RESUMO
Despite being highly preventable, cervical cancer is the fourth most common cancer and cause of cancer death in women globally. In low-income countries, cervical cancer is often the leading cause of cancer-related morbidity and mortality. Women living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome are at a particularly high risk of cervical cancer because of an impaired immune response to human papillomavirus, the obligate cause of virtually all cervical cancers. Globally, approximately 1 in 20 cervical cancers is attributable to HIV; in sub-Saharan Africa, approximately 1 in 5 cervical cancers is due to HIV. Here, the authors provide a critical appraisal of the evidence to date on the impact of HIV disease on cervical cancer risk, describe key methodologic issues, and frame the key outstanding research questions, especially as they apply to ongoing global efforts for prevention and control of cervical cancer. Expanded efforts to integrate HIV care with cervical cancer prevention and control, and vice versa, could assist the global effort to eliminate cervical cancer as a public health problem.
Assuntos
Infecções por HIV/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Detecção Precoce de Câncer , Feminino , Humanos , Hospedeiro Imunocomprometido , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Lesões Pré-Cancerosas/terapia , Prevenção Primária , Prevenção SecundáriaRESUMO
The tumor microenvironment (TME) directly determines patients' outcomes and therapeutic efficiencies. An in-depth understanding of the TME is required to improve the prognosis of patients with cervical cancer (CC). This study conducted single-cell RNA and TCR sequencing of six-paired tumors and adjacent normal tissues to map the CC immune landscape. T and NK cells were highly enriched in the tumor area and transitioned from cytotoxic to exhaustion phenotypes. Our analyses suggest that cytotoxic large-clone T cells are critical effectors in the antitumor response. This study also revealed tumor-specific germinal center B cells associated with tertiary lymphoid structures. A high-germinal center B cell proportion in patients with CC is predictive of improved clinical outcomes and is associated with elevated hormonal immune responses. We depicted an immune-excluded stromal landscape and established a joint model of tumor and stromal cells to predict CC patients' prognosis. The study revealed tumor ecosystem subsets linked to antitumor response or prognosis in the TME and provides information for future combinational immunotherapy.
Assuntos
Neoplasias do Colo do Útero , Humanos , Feminino , Microambiente Tumoral , Ecossistema , Células Matadoras Naturais , ImunoterapiaRESUMO
Cervical cancer is caused by human papillomavirus (HPV) infection, has few approved targeted therapeutics, and is the most common cause of cancer death in low-resource countries. We characterized 19 cervical and four head and neck cancer cell lines using long-read DNA and RNA sequencing and identified the HPV types, HPV integration sites, chromosomal alterations, and cancer driver mutations. Structural variation analysis revealed telomeric deletions associated with DNA inversions resulting from breakage-fusion-bridge (BFB) cycles. BFB is a common mechanism of chromosomal alterations in cancer, and our study applies long-read sequencing to this important chromosomal rearrangement type. Analysis of the inversion sites revealed staggered ends consistent with exonuclease digestion of the DNA after breakage. Some BFB events are complex, involving inter- or intra-chromosomal insertions or rearrangements. None of the BFB breakpoints had telomere sequences added to resolve the dicentric chromosomes, and only one BFB breakpoint showed chromothripsis. Five cell lines have a chromosomal region 11q BFB event, with YAP1-BIRC3-BIRC2 amplification. Indeed, YAP1 amplification is associated with a 10-year-earlier age of diagnosis of cervical cancer and is three times more common in African American women. This suggests that individuals with cervical cancer and YAP1-BIRC3-BIRC2 amplification, especially those of African ancestry, might benefit from targeted therapy. In summary, we uncovered valuable insights into the mechanisms and consequences of BFB cycles in cervical cancer using long-read sequencing.
