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BACKGROUND: Small cell carcinoma of the cervix is a rare but poor prognosis pathological type of cervical cancer, for which advice in clinical guidelines is unspecific. We therefore aimed to investigate the factors and treatment methods that affect the prognosis of patients with small cell carcinoma of the cervix. METHODS: In this retrospective study, we collected data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries cohort and a Chinese multi-institutional registry. The SEER cohort included females diagnosed with small cell carcinoma of the cervix between Jan 1, 2000, and Dec 31, 2018, whereas the Chinese cohort included women diagnosed between Jun 1, 2006, and April 30, 2022. In both cohorts, eligibility was limited to female patients older than 20 years with a confirmed diagnosis of small cell carcinoma of the cervix. Participants who were lost to follow-up or those for whom small cell carcinoma of the cervix was not the primary malignant tumour were excluded from the multi-institutional registry, and those with an unknown surgery status (in addition to those for whom small cell carcinoma of the cervix was not the primary malignant tumour) were excluded from the SEER data. The primary outcome of this study was overall survival (length of time from the date of first diagnosis until the date of death from any cause, or the last follow-up). Kaplan-Meier analysis, propensity score matching, and Cox-regression analyses were used to assess treatment outcomes and risk factors. FINDINGS: 1288 participants were included in the study; 610 in the SEER cohort and 678 in the Chinese cohort. Both univariable and multivariable Cox regression analysis (SEER hazard ratio [HR] 0·65 [95% CI 0·48-0·88], p=0·0058; China HR 0·53 [0·37-0·76], p=0·0005) showed that surgery was associated with a better prognosis. In subgroup analyses, surgery remained a protective factor for patients with locally advanced disease in both cohorts (SEER HR 0·61 [95% CI 0·39-0·94], p=0·024; China HR 0·59 [0·37-0·95]; p=0·029). Furthermore, the protective effect of surgery was observed among patients with locally advanced disease after propensity score matching in the SEER cohort (HR 0·52 [95% CI 0·32-0·84]; p=0·0077). In the China registry, surgery was associated with better outcomes in patients with stage IB3-IIA2 cancer (HR 0·17 [95% CI 0·05-0·50]; p=0·0015). INTERPRETATION: This study provides evidence that surgery improves outcomes of patients with small cell carcinoma of the cervix. Although guidelines recommend non-surgical methods as first-line treatment, patients with locally advanced disease or stage IB3-IIA2 cancer might benefit from surgery. FUNDING: The National Key R&D Program of China and the National Natural Science Foundation of China.
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Carcinoma de Células Pequenas , Neoplasias do Colo do Útero , Feminino , Humanos , Carcinoma de Células Pequenas/epidemiologia , Carcinoma de Células Pequenas/terapia , Carcinoma de Células Pequenas/patologia , População do Leste Asiático , Estadiamento de Neoplasias , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Programa de SEER , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapiaRESUMO
Cervical carcinoma is a serious type of gynecological cancer that can affect women of all ages. Cervical carcinoma presents challenges for precision medicine, as not all tumors have specific gene mutations or alterations that can be targeted with existing drugs. Nonetheless, there are some promising targets in cervical carcinoma. Herein, genomic mutation data from The Cancer Genome Atlas and Catalogue of Somatic Mutations in Cancer were used to identify genomic targets for cervical carcinoma. PIK3CA was the most mutant gene among the promising targets, especially in cervical squamous cell carcinoma, and the mutated genes of cervical carcinoma were enriched in the RTK/PI3K/MAPK and Hippo pathways. In vitro, PIK3CA-mutant cervical cancer cell lines showed higher sensitivity to Alpelisib than cancer cells without the PIK3CA mutation and the normal cells (HCerEpic). Protein-protein networks and co-immunoprecipitation of PIK3CA revealed reduced interaction between p110α and ATR in PIK3CA-mutant cervical cancer cells, which were sensitive to the combination of Alpelisib and cisplatin in vivo. Furthermore, Alpelisib significantly suppressed the proliferation and migration of PIK3CA-mutant cervical cancer cells via inhibition of the AKT/mTOR pathway. Overall, Alpelisib showed antitumor effects and enhance cisplatin efficacy in PIK3CA-mutant cervical cancer cells via PI3K/AKT pathways. Our study demonstrated the therapeutic potential of Alpelisib in PIK3CA-mutant cervical carcinoma, which provides insights into precision medicine in cervical carcinoma.
