Cervical Squamous Cell Carcinoma Research Articles

Head and Neck Squamous Cell Carcinoma of Unknown Primary-Who Can Be Offered Surgery as the Sole Treatment Modality? A Systematic Review.

Evaluate the role of surgery as the sole treatment modality for patients with cervical head and neck squamous cell carcinoma of unknown primary (HNSCCUP). Systematic review of observational cohort studies with qualitative synthesis. PubMed, Ovid EMBASE, and Cochrane Controlled register of Trials (CENTRAL) were screened from January 2000 up to October 2021. Patients with HNSCCUP after completing diagnostic workup subsequently treated with single-modality surgery. The primary outcome was 3-year overall survival (OS). Secondary outcomes included disease-free survival (DFS), primary emergence, regional recurrence, and distant metastasis. Fourteen eligible studies were identified, including 1780 patients, of whom 294 received surgery as their sole treatment (seven studies) with 3-year OS ranging from 43.9% to 100%. 3-year DFS was reported in four studies (n = 62) ranging from 42.8% to 67.0%. 5-year OS and DFS were available in three studies (n = 31), ranging from 36.6% to 75.0%, and 43.6% to 67.0%, respectively. The rate of primary emergence ranged from 11.1% to 33.3% (seven studies, n = 157), regional relapse from 0.0% to 50.0% (five studies, n = 60) and distant metastasis from 0.0% to 3.3% (three studies, n = 45). Patients undergoing surgery as a sole treatment had predominantly p16/HPV positive N1 (TNM7) disease without ECS. Outcomes for HNSCCUP patients undergoing surgery alone range widely in the literature but may be reasonable in a subset of patients with early-stage p16/HPV positive disease. Data is lacking for p16/HPV negative disease where the potential primary site is more varied and primary emergence appears more common.

Deep learning for predicting prognostic consensus molecular subtypes in cervical cancer from histology images

Cervical cancer remains the fourth most common cancer among women worldwide. This study proposes an end-to-end deep learning framework to predict consensus molecular subtypes (CMS) in HPV-positive cervical squamous cell carcinoma (CSCC) from H&E-stained histology slides. Analysing three CSCC cohorts (n = 545), we show our Digital-CMS scores significantly stratify patients by both disease-specific (TCGA p = 0.0022, Oslo p = 0.0495) and disease-free (TCGA p = 0.0495, Oslo p = 0.0282) survival. In addition, our extensive tumour microenvironment analysis reveals differences between the two CMS subtypes, with CMS-C1 tumours exhibit increased lymphocyte presence, while CMS-C2 tumours show high nuclear pleomorphism, elevated neutrophil-to-lymphocyte ratio, and higher malignancy, correlating with poor prognosis. This study introduces a potentially clinically advantageous Digital-CMS score derived from digitised WSIs of routine H&E-stained tissue sections, offers new insights into TME differences impacting patient prognosis and potential therapeutic targets, and identifies histological patterns serving as potential surrogate markers of the CMS subtypes for clinical application.

Prognostic impact of glucagon-like peptide-1 receptor (GLP1R) expression on cancer survival and its implications for GLP-1R agonist therapy: an integrative analysis across multiple tumor types.

Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exenatide (Byetta, Bydureon), liraglutide (Victoza, Saxenda), albiglutide (Tanzeum), dulaglutide (Trulicity), lixisenatide (Lyxumia, Adlyxin), semaglutide (Ozempic, Rybelsus, Wegovy), and tirzepatide (Mounjaro, Zepbound), are widely used for the treatment of type 2 diabetes mellitus (T2DM) and obesity. While these agents are well known for their metabolic benefits, there is growing interest in their potential effects on cancer biology. However, the role of GLP-1R agonists in cancer remains complex and not fully understood, particularly across different tumor types. This study aimed to evaluate the prognostic significance of GLP1R expression on overall survival across various cancer types. Using a comprehensive analysis of gene expression data and survival outcomes a large cohorts of different tumor types, we employed Cox proportional hazards survival analyses, coupled with false discovery rate determinations, to explore correlations between GLP1R expression and survival. The integrated database included thousands of cancer specimens with available overall survival time and event data from numerous independent cohorts, providing a robust platform for survival analysis. Our findings reveal that increased GLP1R expression is associated with improved overall survival in cancers such as bladder cancer, breast cancer, esophageal adenocarcinoma, renal clear cell carcinoma, and thyroid carcinoma. Conversely, higher GLP1R expression is linked to poorer survival outcomes in cervical squamous cell carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Additionally, GLP1R expression showed no significant impact on overall survival in cancers such as esophageal squamous cell carcinoma, colon cancer, head-neck squamous cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, ovarian cancer, and pancreatic cancer. In conclusion, GLP1R expression levels serve as an important biomarker with potential prognostic significance across multiple cancers, demonstrating both protective and adverse associations depending on the tumor type. These findings highlight the complex role of GLP-1R agonists in cancer risk and survival, suggesting that the therapeutic use of these agents should be carefully tailored to the individual patient's cancer risk profile.

