IRAN AMORIM DA SILVA

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Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/55 - Laboratório de Urologia, Hospital das Clínicas, Faculdade de Medicina

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  • article 10 Citação(ões) na Scopus
    MicroRNAs 143 and 145 may be involved in benign prostatic hyperplasia pathogenesis through regulation of target genes and proteins
    (2014) VIANA, Nayara I.; REIS, Sabrina T.; DIP, Nelson G.; MORAIS, Denis R.; MOURA, Caio M.; SILVA, Iran A.; KATZ, Betina; SROUGI, Miguel; LEITE, Katia R. M.; ANTUNES, Alberto A.
    Objectives: The aim of this study was to analyze the roles of miR-143 and miR-145, as well as the gene and protein expression of their targets (KRAS, ERK5, MAP3K3, and MAP4K4) in the pathogenesis of benign prostatic hyperplasia (BPH). Methods: We analyzed the specimens of 44 patients diagnosed with BPH who underwent surgical treatment. The control group consisted of prostate samples from 2 young patients who were organ donors. miRNAs and their target genes were assessed using real-time polymerase chain reaction (qRT-PCR), and protein levels were assessed by Western blotting. Results: miR-143 and miR-145 were overexpressed in, respectively, 62.5% and 73.8% of the cases. The ERK5 and MAP4K4 genes were underexpressed respectively in 59.4% and 100% of the BPH samples, whereas KRAS and MAP3K3 were overexpressed respectively in 79.4% and 61.5% of the samples. Increased protein expression was found for both KRAS (4,312.2 luminance/area) and MAP3K3 (7,461.7 luminance/area), while the ERK5 protein was more abundant in the samples from patients with prostate larger than 60 grams (p = 0.019). Conclusions: The overexpression of miR-143 and miR-145 in BPH samples suggests an association with the pathogenesis of the disease; additionally, the latter miRNA may act through the inhibition of MAP4K4. KRAS and MAP3K3 overexpression may also be associated with BPH pathogenesis. Further analyses are necessary to confirm these results.
  • article 38 Citação(ões) na Scopus
    Comprehensive Study of Gene and microRNA Expression Related to Epithelial-Mesenchymal Transition in Prostate Cancer
    (2014) KATZ, Betina; REIS, Sabrina T.; VIANA, Nayara I.; MORAIS, Denis R.; MOURA, Caio M.; DIP, Nelson; SILVA, Iran A.; ISCAIFE, Alexandre; SROUGI, Miguel; LEITE, Katia R. M.
    Prostate cancer is the most common cancer in men, and most patients have localized disease at the time of diagnosis. However, 4% already present with metastatic disease. Epithelial-mesenchymal transition is a fundamental process in carcinogenesis that has been shown to be involved in prostate cancer progression. The main event in epithelial-mesenchymal transition is the repression of E-cadherin by transcription factors, but the process is also regulated by microRNAs. The aim of this study was to analyze gene and microRNA expression involved in epithelial-mesenchymal transition in localized prostate cancer and metastatic prostate cancer cell lines and correlate with clinicopathological findings. We studied 51 fresh frozen tissue samples from patients with localized prostate cancer (PCa) treated by radical prostatectomy and three metastatic prostate cancer cell lines (LNCaP, DU145, PC3). The expression of 10 genes and 18 miRNAs were assessed by real-time PCR. The patients were divided into groups according to Gleason score, pathological stage, preoperative PSA, biochemical recurrence, and risk group for correlation with clinicopathological findings. The majority of localized PCa cases showed an epithelial phenotype, with overexpression of E-cadherin and underexpression of the mesenchymal markers. MiRNA-200 family members and miRNAs 203, 205, 183, 373, and 21 were overexpressed, while miRNAs 9, 495, 29b, and 1 were underexpressed. Low-expression levels of miRNAs 200b, 30a, and 1 were significantly associated with pathological stage. Lower expression of miR-200b was also associated with a Gleason score >= 8 and shorter biochemical recurrence-free survival. Furthermore, low-expression levels of miR-30a and high-expression levels of Vimentin and Twist1 were observed in the high-risk group. Compared with the primary tumor, the metastatic cell lines showed significantly higher expression levels of miR-183 and Twist1. In summary, miRNAs 200b, 30a, 1, and 183 and the genes Twist1 and Vimentin might play important roles in the progression of prostate cancer and may eventually become important prognostic markers.
