Expression In Cervical Cancer Research Articles

Identification of proteins' expression pathway and the effective miRNAs for the treatment of human papillomavirus-induced cervical cancer: in-silico analyses-experimental research.

Cervical cancer is the fourth most common cancer in women. The risk factors for cervical cancer include human papillomavirus (HPV) infection, age, smoking, number of pregnancies, use of oral contraceptives, and diet. However, long-term HPV infection appears to be the main risk factor for developing cervical cancer. This in-silico analysis aims to identify the expression network of proteins and the miRNAs that play a role in the development of HPV-induced cervical cancer. The critical proteins and miRNAs were extracted using the DisGeNET and miRBase databases. String and Gephi were applied to the network analysis. The GTEx web tool was utilized to Identify tissue expression levels. The Enrichr website was used to explore the molecular function and pathways of found genes. Ten proteins, TP53, MYC, AKT1, TNF, IL6, EGFR, STAT3, CTNNB1, ESR1, and JUN, were identified as the most critical shared gene network among cervical cancer and HPV. Seven miRNAs were found, including hsa-mir-146a, hsa-mir-27, hsa-mir-203, hsa-mir-126, hsa-mir-145, hsa-mir-944, and hsa-mir-93, which have a common expression in cervical cancer and HPV. Overall, the gene network, including TP53, MYC, AKT1, TNF, IL6, EGFR, STAT3, CTNNB1, ESR1, and JUN, and Also, hsa-mir-145, hsa-mir-93, hsa-mir-203, and hsa-mir-126 can be regarded as a gene expression pathway in HPV-induced cervical cancer.

Alterations in miRNA Expression and Their Role in the Pathogenesis of Cervical Cancer.

Cervical cancer has a high incidence and mortality rate, affecting more than half a million women in 2018. Its development is strongly related to high-risk HPV infection. After infection, several cellular molecules are affected, including microRNAs (miRNAs), which are the focus of our study. We aimed to investigate changes in microRNA expression associated with cervical cancer and analyze the biological significance of these changes induced by HPV proteins. We analyzed transcriptome data retrieved from the NCBI website to investigate miRNA and gene expression in cervical cancer. We evaluated the alteration in expression of miRNAs and genes (between normal tissues and cervical cancer) using the GEO2R tool and selected those with significantly altered expression (p-value < 0.05). The target genes of miRNAs were predicted using the miRNA Pathway Dictionary Database. Subsequently, we created a network of biological pathways affected by miRNA deregulation using Cytoscape software and associated the altered miRNAs with the Hallmarks of Cancer using COSMIC v84. We identified 10 miRNAs and 82 target genes with significantly altered expression levels in cervical cancer that matched the predicted results. In addition, the deregulation of these genes causes changes in 52 biological pathways. These miRNAs affected pathways such as interferon signaling (miR-106b-5p and miR-1183), signaling by interleukins (miR-557, miR-106b-5p, miR-15a-5p, and miR-21-5p), oxidative stress-induced senescence (miR-557 and miR-15a-5p), cell cycle checkpoints (miR-557), transcriptional regulation by P53 (miR-557 and miR-15a-5p), and the exchange of oxygen and carbon dioxide in erythrocytes (miR-15a-5p). Alterations in miRNA expression play an important role in the pathogenesis of cervical cancer, affecting several biological pathways and Hallmarks of Cancer, such as immune system regulation, cell cycle regulation, and energy metabolism. Thus, their analysis can contribute to the development of diagnostic and prognostic biomarkers and more effective treatments for cervical cancer.

Unraveling the role of EPHA2 in regulating migration and immunomodulation processes in cervical cancer: exploring the synergic effect of 17β-estradiol on cancer progression.