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Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Cisplatino , Mutação , Genômica , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismoRESUMO
Human papillomavirus (HPV) integration and high expression of HPV oncogenes (E6 and E7) are important mechanisms for HPV carcinogenesis in cervical cancer. However, the relationship between HPV integration and HPV E6 spliced transcripts, as well as the underlying mechanisms of HPV integration in carcinogenesis after HPV E6 splicing remains unclear. We analyzed HPV-coiled-coil domain containing 106 (CCDC106) integration samples to characterize the roles of HPV integration, E6 spliceosome I (E6*I), and high CCDC106 expression in cervical carcinogenesis. We found that E6 was alternatively spliced into the E6*I transcript in HPV-CCDC016 integration samples with low p53 expression, in contrast to the role of E6*I in preventing p53 degradation in cervical cancer cells. In addition, CCDC106 was highly expressed after HPV-CCDC106 integration, and interacted with p53, resulting in p53 degradation and cervical cancer cell progression in vitro and in vivo. Importantly, when E6*I was highly expressed in cervical cancer cells, overexpression of CCDC106 independently degraded p53 and promoted cervical cancer cell progression. In this study, we explored the underlying mechanisms of HPV-CCDC106 integration in HPV carcinogenesis after HPV E6 splicing, which should provide insight into host genome dysregulation in cervical carcinogenesis.
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Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Proteínas Oncogênicas Virais/genética , Papillomavirus Humano , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/complicações , Carcinogênese , Proteínas de TransporteRESUMO
Integration of human papilloma virus (HPV) DNA into the human genome may progressively contribute to cervical carcinogenesis. To explore how HPV integration affects gene expression by altering DNA methylation during carcinogenesis, we analyzed a multiomics dataset for cervical cancer. We obtained multiomics data by HPV-capture sequencing, RNA sequencing, and Whole Genome Bisulfite Sequencing from 50 patients with cervical cancer. We detected 985 and 485 HPV-integration sites in matched tumor and adjacent paratumor tissues. Of these, LINC00486 (n = 19), LINC02425 (n = 11), LLPH (n = 11), PROS1 (n = 5), KLF5 (n = 4), LINC00392 (n = 3), MIR205HG (n = 3) and NRG1 (n = 3) were identified as high-frequency HPV-integrated genes, including five novel recurrent genes. Patients at clinical stage II had the highest number of HPV integrations. E6 and E7 genes of HPV16 but not HPV18 showed significantly fewer breakpoints than random distribution. HPV integrations occurring in exons were associated with altered gene expression in tumor tissues but not in paratumor tissues. A list of HPV-integrated genes regulated at transcriptomic or epigenetic level was reported. We also carefully checked the candidate genes with regulation pattern correlated in both levels. HPV fragments integrated at MIR205HG mainly came from the L1 gene of HPV16. RNA expression of PROS1 was downregulated when HPV integrated in its upstream region. RNA expression of MIR205HG was elevated when HPV integrated into its enhancer. The promoter methylation levels of PROS1 and MIR205HG were all negatively correlated with their gene expressions. Further experimental validations proved that upregulation of MIR205HG could promote the proliferative and migrative abilities of cervical cancer cells. Our data provides a new atlas for epigenetic and transcriptomic regulations regarding HPV integrations in cervical cancer genome. We demonstrate that HPV integration may affect gene expression by altering methylation levels of MIR205HG and PROS1. Our study provides novel biological and clinical insights into HPV-induced cervical cancer.
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Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Papillomavirus Humano , Transcriptoma , Multiômica , Epigenômica , Transformação Celular Neoplásica , Carcinogênese/genética , Papillomavirus Humano 16/genética , RNA/metabolismo , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Proteínas Oncogênicas Virais/genética , Integração ViralRESUMO
Cancer-associated fibroblasts (CAFs), enriched in the tumor stroma, have received increasing attention because of their multifaceted effects on tumorigenesis, development, metastasis, and treatment resistance in malignancies. CAFs contributed to suppressive microenvironment via different mechanisms, while CAFs also exerted some antitumor effects. Therefore, CAFs have been considered promising therapeutic targets for their remarkable roles in malignant tumors. However, patients with malignancies failed to benefit from current CAFs-targeted drugs in many clinical trials, which suggests that further in-depth investigation into CAFs is necessary. Here, we summarize and outline the heterogeneity and plasticity of CAFs mainly by exploring their origin and activation, highlighting the regulation of CAFs in the tumor microenvironment during tumor evolution, as well as the critical roles performed by CAFs in tumor immunity. In addition, we summarize the current immunotherapies targeting CAFs, and conclude with a brief overview of some prospects for the future of CAFs research in the end. Video Abstract.