  • article 10 Citação(ões) na Scopus
    The role of microRNAs 371 and 34a in androgen receptor control influencing prostate cancer behavior
    (2015) LEITE, Katia R. M.; MORAIS, Denis Reis; FLOREZ, Manuel Garcia; REIS, Sabrina T.; ISCAIFE, Alexandre; VIANA, Nayara; MOURA, Caio M.; SILVA, Iran A.; KATZ, Betina S.; PONTES JR., Jose; NESRALLAH, Adriano; SROUGI, Miguel
    Background: The molecular mechanisms involved in androgen receptor (AR) signaling pathways are not completely understood, and deregulation of microRNAs (miRNAs) expression may play a role in prostate cancer (PC) development and progression. Methods: The expression levels of miRNA and AR were evaluated with quantitative real-time polymerase chain reaction using frozen tissue from the surgical specimens of 83 patients submitted to radical prostatectomy. The expression level of miRNAs was correlated with prognostic factors and biochemical recurrence during a follow-up period of 45 months. In vitro and in vivo experiments were performed to understand the effect of miRNAs over AR in the context of that seen in a PC model. Results: MiR-371 underexpression correlated with non-organ-confined (pT3) disease (P = 0.009). In vitro transfection of miR-371 reduced the levels of AR by 22% and 28% in LNCaP and PC3 cell lines, respectively, and in kallikrein 3, it was reduced by 51%. PC was induced in Balb/c mice using PC-3M-luc-C6 cells, and animals were treated with 3 local doses of miR-371. Tumor growth evaluated by in vivo imaging after luciferase injection was slower in animals treated with miR-371. To explore further the possible role of miRNAs in the AR pathway, LNCaP cell line was treated with 5 alpha-dihydrotestosterone and flutamide showing alteration in miRNAs expression, especially miR-34a, which was significantly underexpressed after treatment with high doses of 5 alpha-dihydrotestosterone. Conclusion: Our data support a role for miRNAs, especially miR-371 and miR-34a, in the complex disarrangement of AR signaling pathway and in the behavior of PC.
  • article 1 Citação(ões) na Scopus
    Nomograms using a small panel of genes for predicting the diagnosis and aggressiveness of prostate cancer
    (2020) LEITE, Katia R. M.; ORTEGA, Fabio L.; DAMIANI, Lucas P.; GUIMARAES, Vanessa; VIANA, Nayara; SILVA, Iran A.; REIS, Sabrina T.; PIMENTA, Ruan; ADONIAS, Sanarelly P.; CHAMMAS, Cristina; SROUGI, Miguel; NAHAS, Willian
  • article 8 Citação(ões) na Scopus
    Micro RNA Expression and Prognosis in Low-grade Non-invasive Urothelial Carcinoma
    (2014) DIP, Nelson; REIS, Sabrina T.; ABE, Daniel K.; VIANA, Nayara I.; MORAIS, Denis R.; MOURA, Caio M.; KATZ, Betina; SILVA, Iran A.; SROUGI, Miguel; LEITE, Katia R. M.
    Purpose: To analyze a possible correlation between a miRNA expression profile and important prognostic factors for pTa urothelial carcinomas (UC), including tumor size, multiplicity and episodes of recurrence. Materials and Methods: Thirty low-grade non-invasive pTa bladder UC from patients submitted to transurethral resection were studied, in a mean follow-up of 17.7 months. As controls, we used normal bladder tissue from five patients submitted to retropubic prostatectomy to treat benign prostatic hyperplasia. Extraction, cDNA and amplification were performed for 14 miRNAs (miR-100, -10a, -21, -205, -let7c, -143, -145, -221, -223, -15a, -16, -199a and -452) using specific kits, and RNU-43 and -48 were used as endogenous controls. Statistical tests were used to compare tumor size, multiplicity and episodes of recurrence with miRNAs expression profiles. Results: There was a marginal correlation between multiplicity and miR-let7c over- expression. For all others miRNA no correlation between their expression and prognostic factors was found. Conclusion: We did not find differences for miRNAs expression profiles associated with prognostic factors in tumor group studied. The majority of miRNAs are down-regulated, except miR-10a, over-expressed in most of cases, seeming to have increased levels in tumor with more unfavorable prognostic factors. More studies are needed in order to find a miRNA profile able to provide prognosis in pTa UC to be used in clinical practice.
  • conferenceObject
    Low expression levels of miRNA 200b are related to pT3 and high Gleason score in prostate cancer
    (2013) KATZ, B.; REIS, S.; DIP, N.; VIANA, N.; MORAIS, D.; SILVA, I.; SROUGI, M.; LEITE, K. Ramos Moreira
  • article 3 Citação(ões) na Scopus
    Intratumoral Restoration of miR-137 Plus Cholesterol Favors Homeostasis of the miR-137/Coactivator p160/AR Axis and Negatively Modulates Tumor Progression in Advanced Prostate Cancer
    (2023) PIMENTA, Ruan; MIOSHI, Carolina Mie; GONCALVES, Guilherme L.; CANDIDO, Patricia; CAMARGO, Juliana A.; GUIMARAES, Vanessa R.; CHIOVATTO, Caroline; GHAZARIAN, Vitoria; ROMAO, Poliana; SILVA, Karina Serafim da; SANTOS, Gabriel A. dos; SILVA, Iran A.; SROUGI, Miguel; NAHAS, William C.; LEITE, Katia R.; VIANA, Nayara I.; REIS, Sabrina T.