Expression of vesiculation-related genes is associated with a tumor-promoting microenvironment: a pan-cancer analysis.

Small extracellular vesicles (sEV) released by tumor cells (tumor-derived sEV; TEX) mediate intercellular communication between tumor and non-malignant cells and were shown to impact disease progression. This study investigates the relationship between the expression levels of the vesiculation-related genes linked to sEV production and the tumor microenvironment (TME). Two independent gene sets were analyzed, both previously linked to sEV production in various non-malignant or malignant cells. Expression profiles were compared among 28 tumor types listed in the Cancer Genome Atlas (TCGA). Gene expression and survival analysis (GEPIA2), immunogenomic analysis (TISIDB), and genomic analysis (GSCA) were performed. Vesiculation-related genes were overexpressed in tissues of most tumor types compared to healthy tissues, and high expression levels were associated with worse overall survival in cervical squamous cell carcinoma, kidney chromophobe, lower grade glioma, hepatocellular carcinoma, lung squamous cell carcinoma, and pancreatic adenocarcinoma but with improved overall survival in kidney renal clear cell carcinoma. Expression of these signatures correlated with an increased abundance of infiltrating CD4( +) T cells and dendritic cells, a decreased abundance of B cells and eosinophils, and activation of tumor cell apoptosis and epithelial-mesenchymal transition pathways in all tumor types. 17-AAG was identified as a potential drug candidate to target tumors with elevated expression of vesiculation-related genes. Vesiculation-related genes were associated with distinct immunological and genomic landscapes further emphasizing the important role of TEX in cancer progression.

Investigations for Suspected Head and Neck Squamous Cell Carcinoma of Unknown Primary (HNSCCUP): A National Cohort Study.

Head and neck squamous cell carcinoma from unknown primary (HNSCCUP) is a rare and challenging condition. This study aimed to investigate the diagnostic pathways of suspected HNSCCUP patients in the United Kingdom. A retrospective observational cohort study was conducted, over 5 years from January 2015, in UK Head and Neck centres of consecutive adults undergoing 18F-Fluorodeoxyglucose-PET-CT (PET-CT) within 3 months of diagnosis with metastatic cervical squamous cell carcinoma. Patients with no primary site on examination and no previous head and neck cancer were eligible. Data for 965 patients were received from 57 centres; 68.5% were HPV-related disease. Three investigation cycles were observed: ultrasound with biopsy, cross-sectional imaging (MRI and/or CT) and PET-CT, at median times of 17, 29.5 and 46 days from referral. No primary was identified on PET-CT in 49.8% (n = 478/960). Diagnostic tonsillectomy was performed in 58.2% (n = 278/478) and tongue base mucosectomy (TBM) in 21.7% (n = 104/479). Ipsilateral tonsillectomy carried the highest diagnostic yield (18.7%, n = 52/278), followed by TBM (15.4%, n = 16/104). Contralateral tonsillectomy, performed in 49.0% (n = 234/478), carried the lowest yield (0.9%, n = 2/234). PET-CT with concurrent MRI was associated with higher primary site detection than PET-CT with concurrent CT (p = 0.003). A minority of patients undergoing treatment with curative intent received first-definitive-treatment within 62 days of referral (15.2%, n = 77/505, median 92 days, IQR: 71-117). Most patients experienced a protracted diagnostic pathway and waited over 3 months for definitive treatment. Earlier PET-CT with concurrent MRI may expedite diagnosis. TBM appears more productive than contralateral tonsillectomy for primary site detection.

