges have been met with existing structures, there is still a large unmet scientific and public health need. Broadly, the physical separation of science, engineering, medical campuses and industry has led to silos of excellence and accomplishment with huge gaps in innovation and implementation. The lack of inter-disciplinary educational options has further reinforced the cultural underpinning of “guilds” that have found it difficult to collaborate. Strikingly, with almost a comparable number of institutions that train doctors in the allopathic or traditional disciplines such as Ayurveda, Unani etc., an “integrative medicine” framework has not emerged, apart from an over reliance on specialization at the expense of primary care. This paper is written by two physician-scientists, the first is located in a basic life science research center. The second, a practicing family physician, from the institutional anchor of a life sciences research institution. In this, we trace our experiences, primarily from a principal investigator’s perspective, describing the scientific projects and try to explore the lessons learnt along the way. We will first describe the research in the lab’s core area of human cervical cancer progression and our more recent effort with Dengue genomics and vaccine design. We then describe the lab's engagement with medical campuses and other agencies as well as review our various meetings and interactions so far with our colleagues from Africa to grasp what might be the “generalizable lessons” for the future. The Indian council of medical research initiated a program with Africa in health sciences. Building upon those interactions, we have taken some incremental steps in that direction and described our efforts.

Cx32 promotes autophagy and produces resistance to SN‑induced apoptosis via activation of AMPK signalling in cervical cancer.

The roles of gap junctions (GJs) and its components, connexins, in the autophagy of cervical cancer cells have been rarely investigated. Our previous study demonstrated that connexin32 (Cx32) exerted an anti‑apoptotic effect on cervical cancer. However, as an important regulator of apoptosis, whether the autophagy is involved in the function of Cx32 on cervical cancer cells is not well defined. The present study aimed to investigate the role of Cx32 on autophagy and apoptosis inhibition in cervical cancer cells. The expression levels of Cx32 and the autophagy‑associated protein LC3‑Ⅱ in paracancerous cervical tissues (n=30) and cervical cancer (n=50) tissues were determined via western blotting. In total, 45cervical cancer specimens were used to evaluate the clinical relevance of Cx32 and LC3‑Ⅱ. It was found that both Cx32 and LC3‑Ⅱ were upregulated in cervical cancer tissues compared with those in paracancerous cervical tissues. The effect of Cx32 on autophagy was examined by detecting the change of LC3‑Ⅱ using western blotting, transfection with enhanced green fluorescent protein‑LC3 plasmid and transmission electron microscopy analysis. Overexpression of Cx32 significantly enhanced autophagy in HeLa‑Cx32 cells, whereas knockdown of Cx32 suppressed autophagy in C‑33A cells. The flow cytometry results demonstrated that Cx32 inhibited the apoptosis of cervical cancer cells by promoting autophagy. Moreover, Cx32 triggered autophagy via the activation of the AMP‑activated protein kinase (AMPK) signalling, regardless of the presence or absence of GJs. Collectively, it was identified that Cx32 exerted its anti‑apoptotic effect by activating autophagy via the AMPK pathway in cervical cancer, which demonstrates a novel mechanism for Cx32 in human cervical cancer progression.

Family with sequence similarity 83 member A promotes tumor cell proliferation and metastasis and predicts poor prognosis in cervical cancer

Family with sequence similarity 83 member A (FAM83A) is a member of the FAM83 family and is proven to have oncogenic properties in several cancers. However, the mechanisms of FAM83A in human cervical cancer (CC) progression are unknown. Here, we found that FAM83A is highly expressed in CC tissues and cell lines through western blot and qRT-PCR. We utilized GEO datasets to assess FAM83A expression in CC in comparison to the normal cervical tissue (NCT) (GSE6791), and similarly, in lymph node positive CC compared to the lymph node negative CC (GSE26511). Immunohistochemistry (IHC) was used to quantify FAM83A expression in 20 NCT and 105 CC patient samples. FAM83A expression is upregulated in early-stage CC and correlates with aggressive clinicopathologic features. Moreover, both our hospital’s and TCGA datasets revealed that patients of early-stage CC with higher FAM83A expression had a poorer prognosis. Subsequently, CCK-8 and transwell assays verified that FAM83A promotes proliferation, migration, and invasion of CC cells. Additionally, Gene Set Enrichment Analysis (GSEA) revealed that FAM83A is not only involved in cell development, differentiation, and proliferation but is also correlated with cell junction assembly and cell matrix adhesion. It might also be affiliated with the regulation of tumor necrosis factor-mediated signaling pathway and the regulation of the ErbB signaling pathway in CC. These results indicate that FAM83A promotes tumor cell proliferation, migration, and metastasis. Our study provides novel evidence FAM83A may act as a promising therapeutic target for CC.