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Fibroblastos Associados a Câncer , Neoplasias , Humanos , Fibroblastos , Neoplasias/terapia , Carcinogênese , Imunoterapia , Microambiente TumoralRESUMO
OBJECTIVE: The prognostic impact and treatment responses among cervical cancer patients with different histological types remains inconclusive. To determine the prognostic effects of different histologic types, we identified 39,088 patients with a diagnosis of cervical cancer between 2004 and 2016 from the Surveillance, Epidemiology, and End Results program. METHODS: Variables related to the prognosis of cervical cancer were evaluated using log-rank method and univariate/multivariate Cox models before and after propensity score matching. RESULT: Of the 36,310 patients, Squamous cell carcinoma (SCC) was the most common histological type (n = 27,043, 74.5%), followed by adenocarcinoma (AC, n = 7755, 21.4%) and adenosquamous carcinoma (ASC, n = 1512, 4.1%). Compared to SCC patients, patients with AC (HR = 1.14, 95%CI = 1.09-1.20, P < 0.01) and ASC (HR = 1.28, 95%CI = 1.18-1.40, P < 0.01) showed significantly poorer prognosis. Subgroup analyses indicated that the differences in prognosis between AC and SCC were only observed in stage II and III patients (P < 0.01). In patients with concurrent chemoradiotherapy, survival rates of patients with AC were significantly worse compared with similar patients with SCC (HR = 1.14, 95%CI = 1.03-1.27; P < 0.01). CONCLUSION: The prognostic impact of histologic types among patients with cervical cancer depends on tumor stages and therapeutic approaches. Tailored treatment and follow-up planning need to be developed across patients with different histological types and stages.
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Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Programa de SEER , Estados Unidos/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/terapiaRESUMO
BACKGROUND: We aimed to identify differentially expressed pseudogenes and explore their potential functions in four types of common gynecological malignancies (e.g., cervical squamous cell carcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, and uterine carcinosarcoma) using bioinformatics technology. MATERIALS AND METHODS: We identified up-regulated and down-regulated pseudogenes and built a pseudogene-miRNA-mRNA regulatory network through public datasets to explore their potential functions in carcinogenesis and cancer prognosis. RESULTS: Among the 63 up-regulated pseudogenes identified, LDHAP5 demonstrated the greatest potential as a candidate pseudogene due to its significant association with poor overall survival in ovarian serous cystadenocarcinoma. KEGG pathway analysis revealed that LDHAP5 showed significant enrichment in MicroRNAs in cancer, Pathway in cancer and PI3K-AKT signaling pathway. Further analysis revealed that EGFR was the potential target mRNA of LDHAP5, which may play an important role in ovarian serous cystadenocarcinoma. CONCLUSIONS: LDHAP5 was associated with the occurrence and prognosis of ovarian serous cystadenocarcinoma, and thus shows potential as a novel therapeutic target against such cancer.