Whole-Genome Methylation Sequencing Analysis and Functional Verification of LIM-Homeobox Family Genes in Cervical Cancer.

Gene methylation in cells is an important factor in tumorigenesis, and radiotherapy can change DNA methylation in cells. In this study, complete genome methylation sequencing (BS-Seq) technology was used to analyze the genome-wide methylation of patients with cervical cancer before and after radiotherapy. Three pairs of cervical squamous cell carcinoma samples were collected from patients before and after radiotherapy in July 2020. Genome-wide DNA methylation profiles were generated using WGBS. Bioinformatics analysis was conducted to identify differential methylation regions (DMRs) and their associated genes and pathways. The study focused on the methylation changes of LHX2, LHX5, and LHX9 genes, assessing their expression levels using qRT-PCR and correlating these changes with cervical cancer stages. MCG was the main way of genomic DNA methylation in the three patients. The DNA methylation level and methylation density on each chromosome varied greatly. As revealed by comparison of methylation before and after radiation in the three patients, 1287, 1261 and 789 differential methylation genes were identified, respectively.3) Combined with clinical treatment, methylation level difference and correlation enrichment analysis, it was found that LHX2, LHX5 and LHX9 were closely related to the occurrence and development of cervical cancer. After 5-Aza-DC and radiotherapy, the methylation of the CpG islands in LHX2, LHX5 and LHX9 genes in these patients was decreased (p < 0.01), and the mRNA and protein expression levels were relatively increased (p < 0.01). In our present work, genome-wide DNA methylation maps of cervical cancer tissues before and after radiotherapy were successfully constructed. We found that LHX5 and LHX9 genes are closely related to cervical cancer. LHX5 and LHX9have a negative effect on cervical cancer. The migration ability of LHX9 silenced cells was significantly enhanced after irradiation.

Further confirmation of a highly prognostic grading scheme based upon tumour budding and cell cluster size in cervical squamous cell carcinoma.

Our study aimed to further confirm the clinical significance of the tumour budding activity and cell nest size-based (TBNS) grading scheme in cervical squamous cell carcinomas (SCC). We applied the TBNS system to assess the prognostic value in an institutional cohort of well-annotated cervical SCC consisting of 312 consecutive cases with surgical resection, no neoadjuvant chemotherapy and higher than stage pT1a. We found that high budding activity, single cell and TBNS grade 3 were more frequently associated with a decreased overall survival (OS) time and disease-free survival (DFS) time (P < 0.001) and several other clinicopathological factors, including lymphovascular space invasion, lymph node metastasis, advanced Federation of Gynecology and Obstetrics (FIGO) stage and deep invasion of the cervical wall (> 2/3) (P < 0.05). On multivariate analysis, TBNS grade 3 was an adverse indicator for OS and DFS independently of age, invasion of the cervical wall and FIGO stage (P < 0.05). By comparison, the conventional three-tiered grading system was not associated with OS and DFS in cervical SCC (P > 0.05). Our study further confirms that the TBNS grading scheme is robust in prognostic assessment in cervical SCC that outperforms the conventional three-tiered grading system. It is applicable to add TBNS grade into routine diagnostic practice.

Combined Effects of TLR4 and HIF-1α with COX-2 Genes in Cervical Squamous Cell Carcinoma Associated with HPV Infection

Combined Effects of TLR4 and HIF-1α with COX-2 Genes in Cervical Squamous Cell Carcinoma Associated with HPV Infection

Associations between ADC histogram analysis values and tumor-micro milieu in uterine cervical cancer

