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Objective To evaluate the effects of estrogen, raloxifene and genistein on the expression of KISS1 (kisspeptin), KISS1R (kisspeptin receptor), AR (androgen receptor) and INSR (insulin receptor) in the bones of ovariectomized rats. Methods Forty-eight adult rats were randomly divided into 6 groups, containing 8 animals each: G1-nonovariectomized control; G2-ovariectomized and treated with conjugated equine estrogens (50 µg/Kg/day); G3-ovariectomized and treated with raloxifene (0.75 mg/kg/day); G4-ovariectomized animal that received soy extract with genistein (300 mg/kg/day); G5-ovariectomized animal that received estrogen and genistein; and G6-ovariectomized animal that received estrogen and raloxifene. Three months after surgery, the castrated animals received the drugs orally daily for 120 days. All animals were sacrificed after this period, by deepening the anesthesia. The left tibia was removed for total RNA extraction and analysis of gene expression of KISS1 , KISS1R , AR and INSR , by quantitative real-time polymerase chain reaction (qRT-PCR). Results KISS1 was not detected in any of the treated groups. KISS1R , INSR and AR showed higher expression in the G3 group ( p < 0.001), while lower levels of transcripts for these genes were observed in G4 and G5. G2 animals showed hypoexpression of the evaluated genes. Conclusion The results indicate that raloxifene, alone or combined with estrogen, was able to induce the expression of genes associated with the recovery of bone tissue homeostasis in ovariectomized rats.
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OBJECTIVE: The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis. METHODS: The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes. RESULTS: This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated. CONCLUSIONS: In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies.
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Proteína Forkhead Box O3 , Leiomioma , Neoplasias Uterinas , Humanos , Femenino , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/metabolismo , Persona de Mediana Edad , Leiomioma/genética , Leiomioma/patología , Leiomioma/metabolismo , Adulto , Inmunohistoquímica , Regulación Neoplásica de la Expresión Génica/genética , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Leiomiosarcoma/metabolismo , Tumor de Músculo Liso/genética , Tumor de Músculo Liso/patología , Tumor de Músculo Liso/metabolismo , Regulación hacia Arriba , MicroARNs/genética , MicroARNs/metabolismo , Pronóstico , Anciano , Miometrio/metabolismo , Miometrio/patologíaRESUMEN
Abstract Objective To evaluate the effects of estrogen, raloxifene and genistein on the expression of KISS1 (kisspeptin), KISS1R (kisspeptin receptor), AR (androgen receptor) and INSR (insulin receptor) in the bones of ovariectomized rats. Methods Forty-eight adult rats were randomly divided into 6 groups, containing 8 animals each: G1-nonovariectomized control; G2-ovariectomized and treated with conjugated equine estrogens (50 µg/Kg/day); G3-ovariectomized and treated with raloxifene (0.75 mg/kg/day); G4-ovariectomized animal that received soy extract with genistein (300 mg/kg/day); G5-ovariectomized animal that received estrogen and genistein; and G6-ovariectomized animal that received estrogen and raloxifene. Three months after surgery, the castrated animals received the drugs orally daily for 120 days. All animals were sacrificed after this period, by deepening the anesthesia. The left tibia was removed for total RNA extraction and analysis of gene expression of KISS1, KISS1R, AR and INSR, by quantitative real-time polymerase chain reaction (qRT-PCR). Results KISS1 was not detected in any of the treated groups. KISS1R, INSR and AR showed higher expression in the G3 group (p < 0.001), while lower levels of transcripts for these genes were observed in G4 and G5. G2 animals showed hypoexpression of the evaluated genes. Conclusion The results indicate that raloxifene, alone or combined with estrogen, was able to induce the expression of genes associated with the recovery of bone tissue homeostasis in ovariectomized rats.