Assuntos
Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/genética , Aberrações Cromossômicas , Telômero/genética , DNARESUMO
Brachytherapy is a specific form of radiotherapy consisting of the precise placement of radioactive sources directly into or next to the tumor. This technique is indicated for patients affected by various types of cancers. It is an optimal tool for delivering very high doses to the tumor focally while minimizing the probability of normal tissue complications. Physicians from a wide range of specialties may be involved in either the referral to or the placement of brachytherapy. Many patients require brachytherapy as either primary treatment or as part of their oncologic care. On the basis of high-level evidence from randomized controlled trials, brachytherapy is mainly indicated: 1) as standard in combination with chemoradiation in patients with locally advanced cervical cancer; 2) in surgically treated patients with uterine endometrial cancer for decreasing the risk of vaginal vault recurrence; 3) in patients with high-risk prostate cancer to perform dose escalation and improve progression-free survival; and 4) in patients with breast cancer as adjuvant, accelerated partial breast irradiation or to boost the tumor bed. In this review, the authors discuss the clinical relevance of brachytherapy with a focus on indications, levels of evidence, and results in the overall context of radiation use for patients with cancer.
Assuntos
Braquiterapia/métodos , Quimiorradioterapia/métodos , Medicina Baseada em Evidências/métodos , Terapia Neoadjuvante/métodos , Neoplasias/terapia , Antineoplásicos/uso terapêutico , Progressão da Doença , Fracionamento da Dose de Radiação , Educação Médica Continuada , Humanos , Neoplasias/complicações , Neoplasias/mortalidade , Seleção de Pacientes , Médicos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
High-risk human papilloma viruses (HPVs) cause cervical, anal, and oropharyngeal cancers, unlike the low-risk HPVs, which cause benign lesions. E6 oncoproteins from the high-risk strains are essential for cell proliferation and transformation in HPV-induced cancers. We report that a cellular deubiquitinase, USP46, is selectively recruited by the E6 of high-risk, but not low-risk, HPV to deubiqutinate and stabilize Cdt2/DTL. Stabilization of Cdt2, a component of the CRL4Cdt2 E3 ubiquitin ligase, limits the level of Set8, an epigenetic writer, and promotes cell proliferation. USP46 is essential for the proliferation of HPV-transformed cells, but not of cells without HPV. Cdt2 is elevated in human cervical cancers and knockdown of USP46 inhibits HPV-transformed tumor growth in xenografts. Recruitment of a cellular deubiquitinase to stabilize key cellular proteins is an important activity of oncogenic E6, and the importance of E6-USP46-Cdt2-Set8 pathway in HPV-induced cancers makes USP46 a target for the therapy of such cancers.
Assuntos
Endopeptidases/genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Proteínas Nucleares/genética , Infecções por Papillomavirus/genética , Neoplasias do Colo do Útero/genética , Animais , Ciclo Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endopeptidases/metabolismo , Feminino , Regulação da Expressão Gênica , Células HeLa , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Interações Hospedeiro-Patógeno/genética , Papillomavirus Humano 16/metabolismo , Papillomavirus Humano 16/patogenicidade , Papillomavirus Humano 18/metabolismo , Papillomavirus Humano 18/patogenicidade , Humanos , Injeções Intralesionais , Camundongos , Proteínas Nucleares/metabolismo , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/enzimologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A murine papillomavirus, MmuPV1, infects both cutaneous and mucosal epithelia of laboratory mice and can be used to model high-risk human papillomavirus (HPV) infection and HPV-associated disease. We have shown that estrogen exacerbates papillomavirus-induced cervical disease in HPV-transgenic mice. We have also previously identified stress keratin 17 (K17) as a host factor that supports MmuPV1-induced cutaneous disease. Here, we sought to test the role of estrogen and K17 in MmuPV1 infection and associated disease in the female reproductive tract. We experimentally infected wild-type and K17 knockout (K17KO) mice with MmuPV1 in the female reproductive tract in the presence or absence of exogenous estrogen for 6 mon. We observed that a significantly higher percentage of K17KO mice cleared the virus as opposed to wild-type mice. In estrogen-treated wild-type mice, the MmuPV1 viral copy number was significantly higher compared to untreated mice by as early as 2 wk postinfection, suggesting that estrogen may help facilitate MmuPV1 infection and/or establishment. Consistent with this, viral clearance was not observed in either wild-type or K17KO mice when treated with estrogen. Furthermore, neoplastic disease progression and cervical carcinogenesis were supported by the presence of K17 and exacerbated by estrogen treatment. Subsequent analyses indicated that estrogen treatment induces a systemic immunosuppressive state in MmuPV1-infected animals and that both estrogen and K17 modulate the local intratumoral immune microenvironment within MmuPV1-induced neoplastic lesions. Collectively, these findings suggest that estrogen and K17 act at multiple stages of papillomavirus-induced disease at least in part via immunomodulatory mechanisms.