BackgroundThe complex interactions of the tumor micromilieu may be reflected by diffusion-weighted imaging (DWI) derived from the magnetic resonance imaging (MRI). The present study investigated the association between apparent diffusion coefficient (ADC) values and histopathologic features in uterine cervical cancer.MethodsIn this retrospective study, prebiopsy MRI was used to analyze histogram ADC-parameters. The biopsy specimens were stained for Ki-67, E-cadherin, vimentin and tumor-infiltrating lymphocytes (TIL, all CD45 positive cells). Tumor-stroma ratio (TSR) was calculated on routine H&E specimens. Spearman’s correlation analysis and receiver-operating characteristics curves were used as statistical analyses.ResultsThe patient sample comprised 70 female patients (age range 32–79 years; mean age 55.4 years) with squamous cell cervical carcinoma. The interreader agreement was high ranging from intraclass coefficient (ICC) = 0.71 for entropy to ICC = 0.96 for ADCmedian. Several ADC-histogram parameters correlated strongly with the TSR. The highest correlation coefficient achieved p10 (r = -0.81, p < 0.0001). ADCmean can predict tumors with high TSR, AUC: 0.91, sensitivity: 0.91 (95% CI 0.77;0.96), specificity: 0.91 (95% CI 0.78;0.97). Several ADC-histogram parameters correlated slightly with the proliferation index Ki-67. No associations were found with TIL, E-Cadherin and vimentin. In well and moderately differentiated cancers, ADC histogram values showed stronger correlations with Ki-67 and TSR than in poorly differentiated tumors.ConclusionADC values are strongly associated with tumor-stroma ratio. The ADC mean can be used to predict tumors with high TSR. Associations between histopathology and ADC values depend on tumor differentiation. ADC values show only weak associations with Ki-67 and none with TIL, vimentin and E-cadherin.

Role of lncRNA TPRG1-AS1 in the development of cervical squamous cell carcinoma and its prognostic value

ObjectiveCervical squamous cell carcinoma (CSCC) has a poor prognosis due to persistent HPV infection. LncRNA TPRG1-AS1 is linked to regulating the development of many cancers, so the regulatory mechanism and prognostic value of TPRG1-AS1 in CSCC were explored.Methods138 patients with cervical cancer were included. TPRG1-AS1 expression and miR-590-3p were analyzed by qRT-PCR. The association between TPRG1-AS1 and clinicopathological features was investigated. Independent prognostic factors of CSCC were analyzed by multifactorial Cox regression. Patient survival was analyzed using Kaplan–Meier plotter curves. CCK-8 was employed to evaluate the proliferative capacity of the cells. Transwell assays were performed to evaluate the effects of TPRG1-AS1 and miR-590-3p on cell migration and invasion performance, and the target of both was reported by DLR assay.ResultsTPRG1-AS1 levels were ascended in CSCC, and miR-590-3p levels were reduced. TPRG1-AS1 and miR-590-3p target binding and expression correlated negatively. Knockdown of TPRG1-AS1 expression could facilitate high miR-590-3p expression, which reduced cell proliferation, migration, and invasion ability. TPRG1-AS1 is an independent prognostic factor.ConclusionTPRG1-AS1 has potential as a prognostic marker for CSCC. Silencing the expression of TPRG1-AS1 could contribute to the high miR-590-3p expression thereby slowing down the progression of CSCC.

Metabolism and spatial transcription resolved heterogeneity of glutamine metabolism in cervical carcinoma

BackgroundReprogramming of cellular metabolism is a pivotal mechanism employed by tumor cells to facilitate cell growth, proliferation, and differentiation, thereby propelling the progression of cancer. A comprehensive analysis of the transcriptional and metabolic landscape of cervical squamous cell carcinoma (CSCC) at high resolution could greatly enhance the precision of management and therapeutic strategies for this malignancy.MethodsThe Air-flow-assisted Desorption Electrospray Ionization Mass Spectro-metric Imaging (AFADESI-MSI) and Spatial Transcriptomics techniques (ST) were employed to investigate the metabolic and transcription profiles of CSCC and normal tissues. For clinical validation, the expression of ASCT2(Ala, Ser, Cys transporter 2) was assessed using immune histochemistry in 122 cases of cervical cancer and 30 cases of cervicitis.ResultsThe AFADESI-MSI findings have revealed metabolic differences among different CSCC patients. Among them, the metabolic pathways of glutamine show more significant differences. After in situ detection of metabolites, the intensity of glutamate is observed to be significantly higher in cancerous tissue compared to normal tissue, but the intensity is not uniform. To elucidate the potential factors underlying alterations in glutamine metabolism across tissues, we employ ST to quantify mRNA levels. This analysis unveils significant perturbations in glutamine metabolism accompanied by extensive heterogeneity within cervical cancer tissues. After conducting a comprehensive analysis, it has been revealed that the differential expression of ASCT2(encoded by SLC1A5) in distinct regions of cervical cancer tissues plays a pivotal role in inducing heterogeneity in glutamine metabolism. Furthermore, the higher the expression level of ASCT2, the higher the intensity of glutamate is in the region. Further verification, it is found that the expression of ASCT2 protein in CSCC tissues is significantly higher than that in normal tissues (105/122, 86.07%).ConclusionsThis finding suggests that the variation in glutamine metabolism is not uniform throughout the tumor. The differential expression of ASCT2 in different regions of cervical cancer tissues seems to play a key role in causing this heterogeneity. This research has opened up new avenues for exploring the glutamine metabolic characteristics of CSCC which is essential for developing more effective targeted therapies.