UBE2C Drives Human Cervical Cancer Progression and Is Positively Modulated by mTOR.

Cervical cancer is a common gynecological malignancy, accounting for 10% of all gynecological cancers. Recently, targeted therapy for cervical cancer has shown unprecedented advantages. Several studies have shown that ubiquitin conjugating enzyme E2 (UBE2C) is highly expressed in a series of tumors, and participates in the progression of these tumors. However, the possible impact of UBE2C on the progression of cervical squamous cell carcinoma (CESC) remains unclear. Here, we carried out tissue microarray analysis of paraffin-embedded tissues from 294 cervical cancer patients with FIGO/TNM cancer staging records. The results indicated that UBE2C was highly expressed in human CESC tissues and its expression was related to the clinical characteristics of CESC patients. Overexpression and knockdown of UBE2C enhanced and reduced cervical cancer cell proliferation, respectively, in vitro. Furthermore, in vivo experiments showed that UBE2C regulated the expression and activity of the mTOR/PI3K/AKT pathway. In summary, we confirmed that UBE2C is involved in the process of CESC and that UBE2C may represent a molecular target for CESC treatment.

Long noncoding RNA LINC00173 is downregulated in cervical cancer and inhibits cell proliferation and invasion by modulating the miR-182-5p/FBXW7 axis

Accumulating evidence has supported the concept that long noncoding RNAs (lncRNAs) participate in the initiation and progression of human cervical cancer (CC). The long intergenic nonprotein-coding RNA 173 (LINC00173) is a recently identified cancer-associated factor. However, the expression and biological role of LINC00173 in CC are poorly understood. Here, for the first time, we found that the expression of LINC00173 was decreased in CC tissues compared with that in nontumor tissues. Data from The Cancer Genome Atlas (TCGA) further revealed that the downregulated expression of LINC00173 in CC tissues was correlated with poor survival. Functionally, LINC00173 overexpression suppressed HeLa cell proliferation via induction of G0/G1 phase arrest. Ectopic expression of LINC00173 also repressed the invasiveness of HeLa cells. Conversely, LINC00173 depletion resulted in the enhanced proliferation and invasiveness of C33A cells. Mechanistically, LINC00173 functioned as a molecular sponge for miR-182-5p and inversely regulated the miR-182-5p level in CC cells. F-box and WD repeat domain-containing 7 (FBXW7) was identified as the target of miR-182-5p. LINC00173 overexpression enhanced the FBXW7 level via regulation of miR-182-5p in HeLa Cells. More importantly, the inhibitory effects of LINC00173 on HeLa cell proliferation and invasiveness were reversed by FBXW7 silencing. Taken together, the results indicate that the LINC00173/miR-182-5p/FBXW7 axis is critical for CC progression, which might offer new insights into effective therapy for CC.

Reduced long non-coding RNA PTENP1 contributed to proliferation and invasion via miR-19b/MTUS1 axis in patients with cervical cancer.