Cervical cancer remained among the most prevalent cancers in women. Erythropoietin-producing hepatocellular A2 (EPHA2) is overexpressed in many cancers, including cervical cancer, and the mechanism by which it regulates cervical cancer progression is not yet fully understood. Exosomes are extracellular vesicles that carry information in the form of biomolecules, deliver it to the recipient cell, and play a vital role in cellular communication. 17β-Estradiol is the natural female steroid hormone with the greatest estrogenic activity, and it induces cell death in cancer. In this study, we investigated the function of EPHA2 in cervical cancer migration and immunomodulation and the presence of EPHA2 in the cervical cancer serum-derived exosome. A knockdown of EPHA2 (KD-EPHA2) in cervical cancer reduces cancer cell migration by regulating the CD113/Ezrin pathway. Furthermore, EPHA2 exhibited significant involvement in immunomodulation by orchestrating IL-6-mediated signalling cascades, including the AKT-mTOR and JAK-STAT pathways. Immune infiltration analysis revealed a correlation between EPHA2 expression in cervical cancer and the infiltration of various immune cell populations. KD-EPHA2 enhances the 17β-Estradiol inhibitory effect on cell proliferation and migration during cancer progression. In summary, our study revealed that EPHA2 is overexpressed in cervical cancer and plays a vital role in cancer cell migration and immunomodulation, and 17β-Estradiol, along with KD-EPHA2, enhances the inhibitory effect on cancer cell migration and proliferation.

Association between programmed cell death ligand-1 expression in patients with cervical cancer and apparent diffusion coefficient values: a promising tool for patient´s immunotherapy selection.

To investigate the associations between apparent diffusion coefficient (ADC) values extracted from three different region of interest (ROI) position approaches and programmed cell death ligand-1 (PD-L1) expression, and evaluate the performance of the nomogram established based on ADC values and clinicopathological parameters in predicting PD-L1 expression in cervical cancer (CC) patients. Through retrospective recruitment, a training cohort of 683 CC patients was created, and a validation cohort of 332 CC patients was prospectively recruited. ROIs were delineated using three different methods to measure the mean ADC (ADCmean), single-section ADC (ADCss), and the minimum ADC of tumors (ADCmin). Logistic regression was employed to identify independent factors related to PD-L1 expression. A nomogram was drawn based on ADC values combined with clinicopathological features, its discrimination and calibration performances were estimated using the area under the curve (AUC) of receiver operating characteristic and calibration curve. The clinical benefits were evaluated by decision curve analysis. The ADCmin independently correlated with PD-L1 expression. The nomogram constructed with ADCmin and other independent clinicopathological-related factors: FIGO staging, pathological grade, parametrial invasion, and lymph node status demonstrated excellent diagnostic performance (AUC = 0.912 and 0.903, respectively), good calibration capacities, and greater net benefits compared to the clinicopathological model in both the training and validation cohorts. ADCmin independently correlated PD-L1 expression, and the nomogram established with ADCmin and clinicopathological independent prognostic factors had a strong predictive performance for PD-L1 expression, thereby serving as a promising tool for selecting cases eligible for immunotherapy. The minimum ADC can serve as a reliable imaging biomarker related to PD-L1 expression; the established nomogram combines the minimum ADC and clinicopathological factors that can assist clinical immunotherapy decisions.

Prognostic Value of IMP3 Expression in Squamous Cervical Cancer.

Cervical cancer remains one of the leading causes of death from malignant diseases in women worldwide. Primary and secondary prevention have led to better outcomes in developed countries, whereas in developing countries, cervical cancer continues to be responsible for an unjustifiably high number of fatalities. The discovery of new tumor biomarkers can lead to earlier diagnosis, better therapeutic decisions, and improved treatment methods. IMP3 is a protein responsible for invasiveness and other aggressive characteristics of tumor processes. Its highly specific expression has been proven in various malignant processes. The level of IMP3 expression in cervical cancer cells could be used as a prognostic factor for a worse disease course. In this study, IMP3 expression was examined in 80 patients who underwent surgery for squamous cell cervical cancer in the first FIGO stage of the disease, and its association with disease-free period and overall survival was investigated. Data analysis did not show a statistically significant association between IMP3 expression and the mentioned primary outcomes, despite its association with clinical-pathological indicators of advanced disease. In conclusion, the analysis of IMP3 protein expression in patients with early-stage cervical cancer is of limited utility.

Retraction: Tim-3 Expression in Cervical Cancer Promotes Tumor Metastasis.

