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1.
J Am Chem Soc ; 146(1): 521-531, 2024 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-38110248

RESUMO

Carboxypeptidases (CPs) are a family of hydrolases that cleave one or more amino acids from the C-terminal of peptides or proteins and play indispensable roles in various physiological and pathological processes. However, only a few highly activatable fluorescence probes for CPs have been reported, and there is a need for a flexibly tunable molecular design platform to afford a range of fluorescence probes for CPs for biological and medical research. Here, we focused on the unique activation mechanism of ProTide-based prodrugs and established a modular design platform for CP-targeting florescence probes based on ProTide chemistry. In this design, probe properties such as fluorescence emission wavelength, reactivity/stability, and target CP can be readily tuned and optimized by changing the four probe modules: the fluorophore, the substituent on the phosphorus atom, the linker amino acid at the P1 position, and the substrate amino acid at the P1' position. In particular, switching the linker amino acid at position P1 enabled us to precisely optimize the reactivity for target CPs. As a proof-of-concept, we constructed probes for carboxypeptidase M (CPM) and prostate-specific membrane antigen (also known as glutamate carboxypeptidase II). The developed probes were applicable for the imaging of CP activities in live cells and in clinical specimens from patients. This design strategy should be useful in studying CP-related biological and pathological phenomena.


Assuntos
Carboxipeptidases , Ariloxifosforamidatos , Masculino , Humanos , Fluorescência , Carboxipeptidases/metabolismo , Hidrolases , Aminoácidos , Corantes Fluorescentes/química
2.
Sci Rep ; 12(1): 8520, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35595810

RESUMO

Breast-conserving surgery has become the preferred treatment method for breast cancer. Surgical margin assessment is performed during surgery, as it can reduce local recurrence in the preserved breast. Development of reliable and lower-cost ex vivo cancer detection methods would offer several benefits for patient care. Here, a practical and quantitative evaluation method for the ex vivo fluorescent diagnosis of breast lesions was developed and confirmed through a three-step clinical study. Gamma-glutamyl-hydroxymethyl rhodamine green (gGlu-HMRG) has been reported to generate fluorescence in breast lesions. Using this probe, we constructed a reliable and reproducible procedure for the quantitative evaluation of fluorescence levels. We evaluated the reliability of the method by considering reproducibility, temperature sensitivity, and the effects of other clinicopathological factors. The results suggest that the fluorescence increase of gGlu-HMRG is a good indicator of the malignancy of breast lesions. However, the distributions overlapped. A 5 min reaction with this probe could be used to distinguish at least part of the normal breast tissue. This method did not affect the final pathological examination. In summary, our results indicate that the methods developed in this study may serve as a feasible intraoperative negative-margin assessment tool during breast-conserving surgery.


Assuntos
Neoplasias da Mama , Margens de Excisão , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Feminino , Corantes Fluorescentes , Humanos , Mastectomia Segmentar , Reprodutibilidade dos Testes , gama-Glutamiltransferase
3.
Breast Cancer ; 28(1): 67-74, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32601800

RESUMO

BACKGROUND: Clinical Treatment Score post-5 years (CTS5) is a promising prognostic tool to evaluate late distant recurrence (DR) risk for breast cancer after 5-year adjuvant endocrine therapy. PATIENTS AND METHODS: Among 560 postmenopausal women with pathological stage I-III estrogen receptor-positive (ER+) primary breast cancer, 383 women who had received 5-year adjuvant endocrine therapy without any recurrence at 5 years after surgery were included in this study. The CTS5 was calculated for each patient using a previously published formula, and the patients were stratified by their CTS5 values into the low-, intermediate- and high-CTS5 risk groups. RESULTS: According to the CTS5, 205 (53.5%), 106 (27.7%) and 72 (18.8%) patients were classified into the low-, intermediate-, and high-CTS5 risk groups, respectively. A higher ER expression level was significantly associated with the low CTS5. The increased administration of adjuvant chemotherapy was significantly associated with a high CTS5. The occurrence of DR was higher in the intermediate and high CTS5 groups than in the low CTS5 group. The DRFS in the low CTS5 risk group was significantly better than that in the intermediate- or high-risk groups. In the ER-high or HER2-negative (HER2-) group, the DRFS in the low-risk group was significantly better than that of the intermediate- or high-risk groups. However, in the low-ER or HER2-positive group, there was no significant difference in DRFS among the three risk groups. CONCLUSIONS: In postmenopausal women with ER+ breast cancer, low CTS5 was considered to be associated with a very low risk of late DR. Thus, extended endocrine therapy may be unnecessary for patients with low CTS5 scores. Extended endocrine therapy should be offered for patients with intermediate or high CTS5 scores, especially those with high-ER and HER2- breast cancer.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/farmacologia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/estatística & dados numéricos , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Pós-Menopausa , Prognóstico , Receptor ErbB-2/análise , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/análise , Receptores de Estrogênio/antagonistas & inibidores , Estudos Retrospectivos , Medição de Risco/métodos
4.
Anticancer Res ; 40(6): 3315-3323, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487627

