Prognostic Signatures Based on Ferroptosis- and Immune-Related Genes for Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) are among the most common malignancies of the female genital tract. Ferroptosis and immunity regulate each other and play important roles in the progression of CESC. The present study aimed to screen ferroptosis- and immune-related differentially expressed genes (FI-DEGs) to identify suitable prognostic signatures for patients with CESC. We downloaded the RNAseq count data and corresponding clinical information of CESC patients from The Cancer Genome Atlas database; obtained recognized ferroptosis- and immune-related genes from the FerrDb and ImmPort databases, respectively; and screened for suitable prognostic signatures using a series of bioinformatics analyses. We identified eight FI-DEGs (CALCRL, CHIT1, DES, DUOX1, FLT1, HELLS, SCD, and SDC1) that were independently correlated with the overall survival of patients with CESC. The prediction model constructed using these eight FI-DEGs was also independently correlated with overall survival. Both the sensitivity and specificity of the prediction model constructed using these eight signatures were over 60%. The comprehensive index of ferroptosis and immune status was significantly correlated with the immunity of patients with CESC. In conclusion, the risk assessment model constructed with these eight FI-DEGs predicted the CESC outcomes. Therefore, these eight FI-DEGs could serve as prognostic signatures for CESC.

Radiotherapy for Postsurgical Vaginal Recurrences of Cervical Squamous Cell Carcinoma: Analysis of Dosing and Prognosis

Background: This study aimed to investigate the efficacy of salvage radiotherapy for vaginal recurrence of cervical squamous carcinoma in patients who previously underwent surgery and to explore prognostic factors (particularly dose-related) associated with survival post-recurrence.Methods: Ninety-seven patients with histologically proven squamous cell carcinoma-subtype cervical cancer who were treated for vaginal recurrence at Peking Union Medical College Hospital between July 2011 and November 2019 were identified. All patients had previously undergone surgery for the primary tumor and received salvage external beam radiotherapy, brachytherapy, or both. Factors predictive of overall survival (OS), progression-free survival (PFS), and local control (LC) were investigated, as were adverse effects.Results: The median follow-up time was 42.5 months. The estimated 5-year OS, PFS, and LC rates were 84%, 79%, and 91%, respectively. On multivariate analysis, a tumor size ≤4 cm and an endovaginal recurrence pattern were associated with longer PFS (both P < 0.05); however, only the latter was predictive of a longer LC (P < 0.05). In the 33 patients with recurrences that were paravaginal or invasive of surrounding organs, biologically equivalent doses in 2 Gy fractions of ≥70 Gy were independently predictive of longer LC (P < 0.05). Finally, 12.4% of the patients experienced grades ≥2 late complications; only 1 patient who received EBRT alone experienced grade 5 late complications.Conclusions: RT is an effective treatment for post-surgical vaginal recurrence in patients with cervical squamous cell carcinoma. For patients with extravaginal recurrence, a salvage dose of ≥70 Gy appears to be optimal.

miR-140-Modified Bone Marrow Mesenchymal Stem Cells Enhance Chemotherapy Sensitization in Cervical Squamous Cell Carcinoma Cells via Targeting Microtubule Depolymerization Protein 1 (STMN1)

Effect of bone marrow mesenchymal stem cells (BMSCs) on the sensitivity of chemotherapy drugs and microRNAs (miRNAs) is still unclear. This study explored the role of miR-140 modified BMSCs in enhancing paclitaxel sensitivity of cervical squamous cell carcinoma (CSCC). Hela cells, BMSCs cells, and miR-140 modified BMSCs were transfected with miR-140 mimic, miR-140 inhibitor, and miR-140 NC, respectively. After transfection, they were co-cultured with Hela cells and paclitaxel to set up miR-140 mimic group, miR-140 inhibitor group, and miR-140 NC group (without paclitaxel treatment) followed by analysis of cell proliferation, apoptosis, ROS generation, expression of miR-140, STMN1, STAT3, p-STAT3, and survivin mRNA and protein. miR-140 inhibitor group showed lowest cell proliferation number and expressions of miR-140, STMN1, STAT3, p-STAT3, and survivin mRNA and protein with highest number of apoptotic cells, which were all reversed in miR-140 mimic group. There was a positive correlation between STMN1 level and miR-140 expression (r = 0.449, P = 0.108). BMSCs modified with miR-140 inhibitor can target STMN1, enhance the sensitivity of chemotherapy drugs, and exert an inhibitory effect on CSCC cell proliferation, suggesting that STMN1 might be a therapy target for treating CSCC.