Assuntos
Infecções por Papillomavirus , Camundongos , Feminino , Humanos , Animais , Infecções por Papillomavirus/genética , Queratina-17 , Camundongos Transgênicos , Imunidade , Papillomaviridae/genética , EstrogêniosRESUMO
Most cervical cancers are caused by human papillomavirus (HPV) infection. In HeLa cells, the HPV18 viral genome is integrated at chromosome 8q24.21 and activates transcription of the proto-oncogene c-Myc. However, the mechanism of how the integrated HPV genome and its transcribed RNAs exhibit transcription activation function has not been fully elucidated. In this study, we found that HPV18 transcripts contain an enhancer RNA-like function to activate proximal genes including CCAT1-5L and c-Myc. We showed that the human genome-integrated HPV18 genes are activated by transcription coregulators including BRD4 and Mediator. The transcribed HPV18 RNAs form a liquid-like condensate at chromosome 8q24.21 locus, which in turn accumulates RNA polymerase II. Moreover, we focused on a relatively uncharacterized transcript from the upstream region of CCAT1, named URC. The URC RNA is transcribed as a chimera RNA with HPV18 and is composed of the 3'-untranslated region of the HPV18 transcript. We experimentally showed that the URC contributes to stabilization of HPV18 RNAs by supplying a polyadenylation site for the HPV18 transcript. Our findings suggest that integrated HPV18 at 8q24.21 locus produces HPV18-URC chimera RNA and promotes tumorigenesis through RNA-based condensate formation.
Assuntos
Genoma Viral , Papillomavirus Humano 18 , Proto-Oncogene Mas , Humanos , Papillomavirus Humano 18/genética , Células HeLa , RNA Viral/genética , RNA Viral/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/genética , Integração Viral , Transcrição Gênica , Feminino , Genoma Humano , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas que Contêm BromodomínioRESUMO
BACKGROUND: Cervical cancer (CC), closely linked to persistent human papillomavirus infection, represents a major health problem for women worldwide. The objective of this study is to elucidate KIF23's role in the development of CC and its regulatory mechanism. METHODS: The bioinformatics methods were utilized to extract pyroptosis-associated differentially expressed genes (DEGs) and pivot genes from the GSE9750 and GSE63678 datasets, followed by immune infiltration analysis and quantification of these genes' expression. The effects of kinesin family member 23 (KIF23) were verified through functional experiments in vitro and a mouse xenograft model. The NLPR3 activator, nigericin, was applied for further analyzing the potential regulatory mechanism of KIF23 in CC. RESULTS: A total of 8 pyroptosis-related DEGs were screened out, among which 4 candidate core genes were identified as candidate hub genes and confirmed upregulation in CC tissues and cells. These genes respectively showed a positive correlation with the infiltration of distinct immune cells or tumor purity. Downregulation of KIF23 could suppress the proliferation, migration, and invasion abilities in CC cells and tumorigenesis through enhancing pyroptosis. Conversely, KIF23 overexpression accelerated the malignant phenotypes of CC cells and inhibited pyroptosis activation, which was blocked by nigericin treatment. CONCLUSIONS: KIF23 may play an oncogenic role in CC progression via inhibition of the NLRP3-mediated pyroptosis pathway.