Retraction: Tim-3 Expression in Cervical Cancer Promotes Tumor Metastasis.

M2-type tumor-associated macrophages upregulated PD-L1 expression in cervical cancer via the PI3K/AKT pathway

Background and purposePD-1/PD-L1 inhibitors have become a promising therapy. However, the response rate is lower than 30% in patients with cervical cancer (CC), which is related to immunosuppressive components in tumor microenvironment (TME). Tumor-associated macrophages (TAMs), as one of the most important immune cells, are involved in the formation of tumor suppressive microenvironment. Therefore, it will provide a theoretical basis for curative effect improvement about the regulatory mechanism of TAMs on PD-L1 expression.MethodsThe clinical data and pathological tissues of CC patients were collected, and the expressions of PD-L1, CD68 and CD163 were detected by immunohistochemistry. Bioinformatics was used to analyze the macrophage subtypes involved in PD-L1 regulation. A co-culture model was established to observe the effects of TAMs on the morphology, migration and invasion function of CC cells, and the regulatory mechanism of TAMs on PD-L1.ResultsPD-L1 expression on tumor cells could predict the poor prognosis of patients. And there was a strong correlation between PD-L1 expression with CD163+TAMs infiltration. Similarly, PD-L1 expression was associated with M1/M2-type TAMs infiltration in bioinformatics analysis. The results of cell co-culture showed that M1/M2-type TAMs could upregulate PD-L1 expression, especially M2-type TAMs may elevate the PD-L1 expression via PI3K/AKT pathway. Meanwhile, M1/M2-type TAMs can affect the morphological changes, and enhance migration and invasion abilities of CC cells.ConclusionsPD-L1 expression in tumor cells can be used as a prognostic factor and is closely related to CD163+TAMs infiltration. In addition, M2-type TAMs can upregulate PD-L1 expression in CC cells through PI3K/AKT pathway, enhance the migration and invasion capabilities, and affect the tumor progression.

Decoding dysregulated genes, molecular pathways and microRNAs involved in cervical cancer

AbstractBackgroundThe present study aimed to identify dysregulated genes, molecular pathways, and regulatory mechanisms in human papillomavirus (HPV)‐associated cervical cancers. We have investigated the disease‐associated genes along with the Gene Ontology, survival prognosis, transcription factors and the microRNA (miRNA) that are involved in cervical carcinogenesis, enabling a deeper comprehension of cervical cancer linked to HPV.MethodsWe used 10 publicly accessible Gene Expression Omnibus (GEO) datasets to examine the patterns of gene expression in cervical cancer. Differentially expressed genes (DEGs), which showed a clear distinction between cervical cancer and healthy tissue samples, were analyzed using the GEO2R tool. Additional bioinformatic techniques were used to carry out pathway analysis and functional enrichment, as well as to analyze the connection between altered gene expression and HPV infection.ResultsIn total, 48 DEGs were identified to be differentially expressed in cervical cancer tissues in comparison to healthy tissues. Among DEGs, CCND1, CCNA2 and SPP1 were the key dysregulated genes involved in HPV‐associated cervical cancer. The five common miRNAs that were identified against these genes are miR‐7‐5p, miR‐16‐5p, miR‐124‐3p, miR‐10b‐5p and miR‐27a‐3p. The hub‐DEGs targeted by miRNA hsa‐miR‐27a‐3p are controlled by the common transcription factor SP1.ConclusionsThe present study has identified DEGs involved in HPV‐associated cervical cancer progression and the various molecular pathways and transcription factors regulating them. These findings have led to a better understanding of cervical cancer resulting in the development and identification of possible therapeutic and intervention targets, respectively.