Diagnosis, treatment and oncological outcome of cervical CUP-syndrome depending on p16 status

The incidence of cervical squamous cell carcinoma (SCC)-CUP is increasing, with a significant proportion being HPV-associated. In this 10-year retrospective study, we analyzed clinical and therapeutic parameters of patients with cervical SCC-CUP. Primary tumor detection rates in patients with initial SCC-CUP (SCC-CUPinit) were assessed and mean overall survival and disease-free survival of patients without primary tumor detection after an extended diagnostic workup, i.e. definitive SCC-CUP (SCC-CUPdef), were analyzed taking p16-status into account to derive therapeutic recommendations.85% (n=131/155) of patients with CUPinit, presented with SCC followed by adenocarcinoma metastases in 7% (n=10/155). In 41% (n=54/131) of patients with SCC-CUPinit, a primary tumor was identified after an extended diagnostic workup; the primary tumor detection rate was significantly higher in p16-positive compared to p16-negative cases (63% vs. 23%, p<0,001). PET imaging specificity was 73% for both sensitivity and specificity. SCC-CUPdef were primarily treated surgically with adjuvant radio(chemo)therapy. SCC-CUPdef patients with positive vs. negative p16-status had significantly longer overall survival (53 vs. 41 Monate, p=0,037), as well as patients with cN1- vs. cN3-status and M0- vs. M1-status.p16-status influences diagnosis and therapy response in patients with SCC-CUP: in p16-positive SCC-CUPinit, primary tumor detection rates were significantly higher than in p16-negative SCC-CUPinit. In patients with SCC-CUPdef, p16-positivity was associated with improved overall survival, albeit to an extent which does not justify therapy de-escalation.

Molecular characterization of ovarian squamous cell carcinoma originating from mature teratoma.

Squamous cell carcinoma (SCC) of the ovary, an uncommon form of gynecologic cancer, typically originates from the malignant transformation of a pre-existing mature ovarian teratoma (MOT). However, due to its rarity, the molecular pathways driving its development are not well understood. To address this knowledge gap, we performed molecular inversion probe (MIP) array analysis and targeted sequencing of 275 cancer susceptibility genes on 11 ovarian SCC samples derived from MOTs. Additionally, we conducted the same molecular tests on two samples of ovarian metastases of SCCs that originated from primary sites outside the ovary, specifically, one from endometrial cancer and one from cervical SCC. Utilizing MIP arrays, we identified failures in meiosis I and II, as well as instances of endoreduplication within haploid ova, in five, two, and four samples of ovarian SCCs arising from MOTs, respectively. Notably, such alterations were absent in samples of ovarian metastases, implying that primary ovarian SCCs may derive from teratoma cells. Targeted sequencing identified TP53 as the most frequently mutated gene in ovarian SCCs, occurring in 82% of cases. This was followed by mutations in PIK3CA (36%), PTEN (27%), and KMT2D (27%). Furthermore, mutations in CDKN2A and copy number loss of 9p21.3 were observed in 54.5% of the cohort. In summary, our study elucidates the germ cell origin of ovarian SCC and provides a comprehensive analysis of its genomic landscape, which may assist in differential diagnosis and inform the development of targeted therapies with potential clinical benefits. KEY MESSAGES: Failures in meiosis I/II and endoreduplication found in primary ovarian SCCs. Ovarian SCCs may derive from germ cells in mature teratomas. Alterations absent in ovarian metastases from SCC aid differential diagnosis. TP53 mutations found in 82% of ovarian SCC cases. CDKN2A mutations and 9p21.3 loss observed in 54.5% of ovarian SCC cohort.