Assuntos
Regulação Neoplásica da Expressão Gênica , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Neoplasias do Colo do Útero , Piroptose/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Humanos , Feminino , Animais , Camundongos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Camundongos Nus , Cinesinas/genética , Cinesinas/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Progressão da Doença , Camundongos Endogâmicos BALB C , Proteínas Associadas aos MicrotúbulosRESUMO
N6-methylated adenosine (m6A) is a crucial RNA modification in eukaryotes, particularly in cancer. However, its role in cervical cancer (CC) is unclear. We aimed to elucidate the part of m6A in CC by analyzing methyltransferase-like 3 (METTL3) expression, identifying downstream targets, and exploring the underlying mechanism. We assessed METTL3 expression in CC using western blotting, quantitative polymerase chain reaction (qPCR), and immunohistochemistry. In vitro and in vivo experiments examined METTL3's role in CC. We employed RNA sequencing, methylated RNA immunoprecipitation sequencing, qPCR, and RNA immunoprecipitation qPCR to explore METTL3's mechanism in CC. METTL3 expression was upregulated in CC, promoting cell proliferation and metastasis. METTL3 knockdown inhibited human cervical cancer by inactivating AKT/mTOR signaling pathway. METTL3-mediated m6A modification was observed in CC cells, targeting phosphodiesterase 3A (PDE3A). METTL3 catalyzed m6A modification on PDE3A mRNA through YTH domain family protein 3 (YTHDF3). Our study indicated the mechanism of m6A modification in CC and suggested the METTL3/YTHDF3/PDE3A axis as a potential clinical target for CC treatment.
Assuntos
Adenosina , Proliferação de Células , Metiltransferases , Neoplasias do Colo do Útero , Metiltransferases/metabolismo , Metiltransferases/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Humanos , Feminino , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Camundongos , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Camundongos Nus , Transdução de Sinais , Camundongos Endogâmicos BALB CRESUMO
Small cell cervical carcinoma (SCCC) is the most common neuroendocrine tumor in the female genital tract, with an unfavorable prognosis and lacking an evidence-based therapeutic approach. Until now, the distinct subtypes and immune characteristics of SCCC combined with genome and transcriptome have not been described. We performed genomic (n = 18), HPV integration (n = 18), and transcriptomic sequencing (n = 19) of SCCC samples. We assessed differences in immune characteristics between SCCC and conventional cervical cancer, and other small cell neuroendocrine carcinomas, through bioinformatics analysis and immunohistochemical assays. We stratified SCCC patients through non-negative matrix factorization and described the characteristics of these distinct types. We further validated it using multiplex immunofluorescence (n = 77) and investigated its clinical prognostic effect. We confirmed a high frequency of PIK3CA and TP53 alterations and HPV18 integrations in SCCC. SCCC and other small cell carcinoma had similar expression signatures and immune cell infiltration patterns. Comparing patients with SCCC to those with conventional cervical cancer, the former presented immune excluded or 'desert' infiltration. The number of CD8+ cells in the invasion margin of SCCC patients predicted favorable clinical outcomes. We identified three transcriptome subtypes: an inflamed phenotype with high-level expression of genes related to the MHC-II complex (CD74) and IFN-α/ß (SCCC-I), and two neuroendocrine subtypes with high-level expression of ASCL1 or NEUROD1, respectively. Combined with multiple technologies, we found that the neuroendocrine groups had more TP53 mutations and SCCC-I had more PIK3CA mutations. Multiplex immunofluorescence validated these subtypes and SCCC-I was an independent prognostic factor of overall survival. These results provide insights into SCCC tumor heterogeneity and potential therapies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Carcinoma Neuroendócrino , Microambiente Tumoral , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/imunologia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/mortalidade , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/imunologia , Carcinoma de Células Pequenas/patologia , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Adulto , Mutação , Transcriptoma , Classe I de Fosfatidilinositol 3-Quinases/genética , Prognóstico , Perfilação da Expressão Gênica/métodos , Idoso , MultiômicaRESUMO
Mesonephric adenocarcinomas (MAs) and mesonephric-like adenocarcinomas (MLAs) are rare, aggressive neoplasms that arise in the gynecologic tract and show overlapping morphologic, immunohistochemical, and molecular features. While MAs occur in the cervix and are thought to arise from mesonephric remnants, MLAs occur in the endometrium and ovary and are believed to originate from transdifferentiation of Müllerian lesions. Both MAs and MLAs show a variety of architectural patterns, exhibit frequent expression of GATA3 by immunohistochemistry, and harbor KRAS mutations. In a recent article published in The Journal of Pathology, Kommoss and colleagues used DNA methylation profiling to extend these similarities and showed that MLAs and MAs cluster together based on their epigenetic signatures and are epigenetically distinct from other Müllerian adenocarcinomas. They also showed that MLAs and MAs harbor a high number of global copy number alterations. This study provides evidence that MLAs more closely resemble MAs than Müllerian carcinomas on an epigenetic level. As a result, the authors argue that MLA should be renamed 'mesonephric-type adenocarcinoma.' Further research is needed to establish the relationship between these two entities, their etiology, and pathogenesis. © 2024 The Pathological Society of Great Britain and Ireland.