RESUMO

BACKGROUND/AIM: To evaluate the improvement in the prognosis by adjuvant trastuzumab in clinical practice and the risk factors for distant recurrence, we retrospectively investigated the prognosis of HER2-positive early breast cancer in our department before and after the introduction of adjuvant trastuzumab. PATIENTS AND METHODS: Cohorts A and B included 161 and 182 cases, respectively, who underwent surgery before (2000-2007) and after (2008-2015) the introduction of adjuvant trastuzumab. RESULTS: The rates of relapse-free and distant metastasis-free survival were significantly better in cohort B than in cohort A. The risk factors of distant recurrence found in cohort A, such as the presence of lymph node metastasis, lymphatic invasion, and a low histological grade, did not increase the risk in cohort B. CONCLUSION: Many risk factors seemed to have been negated by adjuvant trastuzumab administration. Therefore, further escalation of adjuvant treatment should be carefully considered.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Trastuzumab/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Estudos Retrospectivos , Análise de Sobrevida , Trastuzumab/farmacologia
5.
Breast Cancer ; 27(6): 1137-1146, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32472474

RESUMO

BACKGROUND: The TNM system, which reflects the anatomical extent of disease, was used for stage definition. In the recently published AJCC 8th edition, the new staging system of the clinical and pathological prognostic stage, which incorporates biological factors, is introduced. PATIENTS AND METHODS: A total of 2622 patients with primary breast cancer at stage I-III were included in this study. The anatomic stage (aStage) and the pathological prognostic stage (ppStage) for each case were determined according to the definition of the AJCC 8th edition, and the influence of these stages on the prognosis was compared. RESULTS: The stage distributions of aStage and ppStage were as follows: aStage, stage IA (54.8%), IB (1.1%), IIA (26.1%), IIB (9.2%), IIIA (5.6%), IIIB (0.1%), and IIIC (3.1%); and ppStage, stage IA (66.6%), IB (13.1%), IIA (11.1%), IIB (3.2%), IIIA (3.3%), IIIB (1.4%), and IIIC (1.2%). Compared with the aStage, the ppStage stayed the same in 1710 patients (65.2%), was downstaged in 778 patients (29.7%), and was upstaged in 134 patients. The pathological tumor size (pT2) and lymph node metastasis (pN1) were associated with downstaging, and histological grade 3 was associated with upstaging. ER positivity, PgR positivity, and HER2-positivity were significantly associated with downstaging, and the TN subtype was associated with upstaging. Both the aStage and ppStage were significantly associated with the prognosis; however, the Kaplan-Meier curves for the relapse-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival were better stratified by the ppStage. CONCLUSION: The ppStage reflects the prognosis of patients with early breast cancer more accurately than the aStage.