    MicroRNAs (miRNAs) have gained a prominent role as biomarkers in prostate cancer (PCa). Our study aimed to evaluate the potential suppressive effect of miR-137 in a model of advanced PCa with and without diet-induced hypercholesterolemia. In vitro, PC-3 cells were treated with 50 pmol of mimic miR-137 for 24 h, and gene and protein expression levels of SRC-1, SRC-2, SRC-3, and AR were evaluated by qPCR and immunofluorescence. We also assessed migration rate, invasion, colony-forming ability, and flow cytometry assays (apoptosis and cell cycle) after 24 h of miRNA treatment. For in vivo experiments, 16 male NOD/SCID mice were used to evaluate the effect of restoring miR-137 expression together with cholesterol. The animals were fed a standard (SD) or hypercholesterolemic (HCOL) diet for 21 days. After this, we xenografted PC-3 LUC-MC6 cells into their subcutaneous tissue. Tumor volume and bioluminescence intensity were measured weekly. After the tumors reached 50 mm3, we started intratumor treatments with a miR-137 mimic, at a dose of 6 mu g weekly for four weeks. Ultimately, the animals were killed, and the xenografts were resected and analyzed for gene and protein expression. The animals' serum was collected to evaluate the lipid profile. The in vitro results showed that miR-137 could inhibit the transcription and translation of the p160 family, SRC-1, SRC-2, and SRC-3, and indirectly reduce the expression of AR. After these analyses, it was determined that increased miR-137 inhibits cell migration and invasion and impacts reduced proliferation and increased apoptosis rates. The in vivo results demonstrated that tumor growth was arrested after the intratumoral restoration of miR-137, and proliferation levels were reduced in the SD and HCOL groups. Interestingly, the tumor growth retention response was more significant in the HCOL group. We conclude that miR-137 is a potential therapeutic miRNA that, in association with androgen precursors, can restore and reinstate the AR-mediated axis of transcription and transactivation of androgenic pathway homeostasis. Further studies involving the miR-137/coregulator/AR/cholesterol axis should be conducted to evaluate this miR in a clinical context.
  • article 13 Citação(ões) na Scopus
    Prima-1 induces apoptosis in bladder cancer cell lines by activating p53
    (2013) PIANTINO, Camila B.; REIS, Sabrina T.; VIANA, Nayara I.; SILVA, Iran A.; MORAIS, Denis R.; ANTUNES, Alberto A.; DIP, Nelson; SROUGI, Miguel; LEITE, Katia R.
    OBJECTIVES: Bladder cancer represents 3% of all carcinomas in the Brazilian population and ranks second in incidence among urological tumors, after prostate cancer. The loss of p53 function is the main genetic alteration related to the development of high-grade muscle-invasive disease. Prima-1 is a small molecule that restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Our aim was to investigate the ability of Prima-1 to induce apoptosis after DNA damage in bladder cancer cell lines. METHOD: The therapeutic effect of Prima-1 was studied in two bladder cancer cell lines: T24, which is characterized by a p53 mutation, and RT4, which is the wild-type for the p53 gene. Morphological features of apoptosis induced by p53, including mitochondrial membrane potential changes and the expression of thirteen genes involved in apoptosis, were assessed by microscopic observation and quantitative real-time PCR (qRT-PCR). RESULTS: Prima-1 was able to reactivate p53 function in the T24 (p53 mt) bladder cancer cell line and promote apoptosis via the induction of Bax and Puma expression, activation of the caspase cascade and disruption of the mitochondrial membrane in a BAK-independent manner. CONCLUSION: Prima-1 is able to restore the transcriptional activity of p53. Experimental studies in vivo may be conducted to test this molecule as a new therapeutic agent for urothelial carcinomas of the bladder, which characteristically harbor p53 mutations.