Assuntos
Adenocarcinoma , Metilação de DNA , Epigênese Genética , Neoplasias do Colo do Útero , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Feminino , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Ductos Paramesonéfricos/patologia , Mesonefroma/genética , Mesonefroma/patologia , Biomarcadores Tumorais/genética , EpigenomaRESUMO
The Human Papillomavirus (HPV) infection is responsible for more than 80% of reported cervical cancer and other virus-associated tumours. Although this global threat can be controlled using effective vaccination strategies, a growing perturbation of HPV infection is an emerging coinfection likely to increase the severity of the infection in humans. Moreover, these coinfections prolong the HPV infections, thereby risking the chances for oncogenic progression. The present review consolidated the clinically significant microbial coinfections/co-presence associated with HPV and their underlying molecular mechanisms. We discussed the gaps and concerns associated with demography, present vaccination strategies, and other prophylactic limitations. We concluded our review by highlighting the potential clinical as well as emerging computational intervention measures to kerb down HPV-associated severities.
Assuntos
Coinfecção , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Papillomavirus Humano , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/patologia , Vacinação , PapillomaviridaeRESUMO
Cervical cancer (CC) is one of the most common gynecological malignancies. Cytological screening, while being the most common and accurate method for detecting cervical cancer, is both time-consuming and costly. Predicting CC based on bioinformatics can assist in the rapid early screening of CC in clinical practice. Most recent CC prediction methods require a large amount of detection data or sequencing data and are not ideal for CC detection in complex disease samples. We developed the Disease trend analysis platform (Dtap), which can quickly predict the occurrence of diseases using only blood routine data. Blood routine data was collected from 1,292 cervical cancer patients, 4,860 patients with complex diseases, and 4,980 healthy individuals from various sources. The results show that the Dtap-based trend model maintained good and stable performance in the prediction task of multiple datasets as well as complex disease samples. Finally, we built DTAPCC (http://bioinfor.imu.edu.cn/dtapcc), a Dtap-based CC disease prediction platform, to help users quickly predict CC and visualize trend features.
RESUMO
Cervical cancer (CC), as a common female malignant tumor in the world, is an important risk factor endangering women's health worldwide. The purpose of this study was to investigate the role of RBM15 in CC. The TCGA database was used to screen differentially expressed m6A genes in normal and tumor tissues. QRT-PCR was used to quantify HEIH, miR-802, EGFR, cell stemness, and epithelial-mesenchymal transition (EMT)-related genes. The interaction between HEIH and miR-802 was verified by dual-luciferase reporter assay and RIP assay. The occurrence of tumor cells after different treatments was detected by CCK-8, transwell and EdU staining. BALB/c nude mice were used to examine the effects of different treatments on tumor growth and cell stemness in vivo. RBM15 was upregulated in tumor tissues and cells. M6A was highly enriched in HEIH and enhances its RNA stability. HEIH acts as an oncogenic lncRNA to promote CC cell proliferation, migration and tumor growth. Mechanistically, HEIH regulates tumor cell stemness and promotes the proliferation and migration of CC cells by competitively adsorbing miR-802 and up-regulating the expression of EGFR. In short, our data shown that the m6A methyltransferase RBM15 could affect tumor cell proliferation, metastasis and cell stemness by stabilizing HEIH expression.