Assuntos
Neoplasias da Mama/diagnóstico , Mama/patologia , Metástase Linfática/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/análise , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/análise , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Adulto Jovem
6.
Int J Mol Sci ; 21(2)2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31947504

RESUMO

BACKGROUND: There is growing evidence that patients with metastatic breast cancer whose disease progresses from a new metastasis (NM) have a worse prognosis than that of patients whose disease progresses from a pre-existing metastasis. The aim of this pilot study is to identify a blood biomarker predicting NM in breast cancer. METHODS: The expression of epithelial (cytokeratin 18/19) or mesenchymal (plastin-3, vimentin, and N-cadherin) markers in the peripheral blood (PB) of recurrent breast cancer patients undergoing chemotherapy with eribulin or S-1 was measured over the course of treatment by RT-qPCR. The clinical significance of preoperative N-cadherin expression in the PB or tumor tissues of breast cancer patients undergoing curative surgery was assessed by RT-qPCR or using public datasets. Finally, N-cadherin expression in specific PB cell types was assessed by RT-qPCR. RESULTS: The expression levels of the mesenchymal markers N-cadherin and vimentin were high in the NM cases, whereas that of the epithelial marker cytokeratin 18 was high in the pre-existing metastasis cases. High preoperative N-cadherin expression in PB or tumor tissues was significantly associated with poor recurrence-free survival. N-cadherin was expressed mainly in polymorphonuclear leukocytes in PB. CONCLUSION: N-cadherin mRNA levels in blood may serve as a novel prognostic biomarker predicting NM, including recurrence, in breast cancer patients.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Caderinas/genética , Ácidos Nucleicos Livres , RNA Mensageiro/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Terapia Combinada , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Prognóstico
7.
Oncol Lett ; 17(2): 2393-2399, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30675305

RESUMO

The plastin3 (PLS3) gene, which encodes an actin bundling protein known to inhibit cofilin-mediated depolymerization of actin fiber, has been previously reported to serve an important role in the epithelial-mesenchymal transition (EMT) in cancer. The aim of the present study was to determine the clinical significance of PLS3 and its role in regulating EMT, as well as in promoting cell invasion and migration in gastric cancer. The expression of plastin3 mRNA was measured in 163 resected gastric cancer specimens, in order to determine the clinicopathological significance. Furthermore, in vitro invasion and migration assays were performed on gastric cancer cells, which revealed that PLS3 expression was suppressed. The high PLS3 expression group had a higher incidence of advanced tumour stage, cancer differentiation, tumour invasion depth and distant metastases compared with the low PLS3 expression group (P<0.05). In addition, the high PLS3 expression group had a significantly poorer prognosis than the low expression group (P=0.012). Multivariate analysis indicated that high PLS3 expression was an independent prognostic factor for survival. The present study also identified that suppression of PLS3 in gastric cancer cells was associated with decreased cell invasion and migration. The findings from the present study indicate that high expression of PLS3 in gastric cancer is independently associated with a poor prognosis, and that PL3 serves an important role in EMT.

8.
Anticancer Res ; 38(8): 4515-4523, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30061217

RESUMO

BACKGROUND/AIM: Circulating microRNAs (miRs) in blood have been highlighted as diagnostic, prognostic and predictive biomarkers for "Precision medicine". This study aimed to explore the possibility of using circulating precursor miRs (pre-miRs) as clinical biomarkers of recurrence in breast cancer. MATERIALS AND METHODS: We performed miR microarray analyses of circulating miRs in blood from patients with or without recurrence of breast cancer and identified miR-488-5p as a recurrence-related miR. Then, the expression levels of pre-miR-488 or miR-488-5p were measured by RT-qPCR and the clinicopathological and prognostic significance of circulating pre-miR-488 was assessed in the blood of breast cancer patients. RESULTS: A positive correlation was noted between pre-miR-488 and miR-488-5p expression in blood. In 330 cases of surgically-treated breast cancer, high expression of circulating pre-miR-488 was an independent poor prognostic factor for recurrence-free survival. CONCLUSION: Circulating pre-miR-488 expression could be a novel prognostic biomarker for predicting recurrence in breast cancer patients.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , MicroRNA Circulante/genética , MicroRNAs/genética , Recidiva Local de Neoplasia/genética , Idoso , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Prognóstico
9.
Cancer Med ; 7(7): 2860-2867, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29845745