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OBJECTIVE: Human papillomavirus (HPV) 16/18 genotyping is an effective method for triage of high-risk (hr) HPV-positive women in primary hrHPV screening for cervical cancer. The present study aimed to evaluate whether co-infected with other hrHPV types will affect the risk of cervical carcinogenesis in HPV16/18 positive women. METHODS: A total of 313,704 women aged ≥30 years were screened in China. Among them, 4,933 HPV16/18-positive participants underwent colposcopy-directed biopsy. The HPV genotypes were identified using the Cobas HPV genotyping system. Multinomial logistic regression was used to model different HPV16/18 infection patterns. RESULTS: The overall prevalence rates of hrHPV and HPV16/18 were 7.85% (24,456/311,382) and 1.95% (6,086/311,382) respectively. Among HPV16/18 positive individuals, 33.24% (2,023/6,086) were co-infection with multiple types. Of the 4933 women who underwent colposcopy, their HPV16/18 infection patterns were as follows: 52.38% (2,584/4,933) HVP16 only, 23.54% (1,161/4,933) HPV16 + other hrHPVs, 14.98% (739/4,933) HPV18 only, 6.83% (337/4,933) HPV18 + other hrHPVs, 1.13% (56/4,933) HPV16 + 18, 1.13% (56/4,933) HPV16 + 18+other hrHPVs. After adjusting for cofactors, compared with single HPV16 infection, the risk of developing cervical intraepithelial neoplasia (CIN) grade 3 or greater (CIN3+) was significantly lower in HPV16 + other hrHPVs group (odds ratio [OR] = 0.637, 95% confidence interval [CI] = 0.493-0.822). CONCLUSION: HPV16/18 co-infection with other hrHPVs is a common phenomenon. Different HPV16/18 infection patterns may influence the risk of cervical carcinogenesis. HPV16 co-infected with other hrHPVs appears to have a lower associated risk of CIN3+ in ≥30 years old women.
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Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Displasia do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Adulto , Carcinogênese , China/epidemiologia , Coinfecção/epidemiologia , Feminino , Genótipo , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , Prevalência , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/virologiaRESUMO
PURPOSE: Endometrial cancer arising in adenomyosis (EC-AIA) is frequently detected accidentally following a general hysterectomy for adenomyosis. Whether supplemental lymphadenectomy in patients with EC-AIA can improve the survival outcome remains inconclusive. Herein, the authors summarized the data of patients with EC-AIA and further explored the impact of lymphadenectomy on the prognosis of these patients. METHODS: Five electronic databases, namely MEDLINE, Web of Science, PubMed, Embase, and the Cochrane Library were employed for searching articles from inception to May 2023. RESULTS: In total, 38 eligible studies enrolling 56 patients were included. Of these, 44 patients had a traceable prognosis. Kaplan-Meier curves demonstrated that patients who had undergone lymphadenectomy had a better progression-free survival (PFS) compared with those who had not undergone lymphadenectomy ( P =0.016), but there was no difference in overall survival. Univariable ( P =0.025, HR=0.25, 95% CI=0.08-0.84) and multivariable ( P =0.042, HR=0.13, 95% CI=0.020-0.930) Cox regression analyses revealed that lymphadenectomy was an independent protective factor for PFS. CONCLUSION: For patients diagnosed with EC-AIA following hysterectomy for benign disease, further supplementary lymphadenectomy is recommended to improve PFS.
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Adenomiose , Neoplasias do Endométrio , Histerectomia , Excisão de Linfonodo , Humanos , Feminino , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/mortalidade , Adenomiose/cirurgia , Adenomiose/complicações , PrognósticoRESUMO
Endometrial cancer (EC) is a highly heterogeneous malignancy characterized by varied pathology and prognoses, and the heterogeneity of its cancer cells and the tumor microenvironment (TME) remains poorly understood. We conducted single-cell RNA sequencing (scRNA-seq) on 18 EC samples, encompassing various pathological types to delineate their specific unique transcriptional landscapes. Cancer cells from diverse pathological sources displayed distinct hallmarks labeled as immune-modulating, proliferation-modulating, and metabolism-modulating cancer cells in uterine clear cell carcinomas (UCCC), well-differentiated endometrioid endometrial carcinomas (EEC-I), and uterine serous carcinomas (USC), respectively. Cancer cells from the UCCC exhibited the greatest heterogeneity. We also identified potential effective drugs and confirmed their effectiveness using patient-derived EC organoids for each pathological group. Regarding the TME, we observed that prognostically favorable CD8+ Tcyto and NK cells were prominent in normal endometrium, whereas CD4+ Treg, CD4+ Tex, and CD8+ Tex cells dominated the tumors. CXCL3+ macrophages associated with M2 signature and angiogenesis were exclusively found in tumors. Prognostically relevant epithelium-specific cancer-associated fibroblasts (eCAFs) and SOD2+ inflammatory CAFs (iCAFs) predominated in EEC-I and UCCC groups, respectively. We also validated the oncogenic effects of SOD2+ iCAFs in vitro. Our comprehensive study has yielded deeper insights into the pathogenesis of EC, potentially facilitating personalized treatments for its varied pathological types.