Assuntos
Adenina/análogos & derivados , MicroRNAs , RNA Longo não Codificante , Neoplasias do Colo do Útero , Animais , Camundongos , Humanos , Feminino , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias do Colo do Útero/patologia , Camundongos Nus , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
HECW1 belongs to ubiquitin ligase (E3) HECT family, and is found to be involved in tumorigenesis and tumor progression. However, the function of HECW1 in cervical cancer (CC) remains unknown. Clinical analysis showed that HECW1 is significantly decreased in CC tumor tissues. Ectopic expression of HECW1 suppressed cell growth, promoting cell cycle arrest and apoptosis in CC cells, while downregulation of HECW1 reversed these trends, impeded proliferation and accelerated cell cycle progression of CC cells. Overexpressing of HECW1 reduced mitochondrial membrane potential and the protein expression of voltage-dependent anion channel 1 (VDAC1). In addition, upregulation of HECW1 inhibited nuclear ß-catenin accumulation, downregulated ß-catenin/TCF/LEF-mediated transcriptional activity and the expression of downstream gene c-Myc, whereas inhibition of HECW1 received opposite results. Further results confirmed HECW1 affects the protein expression of dishevelled-1 (DVL1), a potent activator of Wnt/ß-catenin, and inhibition of HECW1 inhibited the ubiquitination of DVL1, upregulating its expression. Inhibition of DVL1 restrained the promotion effect of HECW1 suppression on cell proliferation. In vivo experiments also verified that HECW1 suppression promoted the tumor formation of CC cells. Summary, we demonstrated that HECW1 inhibits CC cell proliferation and tumor formation by downregulating DVL1 induced Wnt/ß-catenin signaling pathway activation.
Assuntos
Neoplasias do Colo do Útero , Via de Sinalização Wnt , Feminino , Humanos , Via de Sinalização Wnt/genética , Linhagem Celular Tumoral , Neoplasias do Colo do Útero/patologia , beta Catenina/genética , beta Catenina/metabolismo , Ubiquitinação , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas do Tecido Nervoso/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Tie1 orphan receptor has become a focus of research, Tie1 can form a polymer with Tie2, regulate the Ang/Tie2 pathway and play a vital role in pathological angiogenesis and tumor progression, the function of Tie1 has remained uncertain in the progression of cervical cancer (CC). Here, we investigated the functional influences of Tie1 overexpress on CC in vitro and in vivo. METHODS: We used Immunohistochemistry (IHC) analysis to detect the relative expression of Tie1 in CC, and we analyzed its connection with the overall survival (OS) and progression free survival (PFS)of CC patients. To prove the role of Tie1 in cell proliferation and metastatic, Tie1 expression in CC cell lines was upregulated by lentivirus. RESULTS: The high expression of Tie1 in tumor cells of cervical cancer tissues is significantly correlated with FIGO stage, differentiated tumors, tumors with diameters, deep stromal invasion. We found that cell progression was promoted in Tie1-overexpress CC cell lines in vivo and in vitro. Tie1 potentially exerts a commanding influence on the expression of markers associated with epithelial-mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. CONCLUSIONS: Our research indicates that Tie1 is highly connected to CC progression as it may play a role in the EMT process through the PI3K/AKT signaling pathway.
Assuntos
Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptor de TIE-1 , Transdução de Sinais , Neoplasias do Colo do Útero , Animais , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Receptor de TIE-1/metabolismo , Receptor de TIE-1/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismoRESUMO
Natural killer (NK) cells are triggered by the innate immune response in the tumor microenvironment. The extensive set of stimulating and inhibiting receptors mediates the target recognition of NK cells, and controls the strength of the effector reaction countering specific targeted cells. Yet, lacking major MHC (histocompatibility complex) MICA/B class I chain-related proteins on the membrane of tumor cells results in the failure of NK cell recognition and ability to resist NK cell destruction. Searching databases and molecular docking suggested that in cervical cancer, pterostilbene (3,5-dimethoxy-40-hydroxystilbene; PTS) in Vaccinium corymbosum extract could constrain PI3K/AKT signaling and improving the MICA/B expression. In flow cytometry, MTT assay, viability/cytotoxicity assay, and colony development assays, PTS reduced the development of cervical cancer cells and increased apoptosis. The quantitative real-time PCR (qRT-PCR) and a Western blot indicate that PTS controlled the cytolytic action of NK cells in tumor cells via increasing the MICA/B expression, thus modifying the anti-tumor immune response in cervical cancer.