RESUMO

The aim of this study was to elucidate the relationship between family-associated factors and the postoperative prognosis in patients with nonsmall cell lung cancer (NSCLC). Additionally, we investigated whether having children was associated with the postoperative maintenance of the nutritional status. We selected 438 NSCLC patients who had undergone curative lung resection between 2004 and 2011 at Kyushu University (Fukuoka, Japan), whose family-associated factors were available. Nutritional indices, including the prognostic nutritional index (PNI), were used to estimate the change in the nutritional status for 1 year after surgery. A propensity score analysis was conducted after adjusting the following variables: sex, age, smoking history, performance status, pathological stage, and histological type. Three hundred patients (68.5%) had both children and partners. Forty-nine patients (11.2%) only had children, and 56 (12.8%) patients only had a partner. Thirty-three patients (7.5%) did not have a partner or children. The overall survival (OS) and disease-free survival (DFS) of the partner-present and partner-absent patients did not differ to a statistically significant extent (P = .862 and P = .712, respectively). However, childless patients showed significantly shorter OS and DFS in comparison with patients with children (P = .005 and P = .002, respectively). The postoperative exacerbation of PNI was significantly greater in childless patients than in patients with children (P = .003). These results remained after propensity score matching. Childless patients had a significantly poorer postoperative prognosis than those with children. Surgeons caring for childless NSCLC patients should be aware of the poorer postoperative outcomes in this population.

10.
Anticancer Res ; 38(4): 2359-2362, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29599361

RESUMO

BACKGROUND: The LigaSure™ small jaw (LS-SJ) multifunctional tissue sealing system is mainly used in cervical operations. We aimed to evaluate the clinical efficacy of the LS-SJ in axillary lymph node dissection (ALND) in comparison to the conventional method. PATIENTS AND METHODS: Ninety-two patients with breast cancer who underwent total mastectomy and ALND were included in this study. The patients were divided into the LS-SJ group (n=43) and the conventional-ALND (c-ALND) group (n=49). RESULTS: Patients with high body mass index values had a greater drainage volume and longer time to drain removal. The drainage volume was in the LS-SJ group was significantly lower than that in the c-ALND group. The time to drain removal and the hospitalization period were also significantly shorter in the LS-SJ group. The LS-SJ was more effective for ALND in obese patients. CONCLUSION: The results suggest the clinical usefulness of LS-SJ in ALND in patients with breast cancer, especially in obese patients.


Assuntos
Axila/cirurgia , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Excisão de Linfonodo/métodos , Técnicas de Fechamento de Ferimentos , Índice de Massa Corporal , Neoplasias da Mama/complicações , Drenagem , Feminino , Humanos , Tempo de Internação , Metástase Linfática , Mastectomia Segmentar , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/cirurgia , Duração da Cirurgia , Biópsia de Linfonodo Sentinela/métodos , Resultado do Tratamento
11.
Anticancer Res ; 37(4): 1917-1921, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28373460

RESUMO

We herein report a case of locally advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer that achieved a pathological complete response (pCR) with pertuzumab, trastuzumab and docetaxel therapy. A 70-year-old female presented with an elastic hard mass, 5.0 cm in diameter with broad redness and edema of the skin in her right breast. Swollen lymph nodes were also recognized in the right axilla. The pathological diagnosis was invasive ductal carcinoma and its biological character was estrogen receptor (ER)-negative, progesterone receptor (PgR)-negative, HER2 3+ and Ki-67 index 60%. The patient was finally diagnosed with primary unresectable, locally advanced breast cancer and started on pertuzumab, trastuzumab and docetaxel combination therapy. The tumor subsequently reduced in size and, after 4 cycles of this therapy, she underwent surgery. The histopathological examination of the postoperative specimen showed pCR in both the primary tumor and axillary lymph nodes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/patologia , Docetaxel , Feminino , Humanos , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Indução de Remissão , Taxoides/administração & dosagem , Trastuzumab/administração & dosagem
12.
Sci Rep ; 6: 27525, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27277343

