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HER2-positive cancer is a prevalent subtype of malignancy with poor prognosis, yet current targeted therapies, like Trastuzumab and pyrotinib, have resulted in remission in patients with HER2-positive cancer. This study provides a novel approach for immunotherapy based on a hydroxyapatite (HA) gene delivery system producing a bispecific antibody for HER2-positive cancer treatment. An HA nanocarrier has been synthesized by the classical hydrothermal method. Particularly, the HA-nanoneedle system was able to mediate stable gene expression of minicircle DNA (MC) encoding a humanized anti-CD3/anti-HER2 bispecific antibody (BsAbHER2) in vivo. The produced BsAbs exhibited a potent killing effect not only in HER2-positive cancer cells but also in patient-derived organoids in vitro. This HA-nanoneedle gene delivery system features simple large-scale preparation and clinical applicability. Hence, the HA-nanoneedle gene delivery system combined with minicircle DNA vector encoding BsAbHER2 reported here provides a potential immunotherapy strategy for HER2-positive tumors.
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Anticorpos Biespecíficos , Complexo CD3 , Durapatita , Técnicas de Transferência de Genes , Receptor ErbB-2 , Humanos , Receptor ErbB-2/imunologia , Receptor ErbB-2/genética , Anticorpos Biespecíficos/farmacologia , Animais , Complexo CD3/imunologia , Complexo CD3/genética , Organoides/imunologia , Linhagem Celular Tumoral , Feminino , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Terapia Genética/métodosRESUMO
Background: Endoscopic nipple-sparing mastectomy (E-NSM) is a promising procedure in the treatment of breast cancer, but the limitations of endoscopic tools and intrinsic technical complexity of the technique hinder its applicability. Here, we introduce a novel surgery, gasless endoscopic transaxillary subcutaneous mastectomy and immediate reconstruction with implants (GETSMIRI), for breast cancer. and early effects. Methods: A retrospective analysis of the clinical data of 11 female patients, aged 50 (27-78) years, admitted to our hospital from January to December 2022, who underwent gasless endoscopic transaxillary subcutaneous mastectomy and immediate reconstruction with implants (GETSMIRI), was conducted. This study was designed to assess patient satisfaction before and after breast reconstruction, early complications, and breast function. Results: The tumors were all solitary, with a mean maximum diameter of 1.0 (0-2.0) cm and a mean distance of 2.3 (2-4) cm from the nipple, the mean intraoperative bleeding volume was 47.5 mL, and the mean hospital stay was 1.5 d. Postoperatively, 1 patient developed depigmentation of the nipple due to mild ischemia. There were no incisional complications, subcutaneous emphysema, infection, areola necrosis, skin flap necrosis, or removal of the prosthesis and/or patch. No tumor recurrence or metastasis was observed during the follow-up period. The difference between breast satisfaction and psychosocial health scores was not statistically significant (P = 0.680; P = 0.612). Conclusion: GETSMIRI, immediate implantable breast reconstruction, is less invasive than other such procedures, and short-term follow-up results show good postoperative satisfaction, making it an alternative surgical method.
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[This corrects the article DOI: 10.7150/jca.25569.].
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We investigate the impact of lung metastasis versus metastasis of bone, brain, or liver on overall survival (OS) and thyroid cancer-specific survival (TCSS) in patients with thyroid cancer (TC). Therefore, de-identified SEER 18 registry data of primary TC patients diagnosed between 2010 and 2016 were analyzed. The primary outcome was the prognosis of TC patients with lung metastasis compared with other sites. The secondary outcomes included the prognosis comparison between patients with and without surgery and between single and multiple metastasis sites. Isolated lung metastasis was associated with worse OS and TCSS than bone metastasis (both p < 0.05) and was associated with worse OS than liver metastasis (p = 0.0467). Surgery performed either for the primary or distant site was associated with better OS and TCSS in patients with metastasis of lung or bone (p < 0.05). Isolated lung metastasis was related to better OS and TCSS than lung−liver, lung−brain, and lung−other multiple metastases. The multivariable analysis revealed that age < 55 years, surgery to the primary site, and to the distant site(s) were associated with better outcomes, while T4 and Tx were associated with worse outcomes. Nevertheless, it revealed that the other race (i.e., any race other than white, black, or unknown) and male gender were associated with better TCSS only (p < 0.05). Isolated lung metastasis is associated with a worse prognosis in TC patients compared with bone or liver metastasis. Surgery performed either for the primary or distant site(s) is associated with better survival outcomes in TC patients with metastasis of lung or bone.