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Neoplasias do Endométrio , Análise de Célula Única , Transcriptoma , Microambiente Tumoral , Humanos , Feminino , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/metabolismo , Transcriptoma/genética , Regulação Neoplásica da Expressão GênicaRESUMO
RNA processing mechanisms, such as alternative splicing and RNA editing, have been recognized as critical means to expand the transcriptome. Chimeric RNAs formed by intergenic splicing provide another potential layer of RNA diversification. By analyzing a large set of RNA-Seq data and validating results in over 1,200 blood samples, we identified UBA1-CDK16 , a female-specific chimeric transcript. Intriguingly, both parental genes, are expressed in males and females. Mechanistically, UBA1-CDK16 is produced by cis-splicing between the two adjacent X-linked genes, originating from the inactive X chromosome. A female-specific chromatin loop, formed between the junction sites, facilitates the alternative splicing of its readthrough precursor. This unique chimeric transcript exhibits evolutionary conservation, evolving to be female-specific from non-human primates to humans. Furthermore, our investigation reveals that UBA1-CDK16 is enriched in the myeloid lineage and plays a regulatory role in myeloid differentiation. Notably, female COVID-19 patients who tested negative for this chimeric transcript displayed higher counts of neutrophils, highlighting its potential role in disease pathogenesis. These findings support the notion that chimeric RNAs represent a new repertoire of transcripts that can be regulated independently from the parental genes, and a new class of RNA variance with potential implications in sexual dimorphism and immune responses.
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Despite the differences in disease outcomes and pathological features between cervical squamous cell carcinoma (CSCC) and adenocarcinoma (ADC), the molecular characteristics in immune heterogeneity of the tumor microenvironment remain unclear. Here, we explored the immune landscape and heterogeneity between CSCC and ADC. Gene expression and clinical characteristics of cervical carcinoma from The Cancer Genome Atlas (TCGA) were downloaded. Differentially expressed genes (DEGs), immune cell infiltration, and pathway enrichment analyses were used to explore the immune landscape and heterogeneity between CSCC and ADC. Furthermore, distinct immune signatures between CSCC and ADC were validated based on clinical samples. In total, 4,132 upregulated DEGs and 2,307 down-regulated DEGs were identified between CSCC and ADC, with enrichments in immune related-pathways in CSCC. In addition, 54 hub DEGs correlated with patients' prognosis and immunocytes infiltration were identified. The CSCC patients had a higher ImmuneScore and more abundant immunocytes infiltration compared to ADC patients, as validated by immunohistochemistry (IHC) and multicolor immunofluorescence (mIF) analyses of collected samples. Furthermore, CSCC displayed higher inhibitory immune checkpoints expression, tumor mutation burden (TMB), and microsatellite instability (MSI) compared to ADC, which indicated CSCC patients were more likely to benefit from immunotherapy. In summary, our results revealed the huge immune heterogeneity between CSCC and ADC, and provided guidance for immunotherapy selection for different pathological types of cervical cancer.
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Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/patologia , Carcinoma de Células Escamosas/metabolismo , Prognóstico , Adenocarcinoma/genética , Microambiente Tumoral/genéticaRESUMO
Human papillomavirus (HPV) is predominantly associated with HPV-related cancers, however, the precise mechanisms underlying the HPV-host epigenetic architectures in HPV carcinogenesis remain elusive. Here, we employed high-throughput chromosome conformation capture (Hi-C) to comprehensively map HPV16/18-host chromatin interactions. Our study identified the transcription factor Sp1 as a pivotal mediator in programming HPV-host interactions. By targeting Sp1, the active histone modifications (H3K27ac, H3K4me1, and H3K4me3) and the HPV-host chromatin interactions are reprogrammed, which leads to the downregulation of oncogenes located near the integration sites in both HPV (E6/E7) and the host genome (KLF5/MYC). Additionally, Sp1 inhibition led to the upregulation of immune checkpoint genes by reprogramming histone modifications in host cells. Notably, humanized patient-derived xenograft (PDX-HuHSC-NSG) models demonstrated that Sp1 inhibition promoted anti-PD-1 immunotherapy via remodeling the tumor immune microenvironment in cervical cancer. Moreover, single-cell transcriptomic analysis validated the enrichment of transcription factor Sp1 in epithelial cells of cervical cancer. In summary, our findings elucidate Sp1 as a key mediator involved in the programming and reprogramming of HPV-host epigenetic architecture. Inhibiting Sp1 with plicamycin may represent a promising therapeutic option for HPV-related carcinoma.