RESUMO

Sentinel lymph node biopsy is performed as a standard procedure in breast cancer surgery, and the development of quick and simple methods to detect metastatic lesions is in high demand. Here, we validated a new fluorescent method using γ-glutamyl hydroxymethyl rhodamine green to diagnose metastatic lymph nodes in breast cancer. One hundred and forty-nine lymph nodes from 38 breast cancer patients were evaluated in this study. Comparison of fluorescent and pathological images showed that this fluorescent method was successful for visualizing breast cancer cells in lymph nodes. This method had a sufficiently high sensitivity (97%), specificity (79%) and negative predictive value (99%) to render it useful for an intraoperative diagnosis of cancer. These preliminary findings suggest that this novel method is useful for distinguishing non-cancerous specimens from those in need of careful examination and could help save time and cost for surgeons and pathologists.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Dipeptídeos/química , Metástase Linfática/diagnóstico por imagem , Rodaminas/química , Idoso , Carcinoma Lobular/patologia , Feminino , Humanos , Linfonodos/patologia , Microscopia de Fluorescência , Pessoa de Meia-Idade , Metástase Neoplásica , Sensibilidade e Especificidade , Biópsia de Linfonodo Sentinela
13.
PLoS One ; 10(10): e0139808, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26465158

RESUMO

BACKGROUND: Few driver genes have been well established in esophageal squamous cell carcinoma (ESCC). Identification of the genomic aberrations that contribute to changes in gene expression profiles can be used to predict driver genes. METHODS: We searched for driver genes in ESCC by integrative analysis of gene expression microarray profiles and copy number data. To narrow down candidate genes, we performed survival analysis on expression data and tested the genetic vulnerability of each genes using public RNAi screening data. We confirmed the results by performing RNAi experiments and evaluating the clinical relevance of candidate genes in an independent ESCC cohort. RESULTS: We found 10 significantly recurrent copy number alterations accompanying gene expression changes, including loci 11q13.2, 7p11.2, 3q26.33, and 17q12, which harbored CCND1, EGFR, SOX2, and ERBB2, respectively. Analysis of survival data and RNAi screening data suggested that GRB7, located on 17q12, was a driver gene in ESCC. In ESCC cell lines harboring 17q12 amplification, knockdown of GRB7 reduced the proliferation, migration, and invasion capacities of cells. Moreover, siRNA targeting GRB7 had a synergistic inhibitory effect when combined with trastuzumab, an anti-ERBB2 antibody. Survival analysis of the independent cohort also showed that high GRB7 expression was associated with poor prognosis in ESCC. CONCLUSION: Our integrative analysis provided important insights into ESCC pathogenesis. We identified GRB7 as a novel ESCC driver gene and potential new therapeutic target.


Assuntos
Carcinoma de Células Escamosas/genética , Variações do Número de Cópias de DNA , Neoplasias Esofágicas/genética , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Aberrações Cromossômicas , Cromossomos/ultraestrutura , Estudos de Coortes , Carcinoma de Células Escamosas do Esôfago , Feminino , Proteína Adaptadora GRB7/genética , Amplificação de Genes , Expressão Gênica , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Prognóstico , Interferência de RNA
14.
Sci Rep ; 5: 12080, 2015 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-26165706

RESUMO

We previously developed γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) as a tool to detect viable cancer cells, based on the fact that the enzyme γ-glutamyltranspeptidase (GGT) is overexpressed on membranes of various cancer cells, but is not expressed in normal tissue. Cleavage of the probe by GGT generates green fluorescence. Here, we examined the feasibility of clinical application of gGlu-HMRG during breast-conserving surgery. We found that fluorescence derived from cleavage of gGlu-HMRG allowed easy discrimination of breast tumors, even those smaller than 1 mm in size, from normal mammary gland tissues, with 92% sensitivity and 94% specificity, within only 5 min after application. We believe this rapid, low-cost method represents a breakthrough in intraoperative margin assessment during breast-conserving surgery.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Mama/patologia , Corantes Fluorescentes/metabolismo , Rodaminas/metabolismo , gama-Glutamiltransferase/metabolismo , Mama/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7 , Sensibilidade e Especificidade
15.
Mol Clin Oncol ; 3(4): 919-923, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26171207