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BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive type of cancer with few available treatment methods. The aim of the current study was to provide a prognostic autophagy-related gene (ARG) model to predict the outcomes for TNBC patients using bioinformatic analysis. METHODS: mRNA expression data and its clinical information for TNBC samples obtained from The Cancer Genome Atlas (TCGA) and Metabric databases were extracted for bioinformatic analysis. Differentially expressed autophagy genes were identified using the Wilcoxon rank sum test in R software. ARGs were downloaded from the Human Autophagy Database. The Kaplan-Meier plotter was employed to determine the prognostic significance of the ARGs. The sample splitting method and Cox regression analysis were employed to establish the risk model and to demonstrate the association between the ARGs and the survival duration. The corresponding ARG-transcription factor interaction network was visualized using the Cytoscape software. RESULTS: A signature-based risk score model was established for eight genes (ITGA3, HSPA8, CTSD, ATG12, CLN3, ATG7, MAP1LC3C, and WIPI1) using the TCGA data and the model was validated with the GSE38959 and Metabric datasets, respectively. Patients with high risk scores had worse survival outcomes than those with low risk scores. Of note, amplification of ATG12 and reduction of WIPI were confirmed to be significantly correlated with the clinical stage of TNBC. CONCLUSION: An eight-gene autophagic signature model was developed in this study to predict the survival risk for TNBC. The genes identified in the study may favor the design of target agents for autophagy control in advanced TNBC.
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Neoplasias de Mama Triplo Negativas , Humanos , Prognóstico , Neoplasias de Mama Triplo Negativas/genética , Genes Reguladores , Fatores de Transcrição , Autofagia/genética , Glicoproteínas de Membrana , Chaperonas MolecularesRESUMO
INTRODUCTION: Breast cancer (BC) and thyroid dysfunction are common in females, yet the relationship between thyroid hormone and BC is unclear. To search for the connection between thyrotropin and BC, we contradistinguished BC patients with or without synchronous second primary thyroid cancer (TC) with surgery using data from the Surveillance, Epidemiology, and End Results (SEER) database. Theoretically, according to the ATA (American Thyroid Association) guidelines, all TC patients were treated with thyrotropin suppressive therapy only from 2010 to 2015. MATERIALS AND METHODS: Data from BC patients with a synchronous second TC with surgery (BC2TC) and only BC patients (1BC) during 2010-2015 were extracted from the SEER database. Differences in the clinicopathological characteristics between BC2TC and 1BC patients were analyzed by chi-square tests. Comparisons of the disease-specific survival (DSS) and overall survival (OS) curves between these two groups were performed with the log-rank (Mantel-Cox) test. RESULTS: Within this dataset, we identified 134 BC2TC patients during the period from 2010 to 2015. Significant differences between the BC2TC and 1BC groups were found only for different ages and TNM (tumor-node-metastasis status) stages. There were no significant differences in DSS between the two cohorts (P = 0.060). The same tendencies in OS or DSS were observed for the different age groups and different TNM groups, even the stage I, N0 (without metastases to lymph nodes), and ER (+) (estrogen receptor (ER)-positive) groups. CONCLUSIONS: There were no remarkable differences in survival between the BC2TC and 1BC groups, and thyrotropin suppression therapy using levothyroxine did not negatively affect BC prognosis.
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Antineoplásicos , Neoplasias da Mama , Segunda Neoplasia Primária , Neoplasias da Glândula Tireoide , Tireotropina , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Humanos , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/patologia , Prognóstico , Programa de SEER , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Tireotropina/metabolismo , Tiroxina/uso terapêutico , Estados Unidos/epidemiologiaRESUMO
Metastasis is the major cause of mortality in patients with breast cancer. Understanding the metastatic mechanism to guide clinical diagnoses and the treatment of breast cancer remains a challenge. We found that the expression of Mex-3 RNA binding family member A (MEX3A) was upregulated significantly and related to tumor grade in breast cancer. The results of in vitro and in vivo studies showed that knockdown of MEX3A inhibited the metastasis and impaired the stemness of breast cancer cells. Furthermore, activation of the ß-catenin signaling pathway was discovered as a molecular intermediate of MEX3A-mediated regulation. We also found that ectopic expression of ß-catenin restored the migration ability, invasion ability, and CD44+/CD24- percentage of MDA-MB-231 and BT549 cells when MEX3A was depleted. In addition, we revealed that MEX3A positively regulated the expression of ß-catenin by downregulating Dickkopf WNT signaling pathway inhibitor 1 (DKK1) expression. Therefore, a previously undiscovered role of MEX3A comprising a critical contribution to promoting metastasis and maintaining the stemness of breast cancer via the Wnt/ß-catenin pathway was demonstrated in the present study.