Many studies showed that long non-coding RNAs (lncRNAs) may serve as prospective markers for patients with malignant cancers, including cervical cancer (CC). In this study, we mainly investigate the functions of lncRNA PTENP1 in the progression of human CC. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to detect expression levels of PTENP1, miR-19b and MTUS1 in CC tissues, the adjacent tissues and CC cell lines. The correlations between PTENP1 with miR-19b, miR-19b with MTUS1 and PTENP1 with MTUS1 were analyzed. Overall survival (OS) of patients was analyzed using Kaplan-Meier method. Proliferation capacity was measured by CCK-8 assay and the invasion ability in CC cell line was detected by transwell assay. Western blot (WB) assay was performed to measure protein levels of tissues and CC cell lines. Finally, Dual-Luciferase reporter assay was performed to prove the potential binding sites between PTENP1 and miR-19b, miR-19b and MTUS1. We found that PTENP1 was reduced in CC tissues and CC cell lines, which predicted the poor diagnosis of CC patients. MiR-19b was increased in CC tissues, which was negatively correlated with PTENP1 in CC tissues. MTUS1 was reduced in CC tissues, which was negatively correlated with miR-19b and positively correlated within PTENP1 CC tissues. Furthermore, PTENP1 overexpression inhibited cell proliferation ability and invasion capacity in HeLa cells, as well as repressed expressions of Cyclin D1, N-cadherin, and Vimentin. Moreover, Luciferase gene reporter assays verified that miR-19b was a direct target miRNA of PTENP1, and MTUS1 was identified as a direct target of miR-19b. In addition, the inhibited cell proliferation and invasion abilities in HeLa cells with p-PTENP1 were eliminated following with miR-19b mimic transfection. According to the results, this study showed that PTENP1 was reduced in CC patients and it was a prognostic factor for CC patients. Furthermore, we firstly uncovered that PTENP1 could inhibit cell proliferation and invasion via miR-19b/MTUS1 in CC patients, which uncovered the tumor-suppressive role of PTENP1 in CC and suggested that it might be a potential target for treating human CC.

MAP7 promotes migration and invasion and progression of human cervical cancer through modulating the autophagy

BackgroundMicrotubule-associated proteins 7(MAP7) was reported to be engaged into the function of neuronal function. The function of MAP7 in human cervical cancer (CC) was unknown. We aimed to uncover the function and mechanism of MAP7 on CC.MethodsWe applied qRT-PCR, western blot and immunochemistry to detect the expression difference between normal tissue and CC. In vitro, we establish MAP7 stable knocking down and overexpression cell lines and investigated the function and underlying mechanism of MAP7 in CC.ResultsBoth mRNA and protein of MAP7 were upregulated in CC compared with the normal tissue. MAP7 was correlated with the clinical stage and tumor size and lymph node metastasis. MAP7 promotes the invasion and migration of CC cell lines. We next detected EMT pathway and autophagy associated pathway. MAP7 promotes the EMT through modulating the autophagy.ConclusionTaken above, our results showed that MAP7 promotes the migration and invasion and EMT through modulating the autophagy.

The high-risk HPV oncogene E7 upregulates miR-182 expression through the TGF-β/Smad pathway in cervical cancer.

Accumulating experimental evidence has shown that the aberrant expression of microRNAs (miRNAs) is involved in the development and progression of human cervical cancer. Previously, we identified miR-182 as an oncomiRNA in cervical cancer. However, the mechanism by which miR-182 is regulated and the interaction between human papillomavirus (HPV) and miR-182 in cervical cancer development remains unknown. In the present study, we explored the link between HPV E7 and miR-182 and verified that high-risk HPV E7 upregulated miR-182 expression through TGF-β/Smad4 signaling pathway in cervical cancer. By contrast, low-risk HPV E7 did not affect the expression of TGF-β and miR-182. Mechanistically, as high-risk HPV E7 bound to pRb, E2F was released from the complex and bound to the TGF-β promoter region, resulting in TGF-β overexpression. Furthermore, the Smad4 signaling pathway was activated upon TGF-β overexpression, which led to an interaction between Smad4 and the miR-182 promoter region, subsequently inducing the upregulation of miR-182 in both cervical cancer cells and the surrounding normal cells. In conclusion, this newly identified high-risk HPV E7/TGF-β/miR-182 regulatory network might inform the development of specific therapeutic strategies for cervical cancer.

Association of low expression of E-cadherin and β-catenin with the progression of early stage human squamous cervical cancer.