ADAMDEC1 promotes cervical squamous cell carcinoma by enhancing the JAK/STAT signaling pathway through modulation of TYMP.

Cervical squamous cell carcinoma (CSCC) poses a significant health challenge, especially in developing countries. Identifying novel prognostic biomarkers and potential drug targets is crucial for improving CSCC management. We analyzed ADAMDEC1 expression patterns in CSCC using various bioinformatic datasets. Clinical samples from CSCC patients were evaluated for ADAMDEC1 and TYMP levels through Western blot and qRT-PCR. Multiple in vitro techniques, including flow cytometry, CCK-8, Transwell, Western blot, wound healing assays, and Co-IP, were employed to investigate the role and molecular pathways associated with ADAMDEC1. Our findings reveal that ADAMDEC1 is significantly overexpressed in CSCC tissues compared to adjacent healthy tissues. Functional assays demonstrated that ADAMDEC1 overexpression significantly enhances cell proliferation, migration, and invasion in vitro, while concurrently inhibiting apoptosis. Conversely, the knockdown of ADAMDEC1 reversed these effects, leading to reduced cell proliferation and increased apoptosis. Mechanistically, we identified a direct interaction between ADAMDEC1 and TYMP, which activates the JAK/STAT signaling pathway in CSCC cells. This activation was confirmed through Western blot analysis, indicating increased phosphorylation of JAK1 and STAT3 in response to ADAMDEC1 overexpression. ADAMDEC1 promotes CSCC progression by modulating the JAK/STAT pathway through regulation of TYMP. These findings suggest that ADAMDEC1 could serve as a molecular biomarker for early diagnosis and targeted therapy in CSCC.

Preclinical characterization of XB002, an anti-tissue factor antibody-drug conjugate for the treatment of solid tumors.

Tissue factor (TF) is overexpressed in various cancers, where its expression is generally associated with poor disease outcomes. XB002 is an anti-TF antibody-drug conjugate designed to deliver a cytotoxic payload to TF-expressing tumors while minimizing adverse events related to disruption of TF function, notably bleeding. XB002 is composed of a zovodotin linker-payload conjugated to a monoclonal antibody (clone 25A3) that binds to TF with high affinity (KD = 0.86 nM). In vitro coagulation studies indicated that 25A3 did not interfere with the clotting cascade; at a 100 nM concentration, 25A3 had no effect on activation of coagulation factor X or thrombin generation. XB002 was internalized in TF-expressing cancer cell lines and displayed potent cytotoxic activity at sub-nanomolar concentrations. When evaluated in the HPAF-II xenograft model, XB002 (1.5 mg/kg, IV) given once weekly for 2 weeks induced complete regression with no tumor growth even at 5 weeks after the second dose. In murine patient-derived xenograft models, a single dose of XB002 (10 mg/kg, IV) inhibited tumor growth across multiple cancer models including bladder, cervical, gastric, head and neck squamous cell carcinoma (HNSCC), and non-small cell lung cancer. Further, complete tumor regression was observed in both the cervical and HNSCC models by 30 days post-treatment. In non-human primate models, XB002 showed exposure in the desired range and no evidence of bleeding or neutropenia. Taken together, these data demonstrate potential anti-tumor activity across a spectrum of oncology indications and strongly support its clinical development.

TAp73 and ΔTAp73 isoforms show cell-type specific distributions and alterations in cancer

TP73 is a member of the TP53 gene family and produces N- and C-terminal protein isoforms through alternative promoters, alternative translation initiation and alternative splicing. Most notably, p73 protein isoforms may either contain a p53-like transactivation domain (TAp73 isoforms) or lack this domain (ΔTAp73 isoforms) and these variants have opposing or independent functions. To date, there is a lack of well-characterised isoform-specific p73 antibodies. Here, we produced polyclonal and monoclonal antibodies to N-terminal p73 variants and the C-terminal p73α isoform, the most common variant in human tissues. These reagents show that TAp73 is a marker of multiciliated epithelial cells, while ΔTAp73 is a marker of non-proliferative basal/reserve cells in squamous epithelium. We were unable to detect ΔNp73 variant proteins, in keeping with recent data that this is a minor form in human tissues. Most cervical squamous cell carcinomas (79%) express p73α, and the distribution of staining in basal cells correlated with lower tumour grade. TAp73 was found in 17% of these tumours, with a random distribution and no association with clinicopathological features. These data indicate roles for ΔTAp73 in maintaining a non-proliferative state of undifferentiated squamous epithelial cells and for TAp73 in the production of differentiated multiciliated cells.

