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.
Subject(s)
Forkhead Box Protein O3 , Leiomyoma , Uterine Neoplasms , Humans , Female , Forkhead Box Protein O3/metabolism , Forkhead Box Protein O3/genetics , Uterine Neoplasms/genetics , Uterine Neoplasms/pathology , Uterine Neoplasms/metabolism , Middle Aged , Leiomyoma/genetics , Leiomyoma/pathology , Leiomyoma/metabolism , Adult , Immunohistochemistry , Gene Expression Regulation, Neoplastic/genetics , Leiomyosarcoma/genetics , Leiomyosarcoma/pathology , Leiomyosarcoma/metabolism , Smooth Muscle Tumor/genetics , Smooth Muscle Tumor/pathology , Smooth Muscle Tumor/metabolism , Up-Regulation , MicroRNAs/genetics , MicroRNAs/metabolism , Prognosis , Aged , Myometrium/metabolism , Myometrium/pathologyABSTRACT
We conducted a meta-analysis to examine p16INK4a expression in uterine smooth muscle tumors (USMTs). Although the prognostic value of tumor suppressor p16INK4a has been elucidated in a variety of cancers and precancerous lesions, its role in USMTs is not well established. We searched PubMed, Web of Science, and Embase for publication son p16INK4a expression in USMTs. Strict inclusion and exclusion criteria were imposed. Risk ratios (RRs) with 95% confidence intervals (95%CIs) were calculated to assess the strength of association. Publication bias was estimated using funnel plots and the Egger's regression test. Twelve eligible studies comprising 661 patients were included. Compared with leiomyoma (LM), the figures for the strength of association were as follows: LM variants (RR = 1.53, 95%CI = 1.03-2.27, P = 0.036, random effect); leiomyosarcoma (LMS) (RR = 3.20, 95%CI = 1.68-6.12, P < 0.001, random effect); and smooth muscle tumors of uncertain malignant potential (STUMP) (RR = 2.90, 95%CI = 1.17-7.21, P = 0.022, random effect). p16INK4a expression was significantly higher in LMS than in LM variants (RR = 3.74, 95%CI = 1.96-7.13, P < 0.001, random effect) or STUMP (RR = 1.67, 95%CI = 1.26-2.23, P < 0.001, fixed effect). There was a significant correlation between overexpressed p16INK4a and recurrence rates of USMTs (RR = 1.85, 95%CI = 1.11-3.10, P = 0.019, fixed effect). p16INK4a over expression is a potential biomarker for diagnosing problematic USMTs and it might indicate a worse prognosis. However, there is currently insufficient evidence to assess the prognostic value of p16INK4a in USMTs.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p16/biosynthesis , Leiomyoma/metabolism , Leiomyosarcoma/metabolism , Smooth Muscle Tumor/metabolism , Uterine Neoplasms/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Female , Genes, p16 , Genetic Predisposition to Disease , Humans , Leiomyoma/genetics , Leiomyosarcoma/genetics , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/metabolism , Prognosis , Smooth Muscle Tumor/genetics , Uterine Neoplasms/geneticsABSTRACT
AIMS: To examine TOP2A copy number, TOP2A expression, and its prognostic value in uterine leiomyosarcoma (LMS) and other benign smooth muscle tumours. METHODS: We analysed 37 patients treated for uterine LMS with immunohistochemistry for protein expression and fluorescence in situ hybridisation (FISH) for copy number. Twelve cases of leiomyoma variants (LMVs), 4 smooth muscle tumours of uncertain malignant potential (STUMP) and 23 leiomyomas (LMs) were also included. RESULTS: Eighteen patients with LMS (48.6%) were International Federation of Gynecology and Obstetrics (FIGO) stage I, six (16.2%) were stage II, four (10.8%) were stage III, and nine (24.3%) were stage IV. Twenty-one (56.8%) patients with LMS showed high expression of TOP2A. Greater TOP2A levels were found in patients with stage ≥II disease compared with stage I and also in high mitotic index tumours (>20/10 HPF (high power field)). Eleven (36.7%) cases had abnormal TOP2A copy numbers. There was no link between TOP2A copy number and TOP2A expression. All patients with benign smooth muscle tumours had low TOP2A immunohistochemical expression and one (7.7%) patient had TOP2A amplification. TOP2A expression and TOP2A copy number had no impact on disease outcomes. Only the presence of disease outside of the uterus negatively impacted survival compared with early disease (53.4 vs 15.8â months; p<0.001). CONCLUSIONS: TOP2A is highly expressed in advanced LMS but not in non-malignant diseases. TOP2A expression does not correlate with FISH results and does not predict outcome. TOP2A levels are higher in high-mitotic index tumours and in more advanced stages of disease.