RESUMO

MicroRNA-29b (miR-29b) targets numerous important genes that mediate carcinogenesis and tumor development in breast cancer in vitro and in vivo. The aim of the present study was to determine the clinical significance of miR-29b expression in primary breast cancer patients. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) of miR-29b and certain target genes of miR-29b, such as DNA methyltransferase 3A (DNMT3A), ten-eleven translocation 1 (TET1) and thymine DNA glycosylase (TDG), was performed in 94 primary breast cancer samples. Low expression of miR-29b in primary tumors was significantly associated with poorer disease-free survival (DFS) (P=0.0075) and overall survival (OS) (p=0.0012). Multivariate analysis indicated that miR-29b expression was an independent prognostic factor for OS [relative risk=15.6 (2.33-348), P=0.0026]. In addition, a significant inverse correlation was identified between the expression levels of DNMT3A and miR-29b in estrogen receptor-positive breast cancer patients (P=0.027). To the best of our knowledge, this is the first study to investigate the clinicopathological significance of miR-29b in breast cancer cases and miR-29b is shown to act as a tumor suppressive microRNA in breast cancer and as a potential marker for recurrence and metastasis in breast cancer patients.

16.
J Clin Invest ; 125(2): 621-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25555218

RESUMO

The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/biossíntese , Proteínas F-Box/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Experimentais/metabolismo , Proteínas de Neoplasias/biossíntese , Ubiquitina-Proteína Ligases/biossíntese , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Antígenos CD2/genética , Antígenos CD2/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Feminino , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Transgênicos , Metástase Neoplásica , Proteínas de Neoplasias/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Estudos Retrospectivos , Células Estromais/metabolismo , Células Estromais/patologia , Ubiquitina-Proteína Ligases/genética
17.
Anticancer Res ; 35(1): 123-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25550542

RESUMO

BACKGROUND/AIM: MiR-15a targets Cyclin E1 (CCNE1), which regulates the cell cycle and promotes cell proliferation and progression. Herein, we investigated the clinicopathological significance of miR-15a as a prognostic marker in breast cancer (BC) cases. MATERIALS AND METHODS: We collected primary tumor samples of 230 BC cases, including 68 triple-negative cases. The expression levels of miR-15a in primary tumors were measured by qRT-PCR assay. RESULTS: Low expression of miR-15a in primary tumors was significantly correlated with shorter disease-free survival (p=0.0012) and overall survival (p=0.005) compared to the high miR-15a expression in triple-negative BC cases. Multivariate analysis indicated that low miR-15a expression was an independent prognostic factor for overall survival [RR=2.56(1.03-7.18), p=0.04]. CONCLUSION: MiR-15a expression levels could be a promising biological and prognostic marker for overall survival especially in triple-negative BC cases.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , MicroRNAs/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/genética , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais
18.
Ann Surg Oncol ; 21 Suppl 4: S743-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25029990

RESUMO

PURPOSE: Recent studies indicated that the scaffolding adaptor protein GAB2 (GRB2-associated binding protein 2) plays a critical role in the proliferation and migration of various cancers. This study aimed to determine the role of aberrant GAB2 expression in human colorectal cancer (CRC). METHODS: Quantitative real-time reverse transcription polymerase chain reaction was used to evaluate GAB2 mRNA expression in 152 CRC tissues samples to determine the clinicopathological significance of GAB2 expression. We also performed in vitro proliferation assays using siGAB2-transfected CRC cells. RESULTS: GAB2 expression in tumor colorectal tissues was significantly higher than in normal colorectal tissues (p = 0.0212). High GAB2 expression levels were associated with malignant clinicopathologic potential factors, including lymphatic invasion (p = 0.0003), venous invasion (p = 0.0170), and liver metastasis (p = 0.0144). The survival rate of patients with high GAB2 expression levels was significantly lower than that of patients with low GAB2 expression (p = 0.0074). Multivariate analysis indicated that GAB2 expression was a factor affecting lymph node metastasis. Cell proliferation was significantly suppressed by siGAB2 expression in CRC cells in vitro. CONCLUSIONS: GAB2 expression was associated with lymph node metastasis and may play a role in the growth and metastasis of CRC. These results suggest that GAB2 is a potential therapeutic target in CRC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/genética , RNA Mensageiro/análise , Proteínas Adaptadoras de Transdução de Sinal/análise , Idoso , Vasos Sanguíneos/patologia , Linhagem Celular Tumoral , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases , Colo/química , Neoplasias Colorretais/química , Receptores ErbB/análise , Receptores ErbB/genética , Feminino , Expressão Gênica , Humanos , Neoplasias Hepáticas/secundário , Metástase Linfática , Vasos Linfáticos/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/análise , Fosfatidilinositol 3-Quinases/genética , Prognóstico , RNA Interferente Pequeno/genética , Reto/química , Transdução de Sinais , Taxa de Sobrevida , Transfecção
19.
Ann Surg Oncol ; 21 Suppl 4: S640-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24849519