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[This corrects the article DOI: 10.3389/fonc.2020.00148.].
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INTRODUCTION: Breast cancer (BC) and lung cancer (LuC) are common malignancies. The survival of patients with metachronous second primary malignancy (MSPM) of BC and LuC after a first primary of BC and LuC remains unclear. METHODS: Data of patients with BC and LuC, with or without MSPM of BC and LuC, who were diagnosed from 2000 to 2014, were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The baseline characteristics of the different groups were compared using chi-square tests. The survival curves were compared using the log-rank test. Survival analysis was also performed in other malignancies with data extracted from the SEER database using the same method. RESULTS: Significant differences in most of the demographics and clinicopathological factors were found between the groups. Patients with LuC with an MSPM of BC (LuC2BC) exhibited better survival than those with LuC (P < 0.001), while patients with BC with an MSPM of LuC (BC2LuC) exhibited worse survival than those with BC (P < 0.001). A similar trend was found in other malignancies. Prostate cancer (PC) followed by thyroid cancer (TC) (PC2TC) and TC followed by PC (TC2PC) did not show an obvious survival trend against their index malignancy (IM). CONCLUSIONS: MSPM benefits the IM prognosis if the survival rate of MSPM is better than that of the IM and vice versa. However, the situation is somewhat confusing when the survival differences between MSPM and IM are minimal.
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Neoplasias da Mama , Neoplasias Pulmonares , Segunda Neoplasia Primária , Administração dos Cuidados ao Paciente , Programa de SEER , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/terapia , Administração dos Cuidados ao Paciente/métodos , Administração dos Cuidados ao Paciente/estatística & dados numéricos , Prognóstico , Programa de SEER/estatística & dados numéricos , Programa de SEER/tendências , Taxa de SobrevidaRESUMO
Objective: Recently, performing locoregional surgical treatment still remains debatable in patients with metastatic breast cancer (MBC). Current study aimed to develop prognostic nomograms for predicting the long-term survival in MBC patients with or without surgical intervention, thereby assisting clinicians in making individualized choice. Methods: The training set included 5173 patients who were diagnosed with MBC in 2010-2013 from the Surveillance, Epidemiology, and End Results Program, while the validation set comprised 2924 patients diagnosed in 2014-2015. Multivariant Cox hazard model was applied to determine the independent risk factors for overall survival (OS) and breast cancer specific survival (BCSS). Then, individualized pre- and postoperative nomograms for predicting 1- or 3-year survival probabilities were constructed accordingly. Internal and external validations were conducted to determine the accuracy of these nomograms by calculating concordance index (C-index) and plotting calibration curves. Results: The survival analysis indicated that surgical management conferred improved OS and BCSS in patients with metastatic breast cancer. Age, T stage, grade, distant metastatic site, ER, PR and HER2 status, radiation, and chemotherapy were independent risk factors for OS and BCSS both in surgery and non-surgery group. All these factors were subsequently incorporated into the nomogram which showed acceptable predictive capabilities with C-index range of 0.65-0.80 both in training set and external validation set. In addition, a preoperative nomogram incorporating variables capable of being determined before surgery was also built with C-index above 0.70 both in training and validation set. Conclusion: Surgical management in patients with metastatic breast cancer suggests a potential survival advantage. In addition, these well-validated pre- and postoperative nomograms may provide a useful tool to assist clinicians in treatment decision-making and in evaluating patients' long term prognosis.