Transcriptomic Profiling Reveals Cancer-Associated Fibroblasts as Potential Targets for the Prognosis and Treatment of Cervical Squamous Cell Carcinoma

To understand the etiological, structural, and immunological characteristics of cervical squamous cell carcinoma (CSCC), we conducted single nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics (ST) experiments for cervical samples from 20 individuals. When exploring the possible factors shaping the intra-individual immune heterogeneity in CSCC, we identified a cluster of cancer-associated fibroblasts (CAFs) enriched around some tumors, which highly expressed ACTA2, POSTN, ITGB4, and FAP. Results showed that the CAFs might support the growth and metastasis of tumors by inhibiting lymphocyte infiltration and remodeling the tumor extracellular matrix. Moreover, high CAF signals predicted poorer clinical outcomes for CSCC patients. Our data also revealed the infection profiles of HPV in tumors, the critical factors involved in the progression of cervical cancerous lesions, and the association between tumor metabolism and immune response intensity. Collectively, our findings may improve the prognostic and therapeutic methods for CSCC.

Comprehensive Analysis of The Clinical Significance and Prognostic Value of The CBX Family in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC)

Background: Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is the second most common type of cancer among gynecologic malignancies worldwide. Chromobox (CBX) family proteins are associated with the regulation of tumorigenesis, metastasis, and evolution of various cancers.Methods: The clinical features, expression levels, and prognostic value of CBXs in CESC were analyzed through several databases, including ONCOMINE, GEPIA, HPA, UALCAN, cBioPortal,Kaplan-Meier plotter and .Results: We concluded that the expression level of CBX2/4/8 was upregulated, while the expression level of CBX6/7 was downregulated in CESC specimens. Immune infiltration analysis revealed that CBX1/2/3/4/5/6/8 proteins were downregulated in normal cervical tissues, and upregulated in CESC specimens. In contrast, CBX7 protein expression was significantly higher in normal adjacent cervical tissues and was not detected in CESC tissues. CBX1/3/6 mRNA expression was significantly correlated with the pathological stage of CESC. Prognostic analysis showed that patients with high CBX7 levels of CESC had a favorable prognosis.Conclusions: Our study indicated that CBX7 could be an attractive biomarker for the prognosis of CESC.

Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance.

Human papillomavirus (HPV)-associated cervical cancer represents one of the leading causes of cancer death worldwide. Although low-middle income countries are disproportionately affected, our knowledge of the disease predominantly originates from populations in high-income countries. Using the largest multi-omic analysis of cervical squamous cell carcinoma (CSCC) to date, totalling 643 tumours and representing patient populations from the USA, Europe and Sub-Saharan Africa, we identify two CSCC subtypes (C1 and C2) with differing prognosis. C1 tumours are largely HPV16-driven, display increased cytotoxic T-lymphocyte infiltration and frequently harbour PIK3CA and EP300 mutations. C2 tumours are associated with shorter overall survival, are frequently driven by HPVs from the HPV18-containing alpha-7 clade, harbour alterations in the Hippo signalling pathway and increased expression of immune checkpoint genes, B7-H3 (also known as CD276) and NT5E (also known as CD73) and PD-L2 (also known as PDCD1LG2). In conclusion, we identify two novel, therapy-relevant CSCC subtypes that share the same defining characteristics across three geographically diverse cohorts.

Infection by High-Risk Human Papillomaviruses, Epithelial-to-Mesenchymal Transition and Squamous Pre-Malignant or Malignant Lesions of the Uterine Cervix: A Series of Chained Events?

Wound healing requires static epithelial cells to gradually assume a mobile phenotype through a multi-step process termed epithelial-to-mesenchymal transition (EMT). Although it is inherently transient and reversible, EMT perdures and is abnormally activated when the epithelium is chronically exposed to pathogens: this event deeply alters the tissue and eventually contributes to the development of diseases. Among the many of them is uterine cervical squamous cell carcinoma (SCC), the most frequent malignancy of the female genital system. SCC, whose onset is associated with the persistent infection of the uterine cervix by high-risk human papillomaviruses (HR-HPVs), often relapses and/or metastasizes, being resistant to conventional chemo- or radiotherapy. Given that these fearsome clinical features may stem, at least in part, from the exacerbated and long-lasting EMT occurring in the HPV-infected cervix; here we have reviewed published studies concerning the impact that HPV oncoproteins, cellular tumor suppressors, regulators of gene expression, inflammatory cytokines or growth factors, and the interactions among these effectors have on EMT induction and cervical carcinogenesis. It is predictable and desirable that a broader comprehension of the role that EMT inducers play in SCC pathogenesis will provide indications to flourish new strategies directed against this aggressive tumor.