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Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Cromatina/genética , Epigênese Genética , Papillomavirus Humano 16/metabolismo , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/metabolismo , Papillomavirus Humano , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/terapia , Fatores de Transcrição/genética , Microambiente Tumoral , Neoplasias do Colo do Útero/patologiaRESUMO
Cuproptosis is a copper-dependent model of cell death involved in tumor genesis and progression. Its roles in uterine corpus endometrial carcinoma (UCEC) remains elusive. Here, we aimed to explore the expression and prognostic values of cuprotosis-related genes (CRGs) in UCEC. Expression profiles and clinical data of UCEC were downloaded from The Cancer Genome Atlas (TCGA), and randomly divided into testing or training cohort (1:1 ratio). The CRG signature was identified by LASSO regression analysis. The differentially expressed genes and their functional enrichment analysis were performed by the "limma" R package and Metascape, respectively. The immunocytes infiltration was measured by TIMER, and "GSVA" R package. In total, seven differentially expressed prognostic genes of CRGs in UCEC were identified, and four genes (GLS, CDKN2A, PC, and SUCLG1) were selected to construct a predictive model in training cohort. UCEC patients from training and testing cohorts were further divided into high- or low-risk groups according to the median risk score. High-risk group favored poor prognosis compared to low-risk group. Functional enrichment analysis revealed this CRG signature were got involved in the process of cell-cell adhesion and immune activities (e.g., IL-1 signaling pathway, cellular response to cytokine stimulus). Further analyses revealed there were significant differences between high- and low-risk patients regarding immunocytes infiltration, chemokines, and chemokine receptors. Finally, the expression and biological functions of identified CRGs were confirmed by UCEC samples and experimental methods in vitro. In summary, the CRG signature was significantly correlated with patients' overall survival, which could provide insights into the diagnosis and prognosis prediction for UCEC.
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BACKGROUND: Cervical squamous cell carcinoma (CSCC) and adenocarcinoma (CAde) are two major pathological types of cervical cancer (CC), but their high-resolution heterogeneity of tumor and immune microenvironment remains elusive. METHODS: Here, we performed single-nucleus RNA sequencing (snRNA-seq) from five CSCC and three CAde samples, and systematically outlined their specific transcriptome atlas. FINDINGS: We found CD8+ T cells in CSCC were more cytotoxic but lower exhausted compared to those in CAde, and phagocytic MRC1+ macrophages were specifically enriched in CSCC. Interestingly, we discovered that pro-tumoral cancer-associated myofibroblasts (myoCAFs) and cancer-associated vascular-fibroblasts (vCAFs) were more abundant in CSCC, and further verified their pro-metastatic roles in vitro. Furthermore, we also identified some specific chemotherapy drugs for CSCC (Dasatinib and Doramapimod) and CAde (Pyrimethamine and Lapatinib) by revealing their heterogeneity in transcriptomic profiles of malignant epithelial cells, and further verified their specific sensitivity in cell lines and constructed CC-derived organoids. Cell-cell communication networks revealed that the pathways of NRG1-ERBB2, and FN1-ITAG3 were specific for CAde and CSCC, respectively, which may partly explain the specificities of identified chemotherapy drugs. INTERPRETATION: Our study described the immune heterogeneity and specific cellular interactions between CSCC and CAde, which could provide insights for uncovering pathogenesis and designing personalized treatment. FUNDINGS: National Key R&D Program of China (2021YFC2701201), National Natural Science Foundation of China (82072895, 82141106, 82103134, 81903114).