Prevalence of HER-2 expression and correlation with clinicopathological features in gynecological cancer: A single-center retrospective study in China.

e17500 Background: Targeted therapy for human epidermal growth factor receptor 2 (HER2) has become a standard of care in several HER2-expressing solid tumors. Nonetheless, there remains an unmet need for effective treatment, for instance, anti-HER2 antibody-drug conjugates (ADCs), in advanced stage gynecological cancer. In this context, we presented a retrospective study on the incidence of HER2 expression in primary gynecological cancer based on a single-center data from southwestern China. Methods: Paraffin-embedded tumor tissue blocks, clinicopathological, and survival data of gynecological cancer patients were collected from Chongqing University Cancer Hospital. HER2 IHC scoring was carried out according to the updated ASCO/CAP guidelines for breast and gastroesophageal adenocarcinoma by two pathologists independently. Data analysis was performed using SPSS v.24. Results: A total of 104 cases of cervical cancer, 102 cases of endometrial cancer and 103 cases of ovarian cancer were included between 2019 and 2023. HER2 expression was detected in 31.7% samples, with scores of 1+, 2+, and 3+ in 23.9% (74/309: 36/104, 16/102, 22/103), 5.8% (18/309: 7/104, 7/102, 4/103), and 1.9% (6/309: 2/104, 1/102, 3/103) of patients, respectively. Notably, ultra-low HER2 expression with incomplete and faint staining in ≤10% of tumor cells was observed in 41.1% (127/309: 37/104, 53/102, 37/103) of patients. Metastasis and lymphovascular invasion were associated with elevated HER2 expression in endometrial cancer (p=0.037, 0.040, respectively), while a larger tumor size was associated with elevated HER2 expression in cervical cancer (p=0.004). However, no positive association between HER2 status and overall survival (OS) was found in cervical, endometrial or ovarian cancer. In our cohort, metastasis was the only risk factor related to reduced OS of gynecological cancer patients by COX regression analysis (HR=14.00, 95%CI=1.32-148.21, p=0.028). Conclusions: Our data revealed a considerable number of patients with HER2-low and ultra-low gynecological cancer. It might represent a significant portion in real-world scenarios and warrant more consideration in selecting candidates for HER2-targeted ADCs, especially for those with relapsed or refractory conditions. Given the inherent challenge in interpretation, the study highlights the necessity for a consensus on evaluating HER2 immuno-staining results in gynecological cancer. Clinical trial information: MR-50-23-019676 . [Table: see text]

The efficacy of immune checkpoint inhibitors on low PD-L1 cervical cancer: A meta-analysis.

The effectiveness of immune checkpoint inhibitors (ICIs) in low programmed death ligand 1 (PD-L1) expression in cervical cancer (CC) patients remains unknown. We aimed to evaluate the efficacy of ICIs in low PD-L1 expression CCpatients. The study is an individual patient data (IPD)-based meta-analysis. IPD were compiled through KMSubtraction and IPDfromKM methodologies from high-quality randomized clinical trials and single-arm studies which reported overall survival (OS) or progression-free survival (PFS) stratified by PD-L1 expression. Kaplan-Meier curves and Cox regression analysis were employed to evaluate the survival benefits of ICIs. A total of eightstudies and 1110 cases were included in the analysis. Within the low PD-L1 expression subgroup, ICI combination therapy, but not ICI monotherapy, demonstrated significant OS benefits over non-ICI treatment (hazard ratio [HR] = 0.61, 95% confidence interval [CI]:0.36-1.04, p = 0.06). Concerning PFS, ICI monotherapy was associated with a negative effect compared to non-ICI treatment (HR = 4.59, 95% CI:2.32-9.07, p < 0.001). Notably, both OS and PFS outcomes were unfavorable for ICI monotherapy compared to both non-ICI and ICI combination therapy in the combined positive score <1 subgroup (OS: HR = 2.60, 95% CI:1.31-5.16, p = 0.008; PFS: HR = 7.59, 95% CI:3.53-16.31, p < 0.001). In patients with CCand low PD-L1 expression, ICI monotherapy may not be considered as the optimal treatment strategy when compared to non-ICI treatment or ICI combination therapy. CRD42023395103.