The precise involvement and mechanisms of human papilloma virus type 16 (HPV16) in epithelial-mesenchymal transition (EMT) of cervical intraepithelial neoplasia (CIN) and squamous cervical cancer (SCC) remain unknown. The present study aimed to examine the expression of EMT indicators and their association with HPV16 in CIN and early stage SCC, and their prognostic value in early stage SCC. The expression levels of E-cadherin, N-cadherin, β-catenin, vimentin, and fibronectin were determined by immunohistochemistry in 40 patients with normal uterine cervix, 22 patients with CIN1, 60 patients with CIN2-3, and 86 patients with SCC, stage Ia-IIa, according to the International Federation of Gynecology and Obstetrics. The expression of the epithelial indicators E-cadherin and β-catenin gradually declined, and the mesenchymal indicators N-cadherin, vimentin, and fibronectin increased with progression of the cervical lesions (P<0.05). Patients with SCC with lymph node metastasis, parametrial invasion, negative E-cadherin, and negative β-catenin expression had shorter overall survival (P=0.001, P=0.015, P=0.014, and P=0.043, respectively) and disease-free survival (P=0.002, P=0.021, P=0.025, and P=0.045, respectively) time. Multivariate survival analysis indicated that lymph node metastasis [Hazard ratio (HR)=3.544; P=0.010], parametrial invasion (HR=2.014; P=0.007) and E-cadherin expression (HR=0.163; P<0.001) were independently associated with overall survival, but also with disease-free survival (HR=3.612, P=0.009; HR=1.935, P=0.011; HR=0.168, P<0.001, respectively). In patients with CINs, HPV16 infection was negatively correlated with the expression of E-cadherin, and positively correlated with the expression of N-cadherin, vimentin, and fibronectin. EMT occurs during the progression of CINs to early stage SCC, and is associated with HPV16 infection in CINs. Lymph node metastasis and parametrial invasion are poor prognostic factors for SCC, while positive E-cadherin expression may serve as a protective prognostic factor for SCC.

RETRACTED ARTICLE: Melatonin enhances TNF-α-mediated cervical cancer HeLa cells death via suppressing CaMKII/Parkin/mitophagy axis

BackgroundTumor necrosis factor-α (TNF-α) immunotherapy controls the progression of human cervical cancer. Here, we explored the detailed molecular mechanisms played by melatonin in human cervical cancer (HeLa cells) death in the presence of TNF-α injury, with a particular attention to the mitochondrial homeostasis.MethodsHeLa cells were incubated with TNFα and then cell death was determined via MTT assay, TUNEL staining, caspase ELISA assay and western blotting. Mitochondrial function was detected via analyzing mitochondrial membrane potential using JC-1 staining, mitochondrial oxidative stress using flow cytometry and mitochondrial apoptosis using western blotting.ResultsOur data exhibited that treatment with HeLa cells using melatonin in the presence of TNF-α further triggered cancer cell cellular death. Molecular investigation demonstrated that melatonin enhanced the caspase-9 mitochondrion death, repressed mitochondrial potential, increased ROS production, augmented mPTP opening rate and elevated cyt-c expression in the nucleus. Moreover, melatonin application further suppressed mitochondrial ATP generation via reducing the expression of mitochondrial respiratory complex. Mechanistically, melatonin augmented the response of HeLa cells to TNF-α-mediated cancer death via repressing mitophagy. TNF-α treatment activated mitophagy via elevating Parkin expression and excessive mitophagy blocked mitochondrial apoptosis, ultimately alleviating the lethal action of TNF-α on HeLa cell. However, melatonin supplementation could prevent TNF-α-mediated mitophagy activation via inhibiting Parkin in a CaMKII-dependent manner. Interestingly, reactivation of CaMKII abolished the melatonin-mediated mitophagy arrest and HeLa cell death.ConclusionsOverall, our data highlight that melatonin enhances TNF-α-induced human cervical cancer HeLa cells mitochondrial apoptosis via inactivating the CaMKII/Parkin/mitophagy axis.