Resumo Objetivo Avaliar os efeitos do estrogênio, raloxifeno e genisteína na expressão de KISS1 (kisspeptina), KISS1R (receptor da kisspeptina), AR (receptor de androgênio) e INSR (receptor de insulina) nos ossos de ratas ovariectomizadas. Métodos Quarenta e oito ratas adultas foram divididas aleatoriamente em 6 grupos, contendo 8 animais cada: G1-controle não ovariectomizado); G2-ovariectomizado e tratado com estrogênios conjugados equinos (50 µg/Kg/dia); G3-ovariectomizado e tratado com raloxifeno (0,75 mg/kg/dia); G4-ovariectomizado que recebeu extrato de soja com genisteína (300 mg/kg/dia); G5-ovariectomizado que recebeu estrogênio e genisteína; e G6-ovariectomizado que recebeu estrogênio e raloxifeno. Após 3 meses da cirurgia, os animais castrados receberam os fármacos diariamente por via oral, durante 120 dias. Todos os animais foram sacrificados após esse período, por aprofundamento da anestesia. A tíbia esquerda foi removida para extração de RNA total e análise da expressão gênica de KISS1, KISS1R, AR e INSR, por reação de cadeia de polimerase quantitativa em tempo real (quantitative real-time polymerase chain reaction, qRT-PCR, em inglês). Resultados KISS1 não foi detectado em nenhum dos grupos tratados. KISS1R, INSR e AR mostraram maior expressão no grupo G3 (p < 0,001), enquanto menores níveis de transcritos para esses genes foram observados em G4 e G5. Os animais de G2 apresentaram hipoexpressão dos genes avaliados. Conclusão Os resultados indicam que o raloxifeno, isolado ou combinado com estrogênio, foi capaz de induzir a expressão de genes associados à recuperação da homeostase do tecido ósseo em ratas ovariectomizadas.
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Animales , Ratas , Osteoporosis , Genisteína , Clorhidrato de Raloxifeno/uso terapéutico , Estrógenos , KisspeptinasRESUMEN
Abstract Objective The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis. Methods The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes. Results This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated. Conclusions In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies.
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Leiomyomas (LMs) are the most frequent uterine benign tumors, representing the leading cause of hysterectomy indications worldwide. They are highly associated with women's reproductive complications, and endocrine disruptors may influence their etiology. In this sense, air pollution represents a relevant hormonal disruptor that acts on key signaling pathways, resulting in tumor development and infertility. Our goal was to evaluate submucosal LM samples from patients living in the metropolitan and Sao Paulo city regions, focusing on genes involved in tumor development and infertility features. Twenty-four patients were selected based on their region of residence and clinical information availability. Several genes were differentially expressed between women living in metropolitan areas and Sao Paulo city. Significant associations were observed between BCL-2, DVL1, FGFR3, and WNT5b downregulation and contraceptive use in the samples from women living in Sao Paulo city. ESR1 and HHAT downregulation was associated with ethnicity. WNT5b and GREM were associated with LM treatment and related pathologies, respectively. In the samples from women living in other cities of the metropolitan region, abortion occurrence was associated with BMP4 upregulation. Although further studies may be necessary, our results showed that air pollution exposure influences the expression of genes related to LM development and female reproductive features.
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Contaminantes Atmosféricos , Contaminación del Aire , Infertilidad , Leiomioma , Embarazo , Humanos , Femenino , Ciudades , Brasil/epidemiología , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Transcriptoma , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Leiomioma/etiología , Leiomioma/genéticaRESUMEN
FOXO3a dysregulation is frequently implicated in tumorigenesis, and its inhibition can occur by several molecular mechanisms. Among these, post-transcriptional suppression by miRNAs has been associated with various cancers initiation. Here, we assessed the expression profiles of the most relevant miRNAs for breast tumorigenesis, using Luminal A (LA) and Triple-Negative (TN) breast cancer from Brazilian patients, by the quantitative real time-PCR method. Their potential prognostic role for the patients was also evaluated. We identified the miRNAs miR-96-5p and miR-182-5p, de-scribed as negative regulators of FOXO3A, with differential expression both in LA and TN tumors when compared to normal tissue. The miR-96-5p and miR-182-5p miRNAs were upregulated in LA (7.82 times, p < 0.005; 6.12 times, p < 0.005, respectively) and TN breast cancer samples (9.42 times, p < 0.0001; 8.51 times, p < 0.0001) compared to normal tissues. The samples with higher miR-96-5p and miR-182-5p expression (FR ≥ 4) were submitted for FOXO3a immunostaining. Reduced protein detection was observed in all of the tumors compared to normal tissues. The most prominent miRNA expression and FOXO3a protein suppression were observed in TN samples (p < 0.001), indicating the relevant role of these molecules in this tumor biology and clinical behavior. Our results corroborate the literature regarding to the relevance of FOXO3a in the breast cancer, and they open new perspectives for alternative target therapy options for Brazilian patients expressing both FOXO3a and its regulatory miRNAs.