TRIM3 modulates cisplmatin-resistant of cervical squamous cell carcinoma via endoplasmic reticulum stress signaling in vitro.

TRIM3 is widely recognized as a tumor suppressor gene. However, its precise role in cervical squamous cell carcinoma (CESC) remains elusive. Here, we observed a significant decrease in the expression of TRIM3 in CESC cells. Overexpression of TRIM3 suppresses cell proliferation and clonal formation. Through the establishment of cisplatin (cDDP)-resistant CESC cell lines, we discovered that the expression of TRIM3 was further downregulated in cDDP-resistant cells, while overexpression of TRIM3 enhanced cellular sensitivity to cDDP. Mechanistic investigations revealed that TRIM3 directly interacts with GRP78, a crucial protein involved in endoplasmic reticulum stress (ERS) pathway, promoting its ubiquitination degradation. Under cDDP treatment, the overexpression of TRIM3 in cDDP-resistant cells suppressed cell proliferation and downregulated the expression of drug-resistant genes, while simultaneously enhancing the activation of apoptosis signaling pathways. However, co-expression of TRIM3 and GRP78 restored cellular sensitivity to cDDP back to normal levels. Consequently, overexpressing TRIM3 in drug-resistant cells facilitates PERK activation and subsequent induction of apoptosis through inhibition of GRP78, ultimately suppressing drug resistance and inducing apoptosis in CESC cells. In conclution, our study suggests that the TRIM3/GRP78 axis regulates cDDP resistance in CESC cells by modulating the downstream apoptotic pathway of ERS.

CENPE is a Diagnostic and Prognostic Biomarker for Cervical Cancer

Cervical squamous cell carcinoma (CESC) is a common cancer in women. Despite advancements in early diagnosis through high-risk human papillomavirus (HPV) screening, challenges remain in predicting and treating the disease. Hence, the identification of novel biomarkers for prognosis and therapeutic targets is crucial.CENPE, a microtubule-end directed motor protein that accumulates during the G2 phase, is recognized for its involvement in promoting cancer growth and progression. However, its specific role in CESC remains unclear. This research investigated the expression of CENPE in CESC utilizing data from The Cancer Genome Atlas (TCGA), which was further validated through gene expression profiles, the Human Protein Atlas (HPA), and clinical data. The study utilized Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and immune infiltration analysis to elucidate the role of CENPE in CESC. Additionally, Protein-protein interaction (PPI) networks and competing endogenous RNA (CeRNA) networks involving CENPE and its differentially expressed genes were established. Furthermore, Kaplan-Meier survival analysis was conducted to evaluate the impact of CENPE on patient prognosis.Our study revealed an upregulation of CENPE expression in cervical cancer tissues, which promotes the progression of CESC through IL-6-mediated PI3K-Akt and MAPK signaling pathways. The significant associations with ACNG3, LY6H, and SLC6A7 suggest that CENPE may play a role in tumor growth and metastasis, potentially involving the nervous system. Moreover, the correlations with ARIH1, KDM1A, KDM5B, and NSD3 indicate that CENPE could be a promising target for drug development. Our analysis of the ROC curve demonstrated a high diagnostic accuracy of CENPE in CESC (AUC: 0.997, CI: 0.990-1.000). Subgroup analysis highlighted substantial effects in patients under 50 years old, those with a height under 160 cm, individuals in peri- and post-menopausal stages, and patients in clinical stages 1 and 4. Additionally, COX regression analysis indicated that older age, lower BMI, and higher CENPE expression are associated with decreased 1-year, 3-year, and 5-year survival rates.In conclusion, CENPE emerges as a crucial factor in the initiation and advancement of cervical cancer, showing potential as a novel target for therapeutic interventions.

