RESUMO
The molecular mechanisms driving the development of cervical adenocarcinoma (CADC) and optimal patient management strategies remain elusive. In this study, we have identified circMAN1A2_009 as an oncogenic circular RNA (circRNA) in CADC. Clinically, circMAN1A2_009 showed significant upregulation in CADC tissues, with an impressive area under the curve value of 0.8075 for detecting CADC. Functional studies, involving both gain-of-function and loss-of-function experiments, revealed that circMAN1A2_009 suppressed reactive oxygen species accumulation and apoptosis, and boosted cell viability in CADC cells. Conversely, silencing circMAN1A2_009 reversed these effects. Further mechanistic investigations indicated that circMAN1A2_009 interacted with YBX1, facilitating the phosphorylation levels of YBX1 at serine 102 (p-YBX1S102) and facilitating YBX1 nuclear localization through sequence 245-251. This interaction subsequently increased the activity of the glyoxalase 1 (GLO1) promoter, leading to the activation of GLO1 expression. Consistently, inhibition of either YBX1 or GLO1 mirrored the biological effects of circMAN1A2_009 in CADC cells. Additionally, knockdown of YBX1 or GLO1 partially reversed the oncogenic behaviors induced by circMAN1A2_009. In conclusion, our findings propose circMAN1A2_009 as a potential oncogene and a promising indicator for diagnosing and guiding therapy in CADC patients.
RESUMO
OBJECTIVES: We aim to investigate the effects of fibroblast growth factor 16 (FGF16) on Leydig cell regeneration in ethane dimethane sulphonate (EDS)-treated rat testis. METHODS: We intraperitoneally inject 75 mg/kg EDS to adult male Sprague Dawley rats and then intratesticularly inject FGF16 (0, 10 and 100 ng/testis/day) from post-EDS day 14 for 14 days. We investigate serum hormone levels, Leydig cell number, gene and protein expression in vivo. We also explore the effects of FGF16 treatment on stem Leydig cell proliferation in vitro. RESULTS: FGF16 lowers serum testosterone levels (21.6% of the control at a dose of 100 ng/testis) without affecting the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) on post-EDS day 28 in vivo. FGF16 increases Leydig cell number at doses of 10 and 100 ng/mg without affecting Sertoli cell number, increases the percentage of PCNA-positive Leydig cells, and down-regulates the expression of Leydig cell genes (Lhcgr, Scarb1, Star, Cyp11a1, Cyp17a1 and Hsd17b3) and Sertoli cell genes (Fshr, Dhh and Sox9) and their proteins in vivo. FGF16 increases phosphorylation of AKT1 and AKT2 as well as EKR1/2 in vivo, indicating that it possibly acts via AKT1/ATK2 and ERK1/2 pathways. FGF16 also lowers medium testosterone levels and down-regulates the expression of Leydig cell genes (Lhcgr, Scarb1, Star, Cyp11a1, Cyp17a1 and Hsd17b3) but increases EdU incorporation into stem Leydig cells in vitro. CONCLUSIONS: These data suggest that FGF16 stimulates stem and progenitor Leydig cell proliferation but blocks their differentiation, thus lowering testosterone biosynthesis.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/farmacologia , Células Intersticiais do Testículo/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Animais , Antiespermatogênicos/antagonistas & inibidores , Antiespermatogênicos/farmacologia , Contagem de Células , Diferenciação Celular/genética , Proliferação de Células/genética , Hormônio Foliculoestimulante/sangue , Regulação da Expressão Gênica , Injeções Intraperitoneais , Isoenzimas/genética , Isoenzimas/metabolismo , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/sangue , Masculino , Mesilatos/antagonistas & inibidores , Mesilatos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores do LH/genética , Receptores do LH/metabolismo , Regeneração/genética , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Células de Sertoli/citologia , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Testosterona/sangueRESUMO
OBJECTIVES: The present study used single-cell RNA sequencing (scRNA-seq) to characterize the cellular composition of ovarian carcinosarcoma (OCS) and identify its molecular characteristics. METHODS: scRNA-seq was performed in resected primary OCS for an in-depth analysis of tumor cells and the tumor microenvironment. Immunohistochemistry staining was used for validation. The scRNA-seq data of OCS were compared with those of high-grade serous ovarian carcinoma (HGSOC) tumors and other OCS tumors. RESULTS: Both malignant epithelial and malignant mesenchymal cells were observed in the OCS patient of this study. We identified four epithelial cell subclusters with different biological roles. Among them, epithelial subcluster 4 presented high levels of breast cancer type 1 susceptibility protein homolog (BRCA1) and DNA topoisomerase 2-α (TOP2A) expression and was related to drug resistance and cell cycle. We analyzed the interaction between epithelial and mesenchymal cells and found that fibroblast growth factor (FGF) and pleiotrophin (PTN) signalings were the main pathways contributing to communication between these cells. Moreover, we compared the malignant epithelial and mesenchymal cells of this OCS tumor with our previous published HGSOC scRNA-seq data and OCS data. All the epithelial subclusters in the OCS tumor could be found in the HGSOC samples. Notably, the mesenchymal subcluster C14 exhibited specific expression patterns in the OCS tumor, characterized by elevated expression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1), collagen type XXIII α1 chain (COL23A1), cholecystokinin (CCK), bone morphogenetic protein 7 (BMP7), PTN, Wnt inhibitory factor 1 (WIF1), and insulin-like growth factor 2 (IGF2). Moreover, this subcluster showed distinct characteristics when compared with both another previously published OCS tumor and normal ovarian tissue. CONCLUSIONS: This study provides the single-cell transcriptomics signature of human OCS, which constitutes a new resource for elucidating OCS diversity.