Abstract 2955: HPV E6* and senescence-related gene expression in cervical cancer

Abstract Previous work in our lab found that increased expression of the E6* variant of the HPV E6 viral protein was significantly correlated with worse response to standard-of-care chemoradiation (CRT) and progression-free survival, independently of HPV genotype. In vitro validation showed that overexpression of E6* induces senescence in an HPV 16-positive cervical cancer cell line. Given these findings, we hypothesized that increased E6* expression mediates resistance to CRT by inducing a reversible state of tumor cell senescence. We created a senescence score using ten genes that have been consistently reported in the literature as associated with senescence. Using an institutional cohort of 68 patients with cervical cancer with prospectively collected clinical outcome data, we performed bulk RNA sequencing to assess senescence scores before CRT and determine whether there is an association between senescence scores and E6* expression. Using a second institutional cohort of 35 patients with cervical cancer treated with CRT with pre and posttreatment tumor biopsies, we performed bulk RNA sequencing to evaluate the same relationship and determine whether expression of senescence-related genes was affected by CRT. Nine cervical cancer cell lines stratified into low- and high-E6* expression groups will be assessed regarding their senescence score, beta-galactosidase staining, and SASP expression before and after CRT. In our first cohort, there was no correlation between E6*:E6 expression ratio and senescence score, regardless of HPV genotype. In our second cohort, CRT increased senescence score in CRT-treated samples (p &amp;lt; 0.01), but p16INK4a expression significantly decreased compared to pre-treatment samples (p &amp;lt; 0.01). Increased senescence score was not associated with cancer recurrence. There was no significant difference in senescence scores between different HPV genotypes before therapy. Tumors that were positive for HPV 16 or HPV 18 had significantly lower senescence scores compared to HPV negative tumors (p = 0.037 and p = 0.038, respectively) after CRT. Among HPV 16-positive tumors (n = 12), there was no correlation between E6*:E6 expression ratio and senescence score before or after CRT. We found no association between senescence score and E6* expression, and between senescence score and cancer recurrence after CRT in our dataset. Additionally, our results suggest that p16INK4a might not be an appropriate senescence marker in tumors that have intrinsically high p16INK4a expression, such as in cervical cancer, reinforcing the need for a cervical cancer-specific senescence signature. We are currently testing beta-galactosidase and SASP expression in vitro and in vivo before and after CRT. Citation Format: Louise Medina Bengtsson, Matthew Inkman, Naoshad Muhammad, Leahan Castillo, Naomi Msengi, Tyler McKinnish, Nishanth Gabriel, Jin Zhang, Julie Schwarz. HPV E6* and senescence-related gene expression in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2955.

NUPR1 contributes to activate TFE3-dependent autophagy leading to cervical cancer proliferation

Cervical cancer is a malignant tumor that occurs in the cervix of women and endangers their lives. In this study, we aimed to assess the roles of NUPR1 and TFE3 in cervical cancer. The Cancer Genome Atlas (TCGA) database was used to assess the correlation between NUPR1 and TFE3 expression in cervical cancer. By silencing NUPR1 and TFE3, and through 3-MA treatment, we determined whether their silencing could lead to lysosomal dysfunction, thereby inhibiting autophagy and cervical cancer cell proliferation. Their roles were further analyzed using molecular biological methods. Silencing NUPR1 and TFE3 inhibited cell proliferation and decreased the expression levels of autophagy-related genes, p62 and LC3B. By tracing lysosomes within cells, NUPR1 and TFE3 knockdown were found to induce lysosomal dysfunction, thereby inhibiting autophagy. In vivo experimental studies have shown that knockdown of NUPR1 and TFE3 can inhibit tumor growth, while reducing the ki67, p62, and LC3B expression levels and promoting apoptosis. Furthermore, the expression levels of lamp1 and lamp2, and the phosphorylation of PI3K (p-PI3K) and Akt (p-Akt) were significantly reduced after NUPR1 and TFE3 knockdown. However, treatment with 3-MA and overexpression of TFE3 could partially reverse the effect of silencing NUPR1. Overall, silencing NUPR1 reduced autophagy by inhibiting TFE3 in cervical cancer. Our results supply new evidence for the use of NUPR1 as a therapeutic target in cervical cancer.

A paradigm for post-embryonic Oct4 re-expression: E7-induced hydroxymethylation regulates Oct4 expression in cervical cancer.