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Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
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Resistencia a Medicamentos Antineoplásicos , Terapia de Alvo Molecular , Neoplasias da Próstata/tratamento farmacológico , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Progressão da Doença , Humanos , Masculino , Camundongos Nus , Gradação de Tumores , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Tumores Neuroendócrinos/irrigação sanguínea , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Sistemas Neurossecretores/patologia , Fenótipo , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
Breast cancer (BC) and thyroid cancer (TC) are common malignancies among females. However, the connection between TC and BC is not well understood. To explore the relationship between these two cancers and to determine the effect of second metachronous TC on BC survival, we compared BC patients with or without second primary TC using data from the Surveillance, Epidemiology, and End Results (SEER) database. We extracted data from patients with only BC or TC and from BC patients with a second metachronous cancer from 2000-2014. Differences in the clinicopathological and treatment characteristics between BC patients with or without second metachronous TC were analyzed by chi-square tests. Multivariate analyses of BC survival were performed by using Cox regression models. Comparison of disease-specific survival (DSS) curves between these cohorts was performed with the log-rank (Mantel-Cox) test. Survival analyses were also performed using data from 1980-1994. Within this dataset, we found 1,262 BC cases in which a second metachronous TC (BC2TC) developed, accounting for 3.1% of all metachronous cancers following BC from 2000-2014. No significant differences were found in molecular markers. In addition, the mean age at BC diagnosis was younger in the BC2TC group than in the BC group (55.418 y vs 60.273 y). Half of the BC2TC patients developed TC in the first three years following BC diagnosis. Patients with BC2TC showed better DSS than those with BC alone from 2000-2014 (P<0.001). However, this superiority was not significant from 1980-1994 (P = 0.579) or for TNM stage I BC (P = 0.927) and grade I BC (P = 0.431) from 2000-2014. In conclusion, the incidence of BC2TC has increased dramatically during the past 15 years. In addition, patients with BC2TC showed better DSS than patients with BC alone, especially in cases from 2000-2014.
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Neoplasias da Mama/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Adulto , Neoplasias da Mama/complicações , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Bases de Dados Factuais , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Segunda Neoplasia Primária/complicações , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Análise de Sobrevida , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/patologiaRESUMO
INTRODUCTION: To explore the effect of a second thyroid cancer (TC) on ovarian cancer (OC) patient survival, we compared OC patients with or without a second primary TC using data from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Data for OC only, female TC only and OC patients with a second TC (OC2TC) from two periods, 2000-2014 and 1980-1994, were extracted from the SEER database. Differences in clinicopathological and treatment characteristics were analysed using the chi-square test. Cox regression analyses were used to identify risk factors associated with OC survival. Disease-specific survival (DSS) and overall survival (OS) curves were compared using the log-rank test. RESULTS: There were 109 OC2TC patients from 2000 to 2014, and significant differences (P < 0.001) in the mean age at OC diagnosis, TNM stage and surgical history were found between OC and OC2TC patients. Several factors, including age, grade, TNM stage, histological type and surgical history, influenced OC survival (P < 0.001). OC2TC patients showed better survival than OC patients from 2000 to 2014, regardless of age, TNM stage or surgical history. However, this superiority was not significant in cases from 1980 to 1994 (P = 0.222 for OS). CONCLUSION: Survival was better with OC2TC than with OC from 2000 to 2014 rather than 1980-1994, suggesting that TC improved the survival of OC patients from 2000 to 2014.
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Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias da Glândula Tireoide/secundário , Adulto , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Programa de SEER , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/mortalidadeRESUMO
The concept that human cancer is in essence a genetic disease driven by gene mutations has been well established, yet its utilization in functional studies of cancer genes has not been fully explored. Here, we describe a simple genetics-based approach that can quickly and sensitively reveal the effect of the alteration of a gene of interest on the fate of its host cells within a heterogeneous population, essentially monitoring the genetic selection that is associated with and powers the tumorigenesis. Using this approach, we discovered that loss-of-function of TP53 can promote the development of resistance of castration in prostate cancer cells via both transiently potentiating androgen-independent cell growth and facilitating the occurrence of genome instability. The study thus reveals a novel genetic basis underlying the development of castration resistance in prostate cancer cells and provides a facile genetic approach for studying a cancer gene of interest in versatile experimental conditions.