Assuntos
Carcinossarcoma , DNA Topoisomerases Tipo II , Neoplasias Ovarianas , Análise de Célula Única , Transcriptoma , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Carcinossarcoma/genética , Carcinossarcoma/metabolismo , Carcinossarcoma/patologia , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Microambiente Tumoral , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Citocinas/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Análise de Sequência de RNA , Pessoa de Meia-Idade , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/metabolismo , Proteínas de Ligação a Poli-ADP-RiboseRESUMO
High-grade serous carcinoma (HGSC) is characterized by early abdominal metastasis, leading to a dismal prognosis. In this study, we conducted single-cell RNA sequencing on 109,573 cells from 34 tumor samples of 18 HGSC patients, including both primary tumors and their metastatic sites. Our analysis revealed a distinct S100A9+ tumor cell subtype present in both primary and metastatic sites, strongly associated with poor overall survival. This subtype exhibited high expression of S100A8, S100A9, ADGRF1, CEACAM6, CST6, NDRG2, MUC4, PI3, SDC1, and C15orf48. Individual knockdown of these ten marker genes, validated through in vitro and in vivo models, significantly inhibited ovarian cancer growth and invasion. Around S100A9+ tumor cells, a population of HK2+_CAF was identified, characterized by activated glycolysis metabolism, correlating with shorter overall survival in patients. Notably, similar to CAFs, immunosuppressive tumor-associated macrophage (TAM) subtypes underwent glycolipid metabolism reprogramming via PPARgamma regulation, promoting tumor metastasis. These findings shed light on the mechanisms driving the aggressiveness of HGSC, offering crucial insights for the development of novel therapeutic targets against this formidable cancer.
Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Análise de Célula Única , Microambiente Tumoral , Humanos , Feminino , Microambiente Tumoral/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/metabolismo , Transcriptoma , Animais , Regulação Neoplásica da Expressão Gênica , Camundongos , Macrófagos Associados a Tumor/metabolismo , Linhagem Celular Tumoral , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Calgranulina B/genética , Calgranulina B/metabolismo , PPAR gama/metabolismo , PPAR gama/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Glicólise/genética , Gradação de TumoresRESUMO
To date, surgery, chemotherapy and radiotherapy are mainly used to treat or remove gynecological malignancies. However, these approaches have their limitations when facing complicated female diseases such as advanced cervical and endometrial cancer (EC), chemotherapy-resistant gestational trophoblastic neoplasia and platinum-resistant ovarian cancer. Instead, immunotherapy, as an alternative, could significantly improve prognosis of those patients receiving traditional treatments, with better antitumor activities and possibly less cellular toxicities. Its' development is still not fast enough to meet the current clinical needs. More preclinical studies and larger-scale clinical trials are required. This review aims to introduce the landscape and up-to-date status of immunotherapy against gynecological malignancies, with a discussion of the challenges and future direction.
Assuntos
Neoplasias do Endométrio , Neoplasias dos Genitais Femininos , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias dos Genitais Femininos/tratamento farmacológico , Imunoterapia , Carcinoma Epitelial do Ovário , Neoplasias Ovarianas/patologiaRESUMO
Platinum-based chemotherapy remains the main systemic treatment of ovarian cancer (OC). However, the inevitable development of platinum and poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) resistance is associated with poor outcomes, which becomes a major obstacle in the management of this disease. The present study developed "all-in-one" nanoparticles that contained the PARPi olaparib and gallium (Ga) (III) (olaparib-Ga) to effectively reverse PARPi resistance in platinum-resistant A2780-cis and SKOV3-cis OC cells and in SKOV3-cis tumor models. Notably, the olaparib-Ga suppressed SKOV3-cis tumor growth with negligible toxicity. Moreover, the suppression effect was more evident when combining olaparib-Ga with cisplatin or carboplatin, as evaluated in A2780-cis and SKOV3-cis cells. Mechanistically, the combined treatment induced DNA damage, which elicited the activation of ataxia telangiectasia mutated (ATM)/AMT- and Rad3-related (ATR) checkpoint kinase 1 (Chk1)/Chk2 signal transduction pathways. This led to the arrest of cell cycle progression at S and G2/M phases, which eventually resulted in apoptosis and cell death due to unrepairable DNA damage. In addition, effective therapeutic responses to olaparib-Ga and cisplatin combination or olaparib-Ga and carboplatin combination were observed in SKOV3-cis tumor-bearing animal models. Altogether, the present findings demonstrate that olaparib-Ga has therapeutic implications in platinum-resistant OC cells, and the combination of olaparib-Ga with cisplatin or carboplatin may be promising for treating patients with OC who exhibit resistance to both PARPi and platinum.