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Neoplasias de la Mama , MicroARNs , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Biomarcadores de Tumor/genética , Brasil , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinogénesis , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , Pronóstico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Fenobarbital/metabolismoRESUMEN
Abstract FOXO3a dysregulation is frequently implicated in tumorigenesis, and its inhibition can occur by several molecular mechanisms. Among these, post-transcriptional suppression by miRNAs has been associated with various cancers initiation. Here, we assessed the expression profiles of the most relevant miRNAs for breast tumorigenesis, using Luminal A (LA) and Triple-Negative (TN) breast cancer from Brazilian patients, by the quantitative real time-PCR method. Their potential prognostic role for the patients was also evaluated. We identified the miRNAs miR-96-5p and miR-182-5p, de-scribed as negative regulators of FOXO3A, with differential expression both in LA and TN tumors when compared to normal tissue. The miR-96-5p and miR-182-5p miRNAs were upregulated in LA (7.82 times, p < 0.005; 6.12 times, p < 0.005, respectively) and TN breast cancer samples (9.42 times, p < 0.0001; 8.51 times, p < 0.0001) compared to normal tissues. The samples with higher miR-96-5p and miR-182-5p expression (FR ≥ 4) were submitted for FOXO3a immunostaining. Reduced protein detection was observed in all of the tumors compared to normal tissues. The most prominent miRNA expression and FOXO3a protein suppression were observed in TN samples (p < 0.001), indicating the relevant role of these molecules in this tumor biology and clinical behavior. Our results corroborate the literature regarding to the relevance of FOXO3a in the breast cancer, and they open new perspectives for alternative target therapy options for Brazilian patients expressing both FOXO3a and its regulatory miRNAs.
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There is a consensus that epigenetic alterations play a key role in cancer initiation and its biology. Studies evaluating the modification in the DNA methylation and chromatin remodeling patterns, as well as gene regulation profile by non-coding RNAs (ncRNAs) have led to the development of novel therapeutic approaches to treat several tumor types. Indeed, despite clinical and translational challenges, combinatorial therapies employing agents targeting epigenetic modifications with conventional approaches have shown encouraging results. However, for rare neoplasia such as uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS), treatment options are still limited. LMS has high chromosomal instability and molecular derangements, while ESS can present a specific gene fusion signature. Although they are the most frequent types of "pure" uterine sarcomas, these tumors are difficult to diagnose, have high rates of recurrence, and frequently develop resistance to current treatment options. The challenges involving the management of these tumors arise from the fact that the molecular mechanisms governing their progression have not been entirely elucidated. Hence, to fill this gap and highlight the importance of ongoing and future studies, we have cross-referenced the literature on uterine LMS and ESS and compiled the most relevant epigenetic studies, published between 2009 and 2022.
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OBJECTIVE: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrinopathy, which etiology encompasses complex genetic traits associated with epigenetic factors, including differences in microRNA (miRNA) expression in a variety of tissues. The circulating form of these molecules is raising attention in the syndrome not only as potential biomarkers of PCOS but also as possible therapeutic targets. The aim of this study was to explore the circulating miRNA profiles present in a cohort of Brazilian women with and without PCOS and to evaluate the potential role of miRNAs in the pathophysiology of the syndrome. METHODS: Cross-sectional study of 36 well-characterized PCOS women and 16 healthy controls. Clinical, hormone and metabolic data were recorded and evaluated. The expression profile of the 201 circulating miRNA selected were analyzed by taqman quantitative real time polymerase chain reactions (RT-PCR) using a customized Open Array platform. Statistical and bioinformatic analyzed were performed. RESULTS: Circulating miR-21-5p, miR-23a-3p and miR-26a-5p were upregulated, and miR-103a-3p, miR-376a-3p, miR-19b-3p and miR-222-3p were downregulated in women with PCOS compared to healthy normo-ovulatory controls. miR-21-5p, miR-103a-3p and miR-376a-3p levels correlated positively with androgen levels. These miRNAs, in combination, were related to pathways involved in insulin signaling, steroids biosynthesis and endothelial regulation as well as in folliculogenesis. CONCLUSION: In this study, we identified a specific circulating miRNA signature in Brazilian women with PCOS. According to our data, circulating miR-21-5p, miR-23a-3p, miR-26a-5p, miR-103a-3p, miR-376a-3p, miR-19b-3p and miR-222-3p may represent potential candidates for differential diagnosis of PCOS in the future.