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Mutação com Perda de Função , Neoplasias de Próstata Resistentes à Castração/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Instabilidade Genômica , Células HCT116 , Células HEK293 , Humanos , Masculino , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
MicroRNAs (miRNAs) have been recognized as key regulators of tumorigenesis and progression. Serum miR-302c-3p expression is prominently deregulated in HCV-related hepatocellular carcinoma (HCC). However, the expression of miR-302c-3p and its functional role in HBV-related HCC are rarely investigated. In this study, we found that the expression levels of miR-302c-3p were prominently down-regulated in HCC tissues compared to matched tumor-adjacent tissues. Moreover, miR-302c-3p under-expression was detected in HCC cell lines compared to a normal hepatic cell line LO2. Low miR-302c-3p expression was positively correlated with multiple tumor nodes, venous infiltration and advanced TNM tumor stage of HCC patients. Notably, our follow up data and TCGA data demonstrated that low miR-302c-3p expression predicted a poor survival of HCC patients. Functionally, miR-302c-3p overexpression inhibited migration and invasion of MHCC97H cells in vitro. Additionally, miR-302c-3p knockdown showed an opposite effect on these metastatic behaviors of HepG2 cells. MiR-302c-3p negatively regulated tumor necrosis factor receptor associated factor 4 (TRAF4) abundance by directly targeting 3'-UTR of TRAF4 mRNA. The expression of TRAF4 was up-regulated in HCC tissues. The level of TRAF4 mRNA was inversely correlated with miR-302c-3p expression in HCC specimens. Mechanistically, miR-302c-3p restrained AKT-mediated epithelial-mesenchymal transition (EMT) in HCC cells. Importantly, TRAF4 restoration reversed the inhibitory effect of miR-302c-3p on AKT-induced EMT and HCC cell metastasis. MK2206, an AKT inhibitor, inhibited miR-302c-3p knockdown-induced EMT in HepG2 cells. In summary, these results indicate that miR-302c-3p exhibits a tumor suppressive role in HCC by targeting TRAF4. Inhibition of miR-302c-3p/TRAF4 axis may serve as a therapeutic target for HCC.
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BACKGROUND: Heat shock protein 90 (HSP90) functions as a well-known onco-protein to regulate protein conformation, stability and degradation. Pyruvate kinase M2 (PKM2), a critical regulator of the metabolism, growth and metastasis of cancer cells, has been confirmed to be overexpressed in various human cancer including hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the oncogenic functions of HSP90 and PKM2 overexpression in HCC remain unknown. METHODS: The expression of HSP90 and PKM2 in HCC specimens and cells were detected by immunoblotting and immunostaining. The interaction between HSP90 and PKM2 was confirmed by tandem affinity purification, co-immunoprecipitation and Glutathione S transferase (GST)-pulldown assay. RESULTS: In this study, we found that HSP90 could bind to PKM2 and subsequently increased PKM2 abundance in HCC cells. Immunohistochemistry (IHC) staining showed that HSP90 level was positively correlated with PKM2 level in HCC tissues. Mechanistically, HSP90 was found to increase the phosphorylation of PKM2 at Thr-328. Protein kinase glycogen synthase kinase-3ß (GSK-3ß) formed a protein complex with HSP90 and PKM2, and directly mediated Thr-328 phosphorylation of PKM2 induced by HSP90. Thr-328 phosphorylation was critical for maintaining PKM2 stability and its biological functions in regulating glycolysis, mitochondria respiration, proliferation and apoptosis. Functionally, we found that HSP90 promoted the glycolysis and proliferation and inhibited apoptosis of HCC cells in a PKM2 dependent manner. In vivo experiments disclosed that PKM2 was required for the promoting effects of HSP90 on the growth of HCC cells in mice. Furthermore, we demonstrated that positive expression of HSP90 and PKM2 was correlated with poor clinicopathological features including high alpha fetoprotein (AFP) level, large tumor size, portal vein tumor thrombus (PVTT) and advanced tumor-node-metastasis (TNM) stage. Furthermore, we demonstrated that positive expression of HSP90 and PKM2, and a combination of these proteins could strongly predict the poor prognosis of HCC patients. CONCLUSIONS: We suggest that HSP90 potentiates the glycolysis and proliferation, reduces the apoptosis and thus enhances the growth of HCC cells through PKM2.