The Octamer-binding transcription factor-4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post-embryonic re-expression is inadequately understood. In cervical cancer, Oct4 expression is higher in human papillomavirus(HPV)-related than HPV-unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4-transcriptional output and Oct4-related phenotypes in cervical cancer, however, the underlying mechanism remains elusive. Here, we characterize the Oct4-protein interactions in cervical cancer cells via computational analyses and Mass Spectrometry and reveal that Methyl-binding proteins (MBD2 and MBD3), are determinants of Oct4-driven transcription. E7 triggers MBD2 downregulation and TET1 upregulation, thereby disrupting the methylation status of the Oct4 gene. This coincides with an increase in the total DNA hydroxymethylation leading to the re-expression of Oct4 in cervical cancer and likely affecting broader transcriptional patterns. Our findings reveal a previously unreported mechanism by which the E7 oncogene can regulate Oct4 re-expression and global transcriptional patterns by increasing DNA hydroxymethylation and lowering the barrier to cellular plasticity during carcinogenesis.

Lymphoid-specific helicase inhibits cervical cancer cells ferroptosis by promoting Nrf2 expression.

Cervical cancer is a major cause of morbidity and mortality in women worldwide. The underlying mechanisms of its progression are not well understood. In this study, we investigated the role of lymphoid-specific helicase (HELLS) in cervical cancer. We measured HELLS expression in cervical cancer and assessed its function using gain- and loss-of-function experiments. Cell viability was measured using the Cell Counting Kit-8 (CCK8 ) assay, and cell proliferation was analyzed using colony formation and EdU assays. We found that HELLS was significantly increased in cervical cancer and that its overexpression promoted cell viability (P < 0.01) and colony formation (P < 0.001). In contrast, si-HELLS suppressed these effects. Moreover, HELLS overexpression inhibited cell death induced by the ferroptosis inducer erastin (P < 0.01). Mechanistically, we found that HELLS promoted cervical cancer proliferation by regulating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated ferroptosis. Our data suggest that HELLS promotes cervical cancer proliferation by inhibiting Nrf2 expression. Therefore, HELLS knockdown may be an effective treatment for cervical cancer.

Hsa_Circ_0000021 Sponges miR-3940-3p/KPNA2 Expression to Promote Cervical Cancer Progression.

Circular RNAs (circRNAs) have a vital role in the occurrence of numerous cancers. However, its function and pattern of expression in cervical cancer (CC) remain unclear. This research aims to investigate the hsa_circ_000002's regulatory mechanism in CC. Hsa_circ_0000021, miR-3940-3p, and KPNA2 expression levels were estimated through qRT-PCR. Nuclear/cytoplasmic separation was conducted to find the subcellular location of hsa_circ_0000021. Western blot was done to estimate the levels of KPNA2 protein. CCK-8, BrdU, wound healing, transwell, and tumor xenograft assays were performed to study how hsa_circ_0000021/miR-3940-3P/KPNA2 function affect CC. Hsa_circ_0000021's targeting relationships with miR-3940-3p and KPNA2 were ascertained through RIP and luciferase experiments. Hsa_circ_0000021 and KPNA2 were overexpressed and inversely associated with the levels of miR-3940-3p in CC. Knocking down either hsa_circ_0000021 or KPNA2 repressed the growth of CC tumors as well as the proliferation, invasion, and migration of CC cells. Silencing miR-3940-3p promoted the malignant proliferation of CC cells. Regarding its mechanism, hsa_circ_0000021 affected the malignant CC cell proliferation via the sponging of miR-3940-3p, which targeted KPNA2. Hsa_circ_0000021 regulates the miR-3940-3p/KPNA2 axis to promote CC occurrence. This potentially is a novel target for CC treatment.