KIF18A and CDK1 as combined therapeutic targets in cervical and endometrial carcinomas: based on bioinformatics analysis and in vitro experiments.

Chromosomal instability (CIN) has been identified as a factor that increases the susceptibility of tumor cells to kinesin family member 18A (KIF18A) inhibitors. Limited research exists on genes that are associated with sensitization to KIF18A inhibitors (KIF18Ais). Our study aimed to identify a gene linked to heightened sensitivity to KIF18Ais in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and uterine corpus endometrial carcinoma (UCEC). The Cancer Genome Atlas (TCGA) and X2K Appyter databases were used to analyze potential kinases associated with KIF18A-related genes in CESC and UCEC. In vitro assessments, such as Cell Counting Kit-8 (CCK-8), transwell, and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assays, were performed to evaluate the combined effects of KIF18A and cyclin-dependent kinase 1 inhibitors (CDK1is) in CESC and UCEC cell lines. Our findings indicated that the combination of KIF18A with kinases may potentially augment the efficacy of KIF18Ais, given its close involvement in cell cycle and chromosome segregation. Through bioinformatics analysis, we observed a significant up-regulation of CDK1 expression in CESC and UCEC, which exhibited a strong correlation with KIF18A expression. Our hypothesis regarding the potential of CDK1 as a combination therapeutic target for KIF18A was supported by our cell experiments, which demonstrated that inhibition of CDK1 notably increased the sensitivity of CESC and UCEC cells to KIF18Ais. The combined use of CDK1is and KIF18Ais exhibited a synergistic effect in inhibiting cell migration and inducing apoptosis in CESC and UCEC cells. This study provides evidence that targeting both KIF18A and CDK1 exerts synergistic anti-tumor effects in CESC and UCEC via inhibiting cell proliferation and migration and inducing apoptosis, suggesting a promising therapeutic strategy for these cancers.

New Classification of Tumor Microvessels and the Risk of Regional Metastasis in Squamous Cell and Glandular Cancers

Previously, we proposed a new classification of tumor microvessels (MVs) on the basis of their morphological features and clinical significance. The aim of this study was to summarize the obtained results and establish the predictive value of different types of tumor MVs for assessing the risk of metastasis to regional lymph nodes (RLNs) in glandular and squamous cell carcinomas.&amp;lt;i&amp;gt; Materials and methods.&amp;lt;/i&amp;gt; A total of 385 archival samples of gastric cancer stages I--III, breast cancer stages I--IIIA, cervical squamous cell carcinoma stages I--IIA, and lung squamous cell carcinoma stages I--IIIA were studied. The tumor sections were processed routinely and subjected to immunohistochemistry with antibodies against cluster of differentiation 34 (CD34) and podoplanin. To assess independent predictors of the risk of metastasis to RLNs, correlation analysis and univariate and multivariate logistic regression analyses were performed. Statistical analysis was performed via Statistica 10.0 software. &amp;lt;i&amp;gt;Results.&amp;lt;/i&amp;gt; For patients with gastric cancer and breast cancer, the independent predictors of a high risk of metastasis to RLNs are T2 (p=0.007) and T3 (p&amp;lt;0.00001) stages, tumor grade 3 (p=0.0002), the presence of lymphovascular invasion (LVI) (p=0.044) and peritumoral retraction clefts (p=0.008). For patients with squamous cell carcinoma of the cervix and lung, independent predictors of a high risk of metastasis to RLNs are the T2 (p=0.01) and T3 (p=0.007) stages, the presence of LVI (p=0.0014), dilated capillaries (DCs) of the &amp;quot;contact type&amp;quot; (p=0.0007), capillaries in the tumor solid component (p=0.046) and peritumoral retraction cleftings (p=0.0006). &amp;lt;i&amp;gt;Conclusion&amp;lt;/i&amp;gt;. The results of the present study indicate that when assessing the risk of metastasis to RLNs, it is advisable to consider the presence of peritumoral retraction clefting and LVI in both glandular and squamous cell carcinomas. In addition, in squamous cell carcinomas, the accuracy of assessing the risk of metastasis to RLNs can be increased by taking into account &amp;quot;contact-type&amp;quot; DCs and capillaries in the solid component of the tumor.