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Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Feminino , Humanos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Análise de Sequência de RNA , Microambiente Tumoral/genéticaRESUMO
Background: Kidney renal clear cell carcinoma (KIRC) is the most common pathological subtype of renal cell cancer. APOBEC3 activity has been identified in a variety of human cancers. Although its involvement in cancer has been studied widely, its influence on the tumor immune microenvironment remains poorly understood. Therefore, this study aimed to focus on the effect of APOBEC3 on tumor immune microenvironment of KIRC. Methods: In this study, we comprehensively analyzed the expression and prognostic significance of the APOBEC3 family in pan-cancer using multiple databases. The functions of key APOBEC3 family members were further investigated in KIRC, with APOBEC3G determined to be a candidate biomarker for unfavorable prognosis. We subsequently explored the correlation of APOBEC3G with the tumor immune environment in KIRC by analyzing the Cancer Genome Atlas (TCGA) dataset, then validated the prognostic significance and PD-L1 correlation of APOBEC3G by using tissue microarrays which included 233 primary tumor samples from patients with renal clear cell carcinoma. Results: The APOBEC3 family was overexpressed in KIRC and high APOBEC3 expression predicted poor prognosis. In addition, APOBEC3G was positively correlated with the expression of immunoinhibitors such as TIGIT, LAG3, CD96, PD-1, and CTLA4. In addition, APOBEC3G had a positive correlation with immunosuppressive cells, including regulatory T cell and myeloid-derived suppressor cell. Finally, based on 233 clinical samples, we validated that high expression of APOBEC3G contributed to a poor prognosis for KIRC patients and the positive relationship between APOBEC3G and PD-L1 expression. High APOBEC3G expression was also found to be more common in patients with sarcomatoid histology (P = 0.0026). Conclusions: Our study showed that APOBEC3G was a prognostic biomarker correlated with the immune response in KIRC. In addition, APOBE3G had a positive correlation with PD-L1 expression and sarcomatoid histology, perhaps suggesting the potential impact of APOBEC3G on immunotherapy.
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Lysyl oxidase-like 2 (LOXL2) is a member of the lysine oxidase (LOX) family. Although its overexpression is known to play pivotal roles in carcinogenesis, its involvement in cervical cancer remains undefined. Here, we comprehensively explored the expression level and functional mechanism of LOXL2 in cervical cancer using bioinformatics and experimental methods. Bioinformatics analysis revealed that LOXL2 was significantly upregulated in cervical cancer compared to normal tissues. Enrichment analysis showed that most positively or negatively correlated genes of LOXL2 were correlated with extracellular matrix (ECM) formation and epithelial-mesenchymal transition (EMT). Further experiments confirmed that overexpression of LOXL2 greatly enhanced the malignant transformation abilities (e.g. proliferation, invasion, and migration) of cervical cancer cells via mediation of EMT. Furthermore, the small molecule inhibitor of LOXL2 ((2-Chloropyridin-4-yl) methanamine hydrochloride) significantly decreased the invasive ability of cervical cancer by reversing the process of LOXL2-induced EMT. In summary, LOXL2 may be a promising diagnostic and therapeutic biomarker for cervical cancer, and its small molecule inhibitor may be an effective anti-tumor drug.Abbreviations: LOXL2 Lysyl oxidase-like 2; LOX lysine oxidase; CI confidence interval; HR hazard ratio; ECM extracellular matrix; EMT epithelial-mesenchymal transition; OS overall survival; IC50 median inhibitory concentration; PPI protein-protein interaction.
Assuntos
Aminoácido Oxirredutases , Transição Epitelial-Mesenquimal , Neoplasias do Colo do Útero , Aminoácido Oxirredutases/antagonistas & inibidores , Transformação Celular Neoplásica , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lisina/metabolismo , Proteína-Lisina 6-Oxidase/genética , Proteína-Lisina 6-Oxidase/metabolismo , Neoplasias do Colo do Útero/genéticaRESUMO
Paclitaxel remains the first-line chemotherapy regimen for many malignant tumors. However, prognosis and adverse events under different dosing regimens (one-week versus three-week treatment) remain contradictory in many randomized controlled trials (RCTs). Here, we performed a comprehensive meta-analysis to measure the efficacy and toxicities of these two dosing regimens. Four databases were systematically retrieved. RCTs comparing two paclitaxel dosing regimens for advanced malignant tumors with assessable outcomes (e.g., overall survival (OS), progression-free survival (PFS), toxicities, response rates) were included. In total, 19 eligible RCTs involving 9 674 patients were included. Meta-analysis of pan-cancers revealed that weekly paclitaxel treatment was more beneficial regarding PFS compared to three-week paclitaxel treatment (hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.82-0.99, P = 0.02). Nevertheless, there was no significant difference in terms of OS between the two dosing regimens (HR = 0.98, 95%CI = 0.91-1.06, P = 0.62) or other tested subgroups. In terms of serious adverse events, grade 3 or 4 (G3/4) neutropenia, G3/4 febrile neutropenia, G3/4 arthritis, and G3/4 alopecia occurred less often under weekly paclitaxel treatment. In summary, Weekly paclitaxel treatment demonstrates better PFS and fewer chemotherapy-induced hematological and non-hematological toxicities compared to the three-week paclitaxel regimen.