Association between Human Papilloma Virus (HPV) genotype and protein of retinoblastoma expression in cervical cancer

Link of Video Abstract: https://youtu.be/5Q9QmV4Qmyg Background: Regarding prevalence among females worldwide, cervical cancer ranks fourth and has a high fatality rate. Cervical cancer growth is correlated with high-risk human papillomavirus (HPV) infection. Retinoblastoma protein (pRb) is a protein that interacts with E6/E7 oncoproteins to regulate cell proliferation, differentiation, and death. Mutations on the E6/E7 protein oncogenes of high-risk HPV can disrupt this relationship. This investigation aims to establish the association between pRb expression and the HPV genotype. Methods: This observational cross-sectional study examined 43 patients diagnosed with cervical cancer at Wahidin Sudirohusodo Hospital and its network. Samples were taken using consecutive random sampling based on established criteria. HPV genotype was examined using the polymerase chain reaction (PCR) method, while pRB expression was assessed by immunohistochemical examination. The relationship between the two variables was assessed using the Chi-Square test. Results: There were 5 (11.6%) patients with HPV type 16, 14 (32.6%) with HPV type 18, 12 (27.9%) with other types of HPV and 12 (27.9%) were negative for HPV. Examination of pRb expression showed that 33 (76.7%) samples had +2 expression, 7 (16.3%) had +1 expression, and 3 (7.0%) samples had no pRb expression. The pRb expression and HPV type were not significantly correlated in this study (p = 0.410). However, pRb expression and cervical cancer clinical stage were shown to be significantly correlated (p = 0.007). Conclusion: pRb expression is more prevalent when a malignancy is more advanced. In this investigation, no association between HPV genotype and pRb expression was discovered, despite oncogene mutations being involved in the regulation mechanism of cell proliferation, differentiation, and apoptosis.

Association between Human Papilloma Virus (HPV) genotype and mutant protein 53 (p53) expression in cervical cancer

Link of Video Abstract:https://youtu.be/fff-Unnud2w Background: Human Papilloma Virus (HPV) infection is the main cause of cervical cancer, a primary malignant tumor developing from squamous epithelial cells. HPV expresses oncoproteins E6 and E7, known to inactivate tumor suppressor proteins, one of which is protein 53 (p53). A promising biomarker for diagnosing and prognosis malignancies brought on by the HPV genotype is the identification of p53. This study investigates the association between p53 expression and HPV genotype in cervical cancer patients. Method: This observational cross-sectional study involved patients diagnosed with cervical cancer on histopathological examination who met the requirements. The polymerase chain reaction (PCR) method was used to determine the HPV genotype, and an immunohistochemistry analysis was used to assess the level of p53 expression. A Chi-Square test is utilized to evaluate the association between the two variables. Results: Of the 49 patients, there were 7 (14.3%) patients with HPV type 16, 13 (26.5%) with HPV type 18, 14 (26.5%) other types of HPV and 15 (30.6%) negatives for HPV. Examination of p53 expression showed that 17 (34.6%) samples had &lt;10% expression, 17 (34.6%) had 10-50% expression, and 15 (30.8%) samples had &gt;50% expression. There was no correlation between p53 expression and HPV genotype (p = 0.071). However, an association between p53 expression and cervical cancer's clinical stage was identified (p = 0.028). Conclusion: Increased cervical cancer stage can be associated with increased p53 expression. Thus, p53 can be used as a predictor of cervical cancer stage. However, in cervical cancer, p53 expression cannot be associated with the HPV genotype.

Interactions of EGFR/PTEN/mTOR-Pathway Activation and Estrogen Receptor Expression in Cervical Cancer.

(1) Objective: Late-line chemotherapy rechallenge in recurrent cervical cancer is associated with modest therapy response but significant side effects. As mTOR pathways modulate cellular growth via estrogen receptor (ER) signaling and combined mTOR and ER inhibition previously demonstrated survival benefits in breast cancer, this exploratory study evaluates mTOR pathway and ER expression interactions in a preclinical cervical cancer model. (2) Methods: Immunostaining of a 126-tumor core tissue microarray was performed to assess phosphorylated-mTOR and ER expression. To identify tumor subsets with different clinical behavior, expression results were matched with clinicopathologic patient characteristics, and both univariate and multivariable survival statistics were performed. (3) Results: phosphorylated-mTOR correlates with ER (r = 0.309, p < 0.001) and loss of PTEN expression (r = -2.09, p = 0.022) in tumor samples across stages but not in matched negative controls. Positive ER expression is observed significantly more often in phosphorylated-mTOR positive samples (30.0% vs. 6.3%, p = 0.001). In the subgroup of phosphorylated-mTOR positive tumors (n = 60), ER expression is associated with improved survival (p = 0.040). (4) Conclusion: ER expression appears closely intertwined with EGFR/PTEN/mTOR-pathway activation and seems to define a subgroup with clinically distinct behavior. Considering limited therapeutic options in recurrent cervical cancer, further validation of combined mTOR and ER inhibition in selected patients could appear promising.