Subject(s)
Antigens, Neoplasm/genetics , Biomarkers, Tumor/genetics , DNA Topoisomerases, Type II/genetics , DNA-Binding Proteins/genetics , Leiomyoma/genetics , Leiomyosarcoma/genetics , Smooth Muscle Tumor/genetics , Uterine Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/metabolism , Biomarkers, Tumor/metabolism , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/metabolism , Female , Gene Dosage , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Leiomyoma/diagnosis , Leiomyoma/metabolism , Leiomyosarcoma/diagnosis , Leiomyosarcoma/metabolism , Middle Aged , Poly-ADP-Ribose Binding Proteins , Prognosis , Smooth Muscle Tumor/diagnosis , Smooth Muscle Tumor/metabolism , Tissue Array Analysis , Uterine Neoplasms/diagnosis , Uterine Neoplasms/metabolism , Uterus/metabolism , Uterus/pathologyABSTRACT
BACKGROUND: Undifferentiated Pleomorphic Sarcoma (UPS) and high-grade Leiomyosarcoma (LMS) are soft tissue tumors with an aggressive clinical behavior, frequently developing local recurrence and distant metastases. Despite several gene expression studies involving soft tissue sarcomas, the potential to identify molecular markers has been limited, mostly due to small sample size, in-group heterogeneity and absence of detailed clinical data. MATERIALS AND METHODS: Gene expression profiling was performed for 22 LMS and 22 UPS obtained from untreated patients. To assess the relevance of the gene signature, a meta-analysis was performed using five published studies. Four genes (BAD, MYOCD, SRF and SRC) selected from the gene signature, meta-analysis and functional in silico analysis were further validated by quantitative PCR. In addition, protein-protein interaction analysis was applied to validate the data. SRC protein immunolabeling was assessed in 38 UPS and 52 LMS. RESULTS: We identified 587 differentially expressed genes between LMS and UPS, of which 193 corroborated with other studies. Cluster analysis of the data failed to discriminate LMS from UPS, although it did reveal a distinct molecular profile for retroperitoneal LMS, which was characterized by the over-expression of smooth muscle-specific genes. Significantly higher levels of expression for BAD, SRC, SRF, and MYOCD were confirmed in LMS when compared with UPS. SRC was the most value discriminator to distinguish both sarcomas and presented the highest number of interaction in the in silico protein-protein analysis. SRC protein labeling showed high specificity and a positive predictive value therefore making it a candidate for use as a diagnostic marker in LMS. CONCLUSIONS: Retroperitoneal LMS presented a unique gene signature. SRC is a putative diagnostic marker to differentiate LMS from UPS.
Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Profiling , Leiomyosarcoma/diagnosis , Leiomyosarcoma/genetics , Proto-Oncogene Proteins pp60(c-src)/genetics , Sarcoma/diagnosis , Sarcoma/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Child , Child, Preschool , Diagnosis, Differential , Female , Humans , Leiomyosarcoma/metabolism , Leiomyosarcoma/pathology , Male , Middle Aged , Neoplasm Grading , Nuclear Proteins/genetics , Prognosis , Protein Interaction Mapping , Proto-Oncogene Proteins pp60(c-src)/metabolism , Sarcoma/metabolism , Sarcoma/pathology , Serum Response Factor/genetics , Trans-Activators/genetics , Young Adult , bcl-Associated Death Protein/geneticsABSTRACT
INTRODUCTION: The expression of E-cadherin, beta-catenin and topoisomerase II has been associated with clinical outcome of several cancers including sarcomas. We aimed to evaluate the expression of these markers in leiomyosarcomas (LMS). MATERIALS AND METHODS: Paraffin blocks of 19 primary, nonmetastatic LMS were analysed immunohistochemically for the expression of the above-mentioned markers with a cutoff level for positivity of 20% of cell staining. RESULTS: Expression of E-cadherin was negative in all LMS. Nuclear expression of beta-catenin was also negative in all cases, while positive cytoplasmic beta-catenin expression was observed in approximately half of the patients. The majority of LMS had expression of topoisomerase IIalpha, although only in 10 patients was this expression in more than 20% of tumour cells. From the analysed factors, tumour size was statistically significantly correlated with relapse-free survival. CONCLUSIONS: Further evidence with larger series is required in order to determine the implication of these markers in LMS.
Subject(s)
Antigens, Neoplasm/metabolism , Cadherins/metabolism , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/metabolism , Leiomyosarcoma/metabolism , beta Catenin/metabolism , Adult , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , Leiomyosarcoma/pathology , Male , Middle AgedABSTRACT
BACKGROUND: The low incidence of pancreatic leiomyosarcoma is responsible for the small number of cases correctly diagnosed preoperatively, the tumor being frequently confused with benign pancreatic lesions. RESULTS: We describe a symptom free 52-yr-old male bearing an abdominal mass incidentally found at physical examination. Imaging techniques revealed a nonhomogenous large mass at the head of the pancreas that dislodged the portal vein and the superior mesenteric vein. Increased metabolic activity in the tumor area demonstrated by 18F-fluorodeoxyglicose positron emission tomography scan allowed the diagnosis of a malignant lesion. The patient was operated on and a pylorus preserving pancreatoduodenectomy performed. The pathology diagnosis was a low grade leiomyosarcoma. Immunohistochemistry revealed positivity for vimentin and smooth muscle specific actin. The clinical course was uneventful after 2 yr follow-up. CONCLUSION: Pancreatic leiomyosarcoma may be preoperatively diagnosed by image techniques and differentiated from benign lesions by means of fluorodeoxyglicose positron emission tomography scanning (FDGPET).