RESUMO

BACKGROUND: Human CDCP1 gene, located on chromosome 3p21.3, is a transmembrane glycoprotein widely expressed in epithelial tissues, and its role in cancer remains to be understood. METHODS: Using microarray profiles of gene expression and copy number data from 69 esophageal squamous cell carcinoma (ESCC) samples, we performed informatics analyses to reveal the significance of CDCP1 expression. We also performed migration and invasion assays of siRNA-targeted CDCP1-transfected cells and CDCP1-overexpressing cell in vitro. Moreover, we evaluated the clinical magnitude of CDCP1 expression in esophageal squamous cell cancer cases. RESULTS: Allelic loss of chromosome 3p was confirmed by copy number analysis. The expression level of CDCP1 in tumor tissue was significantly lower than that in corresponding normal tissue. siRNA targeting of CDCP1 promoted the migratory and invasive abilities of esophageal cancer cell lines, whereas both abilities were reduced in CDCP1-overexpressing cells. Gene set enrichment analysis showed that expression levels of CDCP1 were associated with tumor differentiation and metastasis, consistent with the result of clinicopathologic analyses. Finally, multivariate analysis revealed that the expression level of CDCP1 was an independent prognostic factor for survival. CONCLUSIONS: Loss of CDCP1 expression may be a novel indicator for biological aggressiveness in ESCC.


Assuntos
Antígenos CD/genética , Carcinoma de Células Escamosas/genética , Moléculas de Adesão Celular/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Proteínas de Neoplasias/genética , Idoso , Antígenos CD/metabolismo , Antígenos de Neoplasias , Carcinoma de Células Escamosas/secundário , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Feminino , Dosagem de Genes , Expressão Gênica , Inativação Gênica , Humanos , Perda de Heterozigosidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Proteínas de Neoplasias/metabolismo , Prognóstico , Taxa de Sobrevida , Transfecção
20.
Ann Surg Oncol ; 21(11): 3680-90, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24217791

RESUMO

PURPOSE: Plastin-3 (PLS3) is a novel marker for circulating tumor cells (CTCs) in colorectal cancer (CRC). We sought to investigate the mechanisms mediating the aberrant expression of PLS3, the role of PLS3 in the epithelial-mesenchymal transition (EMT), and its association with the acquisition of invasive and metastatic abilities in human CRC. METHODS: The expression levels of PLS3 messenger RNA in the tumor drainage venous blood (TDB) were examined in 177 CRC cases, and the associations between PLS3 expression and Xq23 copy numbers were analyzed in 132 CRC samples. We then established a stable PLS3-expressing CRC cell line and assessed the role of PLS3 in the EMT. RESULTS: In clinical CRC cases, high expression of PLS3 in CTCs of TDB as well as peripheral blood was established as an independent prognostic factor of overall survival (p < 0.001), and the copy number gain of Xq23, which is the locus of the PLS3 gene, was significantly related to PLS3 overexpression. PLS3 induced the EMT via transforming growth factor (TGF)-ß signaling and resulted in the acquisition of invasive ability in CRC cells. CONCLUSIONS: The aberrant expression of PLS3 was associated with copy number gain in CTCs from primary tumors and was involved in the regulation of the EMT, contributing to a poor prognosis in CRC patients.


Assuntos
Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA/genética , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/secundário , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Proteínas dos Microfilamentos/antagonistas & inibidores , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
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