Assuntos
Carcinoma , Paclitaxel , Carcinoma/tratamento farmacológico , Humanos , Paclitaxel/uso terapêutico , Intervalo Livre de ProgressãoRESUMO
LIM homeobox 6 (LHX6) has been reported to be downregulated and inhibits cell proliferation in various cancers. Alternative splicing of LHX6 leads to six annotated isoforms, which can be found in the NCBI database. However, the expression patterns and potential roles of these isoforms remain poorly characterized in cervical cancer. Here, we demonstrated that the LHX6 isoforms containing exon 12 (LHX6EX(+12) group) and isoforms lacking exon 12 (LHX6EX(-12) group) were differentially expressed in cervical tissue by qRT-PCR. The mRNA expression level of LHX6EX(+12) group was higher than that of LHX6EX(-12) group in cervical cancer tissue. Knockdown of LHX6EX(+12) group and all LHX6 isoforms (LHX6All group) inhibited cell growth, increased cell apoptosis, and induced cell cycle arrest from G0/G1 phase to S phase in vitro. Consistently, overexpression of the LHX6EX(+12) group promoted cervical cancer cell proliferation in vitro. In contrast, no significant differences in cell proliferation were found between LHX6EX(-12) isoform knockdown group and its control. RNA-sequencing suggested that the LHX6EX(+12) isoform group might exert its cancer-promoting effects in cervical cancer via regulating MAPK signaling pathway. Downregulation of the LHX6EX(+12) group significantly suppressed the phosphorylation of MRK, ERK, JNK, and P38 at the protein level. We also identified some unique biological processes and signaling pathways in which each isoform group might be involved. In summary, our results indicated that LHX6EX(+12) isoform group was the dominant oncogenic type of LHX6 in cervical cancer, which may be a new biomarker and a potential precise therapeutic target for cervical cancer in the future.
Assuntos
Neoplasias do Colo do Útero , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , Éxons , Feminino , Humanos , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Proteínas do Tecido Nervoso/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA , RNA Mensageiro , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias do Colo do Útero/genéticaRESUMO
RNA methylation has recently emerged as an important category of epigenetic modifications, which plays diverse physiopathological roles in various cancers. Recent studies have confirmed the presence of 5-methylcytosine (m5C) modification on mammalian mRNAs, mainly modified by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), but little is known about the underlying functions of m5C. Gynecologic cancers are malignancies starting from women's reproductive organs. The prevalence of gynecologic cancers leads to a massive economic burden and public health concern. In this study, we investigated the potential biological functions of NSUN2 in common gynecologic cancers including cervical cancer, ovarian cancer, and endometrial cancer. Remarkably, distinct scenarios were found. The levels of NSUN2 did not show alteration in endometrial cancer, and in ovarian cancer, depletion of upregulated NSUN2 did not reduce carcinogenesis in cancer cells, suggesting that the upregulated NSUN2 might be an incidental effect. On the contrary, NSUN2 played a role in tumorigenesis of cervical cancer; depletion of upregulated NSUN2 notably inhibited migration and invasion of cancer cells, and only wild-type but not catalytically inactive NSUN2 rescued these malignant phenotypes of cancer cells. Mechanistically, NSUN2 promoted migration and invasion by leading to m5C methylation on keratin 13 (KRT13) transcripts, and methylated KRT13 transcripts would be recognized and stabilized by an m5C reader, Y-box binding protein 1 (YBX1). Collectively, these results not only displayed the nature of diversity among human malignancies, but also demonstrated a novel NSUN2-dependent m5C-YBX1-KRT13 oncogenic regulatory pathway.