Long non-coding RNA Tsix is associated with human cervical cancer progression

Long non-coding RNA Tsix is associated with human cervical cancer progression

The evaluation of potent antitumor activities of shikonin coumarin-carboxylic acid, PMMB232 through HIF-1α-mediated apoptosis

In current study, a series of shikonin derivatives were synthesized and its anticancer activity was evaluated. As a result, PMMB232 showed the best antiproliferation activity with an IC50 value of 3.25±0.35μM. Further, treatment of HeLa cells with a variety of concentrations of target drug resulted in dose-dependent event marked by apoptosis. What’s more, the mitochondrial potential (Δym) analysis was consistent with the apoptosis result. In addition, PARP was involved in the progress of apoptosis revealed by western blotting. To identify the detailed role and mechanism of PMMB232 in the progression of human cervical cancer, we detected the expression of HIF-1α and E-cadherin in HeLa cells. Results showed that expression of HIF-1α was downregulated, while E-cadherin protein was upregulated. Meanwhile, glycolysis related protein PDK1 was decreased in HeLa cells. Conversely, the expression of PDH-E1α was upregulated. Docking simulation results further indicate that PMMB232 could be well bound to HIF-1α. Taken together, our data indicate that compound PMMB232 could be developed as a potential anticancer agent.

Reduced m6A mRNA methylation is correlated with the progression of human cervical cancer.

The m6A mRNA methylation involves in mRNA splicing, degradation and translation. Recent studies have revealed that reduced m6A mRNA methylation might promote cancer development. However, the role of m6A mRNA methylation in cervical cancer development remains unknown. Therefore, we investigated the role of m6A methylation in cervical cancer in the current study. We first evaluated the m6A mRNA methylation level in 286 pairs of cervical cancer samples and their adjacent normal tissues by dot blot assay. Then the role of m6A on patient survival rates and cervical cancer progression were assessed. The m6A level was significantly reduced in the cervical cancer when comparing with the adjacent normal tissue. The m6A level reduction was significantly correlated with the FIGO stage, tumor size, differentiation, lymph invasion and cancer recurrence. It was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with cervical cancer. Reducing m6A level via manipulating the m6A regulators expression promoted cervical cancer cell proliferation. And increasing m6A level significantly suppressed tumor development both in vitro and in vivo. Our results showed that the reduced m6A level is tightly associated with cervical cancer development and m6A mRNA methylation might be a potential therapeutic target in cervical cancer.

MiR-205 serves as a prognostic factor and suppresses proliferation and invasion by targeting insulin-like growth factor receptor 1 in human cervical cancer.

MicroRNAs are a kind of small and non-coding RNAs, which have been demonstrated to play an important role in the progression of human cervical cancer. Here, we found that the expression of miR-205 was low in cervical cancer cell lines and tissues, compared with matched non-tumor tissues and human endocervical epithelial cells. Also, miR-205 was inversely correlated with histological differentiation, metastasis, International Federation of Gynecology and Obstetrics stage, and the expression of insulin-like growth factor receptor 1 messenger RNA and protein. Besides, miR-205 or insulin-like growth factor receptor 1 expression is an independent prognostic factor. Mechanically, ectopic expression of miR-205 decreased proliferation, colony formation, and some proliferation/apoptosis-related proteins in cervical cancer cells. Ectopic expression of miR-205 caused G1 arrest. Luciferase reporter assays confirmed that binding of miR-205 to the 3' untranslated region of insulin-like growth factor receptor 1 may potentially decrease the expression of insulin-like growth factor receptor 1. Notably, insulin-like growth factor receptor 1 overexpression attenuated the inhibitory effects of miR-205 on cell proliferation and invasion, while small interfering RNA-insulin-like growth factor receptor 1 enhanced the inhibitory effects of miR-205 on cell proliferation and invasion. In conclusion, our findings suggested that miR-205 serves as a prognostic factor and suppresses proliferation and invasion by targeting insulin-like growth factor receptor 1 in human cervical cancer. Thus, miR-205/insulin-like growth factor receptor 1 pathway may be of great benefit to cervical cancer patients.