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MicroARN Circulante , Insulinas , MicroARNs , Síndrome del Ovario Poliquístico , Andrógenos , Biomarcadores , Brasil/epidemiología , MicroARN Circulante/genética , Estudios Transversales , Femenino , Perfilación de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/metabolismo , EsteroidesRESUMEN
The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples (n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC.
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Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Regulación Neoplásica de la Expresión Génica , Tetraspaninas/genética , Transcriptoma , Neoplasias de la Vulva/genética , Neoplasias de la Vulva/mortalidad , Adulto , Anciano , Carcinoma de Células Escamosas/diagnóstico , Susceptibilidad a Enfermedades , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Modelos Biológicos , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Factores de Riesgo , Tetraspaninas/metabolismo , Neoplasias de la Vulva/patologíaRESUMEN
OBJECTIVES: The present study aimed to contribute to the catalog of genetic mutations involved in the carcinogenic processes of uterine sarcomas (USs) and carcinosarcomas (UCSs), which may assist in the accurate diagnosis of, and selection of treatment regimens for, these conditions. METHODS: We performed gene-targeted next-generation sequencing (NGS) of 409 cancer-related genes in 15 US (7 uterine leiomyosarcoma [ULMS], 7 endometrial stromal sarcoma [ESS], 1 adenosarcoma [ADS]), 5 UCS, and 3 uterine leiomyoma (ULM) samples. Quality, frequency, and functional filters were applied to select putative somatic variants. RESULTS: Among the 23 samples evaluated in this study, 42 loss-of-function (LOF) mutations and 111 missense mutations were detected, with a total of 153 mutations. Among them, 66 mutations were observed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. TP53 (48%), ATM (22%), and PIK3CA (17%) were the most frequently mutated genes. With respect to specific tumor subtypes, ESS showed mutations in the PDE4DIP, IGTA10, and DST genes, UCS exhibited mutations in ERBB4, and ULMS showed exclusive alterations in NOTCH2 and HER2. Mutations in the KMT2A gene were observed exclusively in ULM and ULMS. In silico pathway analyses demonstrated that many genes mutated in ULMS and ESS have functions associated with the cellular response to hypoxia and cellular response to peptide hormone stimulus. In UCS and ADS, genes with most alterations have functions associated with phosphatidylinositol kinase activity and glycerophospholipid metabolic process. CONCLUSION: This preliminary study observed pathogenic mutations in US and UCS samples. Further studies with a larger cohort and functional analyses will foster the development of a precision medicine-based approach for the treatment of US and UCS.
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Carcinosarcoma , Sarcoma , Neoplasias Uterinas , Brasil , Carcinosarcoma/genética , Femenino , Humanos , Mutación , Sarcoma/genética , Neoplasias Uterinas/genéticaRESUMEN
OBJECTIVES: The present study aimed to contribute to the catalog of genetic mutations involved in the carcinogenic processes of uterine sarcomas (USs) and carcinosarcomas (UCSs), which may assist in the accurate diagnosis of, and selection of treatment regimens for, these conditions. METHODS: We performed gene-targeted next-generation sequencing (NGS) of 409 cancer-related genes in 15 US (7 uterine leiomyosarcoma [ULMS], 7 endometrial stromal sarcoma [ESS], 1 adenosarcoma [ADS]), 5 UCS, and 3 uterine leiomyoma (ULM) samples. Quality, frequency, and functional filters were applied to select putative somatic variants. RESULTS: Among the 23 samples evaluated in this study, 42 loss-of-function (LOF) mutations and 111 missense mutations were detected, with a total of 153 mutations. Among them, 66 mutations were observed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. TP53 (48%), ATM (22%), and PIK3CA (17%) were the most frequently mutated genes. With respect to specific tumor subtypes, ESS showed mutations in the PDE4DIP, IGTA10, and DST genes, UCS exhibited mutations in ERBB4, and ULMS showed exclusive alterations in NOTCH2 and HER2. Mutations in the KMT2A gene were observed exclusively in ULM and ULMS. In silico pathway analyses demonstrated that many genes mutated in ULMS and ESS have functions associated with the cellular response to hypoxia and cellular response to peptide hormone stimulus. In UCS and ADS, genes with most alterations have functions associated with phosphatidylinositol kinase activity and glycerophospholipid metabolic process. CONCLUSION: This preliminary study observed pathogenic mutations in US and UCS samples. Further studies with a larger cohort and functional analyses will foster the development of a precision medicine-based approach for the treatment of US and UCS.