Assuntos
Proteínas Proto-Oncogênicas c-akt , Neoplasias do Colo do Útero , Feminino , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Antígenos de Histocompatibilidade Classe I/genética , Células Matadoras Naturais , Transdução de Sinais , Citotoxicidade Imunológica , Microambiente TumoralRESUMO
Cancer vaccines have been developed as a promising way to boost cancer immunity. However, their clinical potency is often limited due to the imprecise delivery of tumor antigens. To overcome this problem, we conjugated an endogenous Toll-like receptor (TLR)2/6 ligand, UNE-C1, to human papilloma virus type 16 (HPV-16)-derived peptide antigen, E7, and found that the UNE-C1-conjugated cancer vaccine (UCV) showed significantly enhanced antitumor activity in vivo compared with the noncovalent combination of UNE-C1 and E7. The combination of UCV with PD-1 blockades further augmented its therapeutic efficacy. Specifically, the conjugation of UNE-C1 to E7 enhanced its retention in inguinal draining lymph nodes, the specific delivery to dendritic cells and E7 antigen-specific T cell responses, and antitumor efficacy in vivo compared with the noncovalent combination of the two peptides. These findings suggest the potential of UNE-C1 derived from human cysteinyl-tRNA synthetase 1 as a unique vehicle for the specific delivery of cancer antigens to antigen-presenting cells via TLR2/6 for the improvement of cancer vaccines.
RESUMO
Recently, radioresistance has become a major obstacle in the radiotherapy of cervical cancer. To demonstrate enhanced radiosensitization against radioresistant cervical cancer, radioresistant cervical cancer cell line was developed and the mechanism of radioresistance was explored. Due to the overexpression of (death receptor 5, DR5) in cervical cancer, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-overexpressed cervical cancer cell membrane-camouflaged Cu2-xSe nanomedicine (CCMT) was designed. Since the CCMT was encapsulated with TRAIL-modified cell membrane, it represented high target to cervical cancer cell and immune evasion. Furthermore, Cu2-xSe had the ability to scavenge glutathione (GSH) and produce ·OH with excess H2O2 in the tumor microenvironment. The presence of CCMT combined with radiation therapy could effectively increase the 1O2 produced by X-rays. In vitro and in vivo studies elaborated that CCMT exhibited excellent radiosensitization properties to reverse radiotolerance by scavenging GSH and promoting DNA damage, apoptosis, mitochondrial membrane potential damage and metabolic disruption. Collectively, this study suggested that the development of TRAIL-overexpressed cell membrane-camouflaged Cu2-xSe nanomedicine could advance future cervical cancer treatment and minimize the disadvantages associated with radiation treatment.
Assuntos
Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Peróxido de Hidrogênio , Ligantes , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Apoptose , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
BACKGROUND: Immunosuppressive status is prevalent in cancer patients and increases the complexity of tumor immunotherapy. It has been found that Listeria-vectored tumor vaccines had the potential ability of two-side regulatory effect on the immune response during immunotherapy. RESULTS: The results show that the combined immunotherapy with the LM∆E6E7 and LI∆E6E7, the two cervical cancer vaccine candidate strains constructed by our lab, improves the antitumor immune response and inhibits the suppressive immune response in tumor-bearing mice in vivo, confirming the two-sided regulatory ability of the immune response caused by Listeria-vectored tumor vaccines. The immunotherapy reduces the expression level of myeloid-derived suppressor cells (MDSCs)-inducing factors and then inhibits the phosphorylation level of STAT3 protein, the regulatory factor of MDSCs differentiation, to reduce the MDSCs formation ability. Moreover, vaccines reduce the expression of functional molecules associated with MDSCs may by inhibiting the phosphorylation level of the JAK1-STAT1 and JAK2-STAT3 pathways in tumor tissues to attenuate the immunosuppressive function of MDSCs. CONCLUSIONS: Immunotherapy with Listeria-vectored cervical cancer vaccines significantly reduces the level and function of MDSCs in vivo, which is the key point to the destruction of immunosuppression. The study for the first to elucidate the mechanism of breaking the immunosuppression.