Subject(s)
Leiomyosarcoma/diagnosis , Leiomyosarcoma/surgery , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/surgery , Actins/metabolism , Diagnosis, Differential , Fluorodeoxyglucose F18 , Humans , Leiomyosarcoma/metabolism , Leiomyosarcoma/pathology , Male , Middle Aged , Muscle, Smooth/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreaticoduodenectomy , Tomography, Emission-Computed , Tomography, X-Ray Computed , Ultrasonography , Vimentin/metabolismABSTRACT
El origen de los tumores mesenquimáticos del tracto gastrointestinal tradicionalmente considerados musculares ha sido recientemente debatido postulándose que algunos de ellos serían en realidad derivados de células del sistema nervioso periférico. En el presente trabajo hemos estudiado una serie de tumores mesenquimáticos digestivos empleando un antisuero para S-100 y dos antisueros para proteínas de filamentos intermedios: la proteína gliofibrilar ácida (PGFA), y la desmina. La técnica utilizada fue la de peroxidasa-antiperoxidasa empleando antisueros policlonales obtenidos de DAKO (Dinamarca). Se estudiaron 24 tumores mesenquimáticos del tracto digestivo (Tabla 1). Las localizaciones fueron: 1 de esófago, 16 de estómago, 6 de intestino delgado y 1 de colon. Los mismos fueron diagnosticados como: leiomioma (18 casos), leiomioblastoma (3 casos) y leiomiosarcomas (3 casos). Como grupo control se estudiaron 5 leiomiomas uterinos. Estos resultaron uniformemente positivos para desmina y negativos para S-100 y PGFA. Diez casos fueron positivos con el antisuero para desmina; correspondiendo éstos a 9 leiomiomas y 1 leiomioblastoma (Tabla 2). Seis (25%) de los tumores expresaron marcadores neurales: 5 fueron positivos con S-100, 4 con PGFA y correspondieron a 3 leiomiomas, 1 leiomioblastoma y 2 leiomiosarcomas. En ningún tumor se observó tinción simultánea para desmina y algunos de los marcadores neurales. Ocho casos (33%) fueron negativos con todos los antisueros empleados siendo: 6 leiomiomas; 1 leiomioblastoma y 1 leiomiosarcomas. Nuestros resultados sugieren la existencia de por lo menos dos grupos de tumores de acuerdo a sus características inmunohistoquímicas: aquellos de origen miogénico y los derivados de células del sistema periférico. Los tumores negativos para ambos grupos de marcadores podrán probablemente ser clasificados mediante otras técnicas inmunohistoquímicas o ultraestructurales...
Subject(s)
Humans , Gastrointestinal Neoplasms/metabolism , Leiomyoma/metabolism , Leiomyosarcoma/metabolism , Desmin/metabolism , Glial Fibrillary Acidic Protein/metabolism , Immunoenzyme Techniques , Neoplasms, Muscle Tissue/metabolism , Neurilemmoma/metabolismABSTRACT
El origen de los tumores mesenquimáticos del tracto gastrointestinal tradicionalmente considerados musculares ha sido recientemente debatido postulándose que algunos de ellos serían en realidad derivados de células del sistema nervioso periférico. En el presente trabajo hemos estudiado una serie de tumores mesenquimáticos digestivos empleando un antisuero para S-100 y dos antisueros para proteínas de filamentos intermedios: la proteína gliofibrilar ácida (PGFA), y la desmina. La técnica utilizada fue la de peroxidasa-antiperoxidasa empleando antisueros policlonales obtenidos de DAKO (Dinamarca). Se estudiaron 24 tumores mesenquimáticos del tracto digestivo (Tabla 1). Las localizaciones fueron: 1 de esófago, 16 de estómago, 6 de intestino delgado y 1 de colon. Los mismos fueron diagnosticados como: leiomioma (18 casos), leiomioblastoma (3 casos) y leiomiosarcomas (3 casos). Como grupo control se estudiaron 5 leiomiomas uterinos. Estos resultaron uniformemente positivos para desmina y negativos para S-100 y PGFA. Diez casos fueron positivos con el antisuero para desmina; correspondiendo éstos a 9 leiomiomas y 1 leiomioblastoma (Tabla 2). Seis (25%) de los tumores expresaron marcadores neurales: 5 fueron positivos con S-100, 4 con PGFA y correspondieron a 3 leiomiomas, 1 leiomioblastoma y 2 leiomiosarcomas. En ningún tumor se observó tinción simultánea para desmina y algunos de los marcadores neurales. Ocho casos (33%) fueron negativos con todos los antisueros empleados siendo: 6 leiomiomas; 1 leiomioblastoma y 1 leiomiosarcomas. Nuestros resultados sugieren la existencia de por lo menos dos grupos de tumores de acuerdo a sus características inmunohistoquímicas: aquellos de origen miogénico y los derivados de células del sistema periférico. Los tumores negativos para ambos grupos de marcadores podrán probablemente ser clasificados mediante otras técnicas inmunohistoquímicas o ultraestructurales... (AU)