  • article 24 Citação(ões) na Scopus
    MiR-200c-3p expression may be associated with worsening of the clinical course of patients with COVID-19
    (2021) PIMENTA, Ruan; I, Nayara Viana; SANTOS, Gabriel A. dos; CANDIDO, Patricia; GUIMARAES, Vanessa R.; ROMAO, Poliana; SILVA, Iran A.; CAMARGO, Juliana A. de; HATANAKA, Dina M.; QUEIROZ, Paula G. S.; TERUYA, Alexandre; ECHENIQUE, Leandro; BESEN, Bruno A. M. P.; LEITE, Katia R. M.; SROUGI, Victor; SROUGI, Miguel; REIS, Sabrina T.
    COVID-19 represents a public health emergency, whose mechanism of which is not fully understood. It is speculated that microRNAs may play a crucial role in host cells after infection by SARS-CoV-2. Thus, our study aimed to analyze the expression of miR-200c-3p in saliva samples from patients with COVID-19. One handred eleven samples from patients with COVID-19 were divided into 4 groups. Group I: 39 patients negative for Covid-19; Group II: 37 positive and symptomatic patients, with no indication of hospitalization; Group III: 21 patients with respiratory disorders (hospitalized); Group W: 14 patients with severe conditions (oxygen therapy). The expression levels of miR-200c-3p were determined using qPCR. We found greater expression of miR-200c-3p in patients in group W (p<0.0001), and also verified that patients aged >= 42 years had a higher expression of this miR (p=0.013). Logistic regression analysis revealed that the expression of miR-200c-3p and systemic arterial hypertension are factors independently associated with patients in group IV (p<0.0001). Our results suggest that miR-200c-3p is a predictor of severity independent of COVID-19 risk factors, which could represent a way of screening patients affected by SARS-CoV-2.
  • article 6 Citação(ões) na Scopus
    Cholesterol Triggers Nuclear Co-Association of Androgen Receptor, p160 Steroid Coactivators, and p300/CBP-Associated Factor Leading to Androgenic Axis Transactivation in Castration-Resistant Prostate Cancer
    (2022) PIMENTA, R.; CAMARGO, J. A.; CANDIDO, P.; GHAZARIAN, V.; GONçALVES, G. L.; GUIMARãES, V. R.; ROMãO, P.; CHIOVATTO, C.; MIOSHI, C. M.; SANTOS, G. A. dos; SILVA, I. A.; BIRBRAIR, A.; SROUGI, M.; NAHAS, W. C.; LEITE, K. R.; VIANA, N. I.; REIS, S. T.
    Background/Aims: Cholesterol modulates intratumoral androgenic signaling in prostate cancer; however, the molecular mechanisms underlying these changes in castration-resistant prostate cancer (CRPC) are not fully elucidated. Herein, we investigated the effect of cholesterol on androgen receptor (AR) coactivators expression and tumorigenesis in vitro and in vivo. Methods: Herein, we monitored the expression of AR coactivators (SRC-1, 2, 3 and PCAF) genes in PC-3 cells exposed to 2µg/mL of cholesterol for 8 hours by qPCR. We also performed cell migration at 0, 8, 24, 48 and 72h and flow cytometry assays (viability, apoptosis, and cell cycle) after a 24h exposure. Immunofluorescence assay was performed to evaluate the protein expression of the AR coactivators. Additionally, in vivo experiments were conducted using 22 male NOD/SCID mice. Mice were fed a standard (Control) or hypercholesterolemic (HCOL) diet for 21 days and then subcutaneously implanted with PC-3 cells. The tumor volume was calculated every two days, and after four weeks, the tumors were resected, weighed, and the serum lipid profile was measured. We also measured the intratumoral lipid profile and AR coactivators gene and protein expression by qPCR and Western Blot, respectively. Intratumor testosterone and dihydrotestosterone (DHT) concentrations were determined using ELISA. Results: Cholesterol up-regulated the gene expression of coactivators SRC-1, SRC-2, SRC-3 and PCAF, increasing AR expression in PC-3 cells. Next, cholesterol-supplemented PC-3 cells exhibited increased cell migration and altered cell cycle phases, leading to changes in proliferation and reduced apoptosis. We found that SRC-1, SRC-2, SRC-3 and PCAF proteins co-localized in the nucleus of cholesterol-supplemented cells and co-associate with AR. In the in vivo model, the hypercholesterolemic (HCOL) group displayed higher serum total and intratumoral cholesterol levels, increased testosterone and dihydrotestosterone concentrations, and up-regulated AR coactivator expression. The tumor volume of the HCOL group was significantly higher than the control group. Conclusion: Our findings revealed that increased nuclear translocation of the coactivators leads to up-regulated AR gene and protein expression, potentially influencing tumor progression. Studies targeting cholesterol-modulated changes in AR coactivator expression may provide insights into the molecular mechanisms associated with the CRPC phenotype. © 2022 Cell Physiol Biochem Press GmbH & Co KG. All rights reserved.