Twist1‑mediated transcriptional activation of Claudin‑4 promotes cervical cancer cell migration and invasion.

Claudin-4, a member of the claudin multigene family, participates in events associated with mesenchymal-like activity of cancerous cells. Claudin-4 expression is upregulated in cervical cancer tissue compared with that in adjoining non-neoplastic tissue. However, the mechanisms that regulate Claudin-4 expression in cervical cancer are poorly understood. Moreover, whether Claudin-4 contributes to the migration and invasion of cervical cancer cells remains unclear. By western blotting, reverse transcription-qPCR, bioinformatics analysis, dual-luciferase reporter assay, chromatin immunoprecipitation assay, wound healing assay and Transwell migration/invasion assay, the present study confirmed that Claudin-4 was a downstream target of Twist1, a helix-loop-helix transcriptional factor, the activity of which has a positive correlation with Claudin-4 expression. Mechanistically, Twist1 directly binds to Claudin-4 promoter, resulting in the transactivation of expression. The depletion of the Twist1-binding E-Box1 domain on Claudin-4 promoter via CRISPR-Cas9 knockout system downregulates Claudin-4 expression and suppresses the ability of cervical cancer cells to migrate and invade by elevating E-cadherin levels and lowering N-cadherin levels. Following activation by transforming growth factor-β, Twist1 induces Claudin-4 expression, thus enhancing migration and invasion of cervical cancer cells. In summary, the present data suggested that Claudin-4 was a direct downstream target of Twist1 and served a critical role in promoting Twist1-mediated cervical cancer cell migration and invasion.

Effects of micro-colloidal Rhodomyrtus tomentosa on MMP9, GLUT-1, and IL-1β expression in Rattus norvegicus cervical cancer

Context: Rhodomyrtus tomentosa has the potential to contain compounds that enhance health. One type of disease that requires antioxidants in its healing is cancer. R. tomentosa extract was resized to nano size to optimize cell permeability. Aims: To analyze the effects of micro-colloidal leaves extract of R. tomentosa (MR) on MMP9, GLUT-1, and IL-1β expression in cervical cancer. Methods: Wistar rats were divided into five treatments, namely untreated (C-), cervical cancer (C+), and a cervical cancer rat model that was given R. tomentosa extract (MR) 100 mg/kg (MR100), 200 mg/kg (MR200), and 400 mg/kg (MR400). After receiving the extract for 30 days, all groups were analyzed using an immunohistochemical technique to detect MMP9, GLUT-1, and IL-1β antibodies. Results: From the statistical analysis, there was a substantial difference in the expression of MMP9, GLUT-1, and IL-1 in the C+ group compared to the C-, MR100, MR200, and MR400 groups (p&lt;0.005; p&lt;0.002: p&lt;0.001 p&lt;0.01, respectively). Unrestrained cell development, asymmetric cell shape, a sizeable nucleus-to-cytoplasm ratio, and various nucleus-form variants, and when MR was administered, the cervical histology of the tissues began to improve, similar to group C. In this group decreases the distance between the tumors, slows the growth of the carcinoma, and permits the nucleus to form appropriately in a cervical cancer cell was observed. Dosages of 200 and 400 mg/kg improved the histology of cervical tissue while decreasing MMP-9, GLUT-1, and IL-1β expression. Conclusions: Rhodomyrtus tomentosa ethanolic extract shows antimetastatic properties and could be analyzed as an anticancer therapy in the future.