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Humanos , Femenino , Sarcoma/genética , Neoplasias Uterinas/genética , Carcinosarcoma/genética , Brasil , MutaciónRESUMEN
The temporomandibular muscle dysfunction is characterized by myofascial pain and is more prevalent in women of reproductive age. Sex steroid hormones are hypothetically involved in the dysfunction, but few are the studies of steroid receptors in masticatory and mastication-related muscles. Our aim was to determine estrogen and testosterone receptor expression in rat masticatory and mastication-related muscles within the context of age and gender. Twelve rats were equally divided into four groups: (a) 10-month-old females; (b) 10-month-old males; (c) 24-month-old females; and (d) 24-month-old males. Euthanasia of the females was performed in the proestrous phase (vaginal smears) and the masticatory and accessory muscles were removed for immunohistochemical analysis. Statistical analysis was performed with ANOVA and the Tukey test. Estrogen receptor expression was similarly low in all muscles and groups. Testosterone receptor expression in the Masseter muscle of the 24-month-old male rats was higher than that in the other groups and significantly superior to its expression in the Posterior Digastric muscle. In short, testosterone receptor expression was highest in old male rats. If we generalize to humans, this fact could indicate age- and sex-related hormonal influence on temporomandibular muscle dysfunction. Further studies, however, are necessary to strengthen this hypothesis.
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Envejecimiento/genética , Músculos Masticadores/metabolismo , Receptores Androgénicos/genética , Receptores de Estrógenos/genética , Animales , Estrógenos/sangre , Femenino , Regulación del Desarrollo de la Expresión Génica , Masculino , Masticación/fisiología , Músculos Masticadores/crecimiento & desarrollo , Proestro/fisiología , Ratas , Ratas Wistar , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/metabolismo , Transducción de Señal , Testosterona/sangreRESUMEN
The lethal-7 (let-7) family is an important microRNA (miRNA) group that usually exerts functions as a tumor suppressor. We aimed to evaluate the expression profile of let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, and let-7i and to assess their value as prognostic markers in uterine leiomyosarcoma (LMS) patients. The miRNAs expression profile was assessed in 34 LMS and 13 normal myometrium (MM) paraffin-embedded samples. All let-7 family members showed downregulation in LMS. Our findings showed that patients with let-7e downregulation had worse overall survival (OS) and is an independent prognostic factor (hazard ratio [HR] = 2.24). In addition, almost half the patients had distant metastasis. LMS patients with downregulated let-7b and let-7d had worse disease-free survival (DFS); they are not independent prognostic factors (HR = 2.65). Patients' ages were associated with let-7d, let-7e and let-7f (p = 0.0160) downregulation. In conclusion, all the let-7 family members were downregulated in LMS patients, and the greater the loss of expression of these molecules, the greater their relationship with worse prognosis of patients. Let-7e expression might influence the OS, while let-7b and le-7d might influence the DFS. The lowest expression levels of let-7d, let-7e, and let-7f were associated with the oldest patients. Our findings indicate strong evidence of let-7's role as a potential prognostic biomarker in LMS.