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Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Treonina/química , Hormônios Tireóideos/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/química , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Proteínas de Membrana/química , Camundongos , Estadiamento de Neoplasias , Transplante de Neoplasias , Fosforilação , Prognóstico , Estabilidade Proteica , Hormônios Tireóideos/química , Carga Tumoral , Proteínas de Ligação a Hormônio da TireoideRESUMO
In various studies, metastasis associated with colon cancer 1 (MACC1) has been frequently reported to be abnormally highly expressed in human lung cancer, colon cancer, and hepatocellular carcinoma. Our study focuses on the association of MACC1 expression with gastric cancer (GC). During our experiment, the MACC1 expression was tested in 105 GC samples using an immunohistochemical (IHC) method. The clinical characteristics and prognosis of these patients were summarized. During analysis, MACC1 distribution in GC samples with distant metastasis was higher than that in normal samples and in tumors with no dissemination. Subsequently, a lower 5-year survival rate had a strong correlation with high MACC1 expression. As a consequence, the present results suggest that MACC1 is more frequently expressed in a poor prognosis phenotype of GC and acts as a promising prognostic prediction parameter for GC.
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Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Fatores de Transcrição/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Biópsia , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Metástase Neoplásica , Fenótipo , Prognóstico , Transdução de Sinais , Neoplasias Gástricas/diagnóstico , Transativadores , Regulação para CimaRESUMO
Proteolytic enzymes play a key role in the metastatic stage of gastric cancer (GC). In this study, we aimed to identify the serine proteases (SPs) and their inhibitors (serpins) as related to GC. The gene expression profiles of 40 cases of GC were initially detected by cDNA microarray. The results of the differentially expressed SPs and their inhibitor genes from the microarrays were confirmed by real-time PCR. The status of the immunohistochemical staining of the confirmed genes in patients with complete data was used to develop a survival prediction model. Finally, the prediction model was tested in different groups of GC patients. As a result, seven genes, SERPINB5, KLK10, KLK11, HPN, SPINK1, SERPINA5 and PRSS8, were considered as GC progression-related genes. A survival prediction model including the immunohistochemical scores of three genes and the tumor node metastasis (TNM) score was developed: Survival time (months) = 88.8607 + 2.6395 SERPINB5 - 12.0772 KLK10 + 13.7562 KLK11 - 7.0318 TNM. In conclusion, SERPINB5, KLK10, KLK11, HPN, SPINK1, SERPINA5 and PRSS8 were GC progression-related SPs or serpin genes. The model consisting of the expression profiles of three genes extracted from the microarray study accompanied by the TNM score accurately predicts surgery-related survival of GC patients.
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To assess the prognostic and predictive value of maspin expression for the clinical response to 5-fluorouracil (5-FU)-based chemotherapy in advanced gastric cancer (GC) patients, the expression of maspin in primary tumors from 127 patients with advanced GC was examined using immunohistochemistry. Of the 127 patients, 74 were treated with surgery alone and 53 received additional adjuvant 5-FU-based chemotherapy. Nuclear and cytoplasmic maspin expression was observed in 46.5 (59/127) and 68.5% (87/127) of patients, respectively. Nuclear maspin immunoreactivity was significantly associated with larger tumor size (p=0.036), the depth of tumor invasion (p=0.02) and lymph node metastasis (p=0.002). Cytoplasmic maspin immunoreactivity was associated with tumor cell differentiation but not with the other clinicopathological variables. Nuclear maspin immunoreactivity had a significant association with overall survival (OS). Among the nuclear maspin-expressing patients, those who were treated with 5-FU-based adjuvant chemotherapy showed significantly longer OS than those without chemotherapy (p=0.0004). In conclusion, nuclear maspin expression is associated with adverse clinical outcomes in patients with advanced GC. Patients with positive nuclear maspin expression may be more responsive to adjuvant 5-FU chemotherapy.
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OBJECTIVE: To explore the interaction between SerpinB5 and MAFbx in gastric cancer cell and to identify the interaction sites. METHODS: The interaction between SerpinB5 and MAFbx was screened and validated by yeast two-hybrid screening and co-immunoprecipitation. The expression of MAFbx was analyzed after SerpinB5 expression being modified by RNA interference and pGBKT7-SerpinB5 transfection. The impact of SerpinB5 on the expression of MAFbx was studied in gastric cancer cell line SUN-16. A model of MAFbx was constructed by homology modeling. The related residues for interaction were analyzed by Autodock4.0. RESULTS: The interaction between SerpinB5 and MAFbx was validated. The expression of MAFbx changed along with SerpinB5 expression. Amino acids including PRO261, ASN361, and LYS362 were key residue in the interaction of SerpinB5 and MAFbx. CONCLUSION: SerpinB5 interacts with MAFbx in gastric cancer cell. Amino acids including PRO261, ASN361, and LYS362 are potential binding sites.