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Regulación hacia Abajo , Perfilación de la Expresión Génica/métodos , Leiomiosarcoma/mortalidad , MicroARNs/genética , Neoplasias Uterinas/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
To identify biomarkers that could predict response or lack of response to conventional chemotherapy at the time of diagnosis of highgrade serous ovarian carcinoma (HGSOC), the present study compared largescale gene expression from patients with short or long diseasefree survival times, according to the last cycle of chemotherapy, and validated these findings using reverse transcriptionquantitative polymerase chain reaction (RTqPCR) and conventional immunohistochemical (IHC) analysis. Samples were selected for microarray evaluation, at the time of diagnosis, using the following criteria: Identical debulking primary surgery, International Federation of Gynaecology and Obstetrics staging, histological subtype and grade. These were divided into 2 groups, regarding the outcome after 2 years of follow-up. Prostaglandin D2 synthase 21 kDa (brain) (PTGDS) was found to be expressed at a significantly higher level in the tumours of patients with a short diseasefree survival time, and this was validated by RTqPCR in all samples. Furthermore, the study evaluated PGD2, the protein product of the PTGDS gene, in a large cohort of 114 HGSOC patients using the Ventana Benchmark automated platform, and IHC positivity was correlated with clinicopathological data and outcome. The global gene expression analysis identified 1,149 genes that were differentially expressed in microarray data, according to the patient outcome. Further analysis RTqPCR validated PTGDS gene expression in the same samples (r=0.945; P<0.001). IHC analysis showed an inverse profile, with positivity for PGD2 strongly associated with an increase in diseasefree survival (P=0.009), the absence of relapse (P=0.039) and sensitivity to platinumbased therapy (P=0.016). Multiple Cox regression showed that IHC evaluation of PGD2 was also a prognostic marker associated with relapse (hazard ratio, 0.37; P=0.002). Overall, the results showed that IHC evaluation of PGD2 is an independent marker of good prognosis in HGSOC. This finding contributes to our understanding of the mechanism of tumour regulation and to investigations into biomarkers that predict response to chemotherapy.
Asunto(s)
Biomarcadores de Tumor/análisis , Cistadenocarcinoma Seroso/patología , Oxidorreductasas Intramoleculares/metabolismo , Lipocalinas/metabolismo , Neoplasias Ováricas/patología , Prostaglandina D2/análisis , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/cirugía , Procedimientos Quirúrgicos de Citorreducción/métodos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/cirugía , Ovariectomía/métodos , Ovario/patología , Ovario/cirugía , Pronóstico , Prostaglandina D2/metabolismoRESUMEN
Changes in microRNA (miRNA) expression may lead to cancer development and/or contribute to its progression; however, their role in uterine sarcomas is poorly understood. Uterine sarcomas (US) belong to a rare class of heterogeneous tumors, representing about 1% of all gynecologic neoplasms. This study aimed to assess the expression profile of 84 cancer-related miRNAs and to evaluate their correlation with clinical pathological features. Eighty-two formalin-fixed paraffin-embedded (FFPE) samples were selected. In leiomyosarcoma (LMS), there was an association of lower cancer-specific survival (CSS) with the downregulation of miR-125a-5p and miR-10a-5p, and the upregulation of miR-196a-5p and miR-34c-5p. In carcinosarcoma (CS), lower CSS was associated with the upregulation of miR-184, and the downregulation of let-7b-5p and miR-124. In endometrial stromal sarcomas (ESS), the upregulation of miR-373-3p, miR-372-3p, and let-7b-5p, and the down-expression of let-7f-5p, miR-23-3p, and let-7b-5p were associated with lower CSS. Only miR-138-5p upregulation was associated with higher survival rates. miR-335-5p, miR-301a-3p, and miR-210-3p were more highly expressed in patients with tumor metastasis and relapse. miR-138-5p, miR-146b-5p, and miR-218-5p expression were associated with higher disease-free survival (DFS) in treated patients. These miRNAs represent potential prediction markers for prognosis and treatment response in these tumors.
RESUMEN
BACKGROUND: Precocious puberty (PP) is defined as premature pubertal development. Its consequences surpass the physical evidence of sexual maturity with the premature epiphyseal closure of the long bones and the reduction of adult stature by varied degrees. Central PP is characteristically dependent on GnRH and most of its causes are not completely known. Altered estrogen action is also believed to be involved in the genesis of PP. In fact, estrogen receptor alpha (Rea) gene polymorphisms may be associated with early age at menarche. The objective of this study was to investigate the relationship between Reα gene polymorphisms (PvuII and XbaI) and the occurrence of central PP. METHODS: A total of 73 girls with central PP and 101 girls with normal pubertal maturation were evaluated. Both groups were genotyped for the PvuII (T/C) and XbaI (A/G) polymorphisms in the Reα gene. RESULTS: The frequency distribution of the XbaI (p = 0.28) and of the PvuII (p = 0.12) genotypes, as well as the XbaI and PvuII allelic variants (p = 0.23 and p = 0.86, respectively), did not differ between the groups. CONCLUSION: The PvuII and XbaI Rea gene polymorphisms do not appear to be related to development of central PP.