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OBJECTIVES: This consensus was developed by the Asian EUS Group (AEG), who aimed to formulate a set of practice guidelines addressing various aspects of endoscopic ultrasound-guided tissue acquisition (EUS-TA). METHODS: The AEG initiated the development of consensus statements and formed an expert panel comprising surgeons, gastroenterologists, and pathologists. Three online consensus meetings were conducted to consolidate the statements and votes. The statements were presented and discussed in the first two consensus meetings and revised according to comments. Final voting was conducted at a third consensus meeting. The Grading of Recommendations, Assessment, Development, and Evaluation system was adopted to define the strength of the recommendations and quality of evidence. RESULTS: A total of 20 clinical questions and statements regarding EUS-TA were formulated. The committee recommended that fine-needle biopsy (FNB) needles be preferred over conventional fine-needle aspiration (FNA) needles for EUS-TA of subepithelial lesions. For solid pancreatic masses, rapid on-site evaluation is not routinely recommended when FNB needles are used. For dedicated FNB needles, fork-tip and Franseen-tip needles have essentially equivalent performance. CONCLUSION: This consensus provides guidance for EUS-TA, thereby enhancing the quality of EUS-TA.
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Consenso , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Humanos , Asia , Endosonografía , Guías de Práctica Clínica como AsuntoRESUMEN
Nα-acetyltransferase 10 protein (Naa10p) is known as the catalytic subunit of N-terminal acetyltransferases A (NatA) complex, associating with Naa15p to acetylate N-termini of the human proteome. Recent investigations have unveiled additional functions for Naa10p, encompassing lysine ε-acetylation and acetyltransferase-independent activities. Its pleiotropic roles have been implicated in diverse physiological and pathological contexts. Emerging evidence has implicated Naa10p in cancer progression, demonstrating dual attributes as an oncogene or a tumor suppressor contingent on the cancer type and acetyltransferase activity context. In this comprehensive review, we present a pan-cancer analysis aimed at elucidating the intricacies underlying Naa10p dysregulation in cancer. Our findings propose the potential involvement of c-Myc as a modulatory factor influencing Naa10p expression. Moreover, we provide a consolidated summary of recent advancements in understanding the intricate molecular underpinnings through which Naa10p contributes to cancer cell proliferation and metastasis. Furthermore, we delve into the multifaceted nature of Naa10p's roles in regulating cancer behaviors, potentially attributed to its interactions with a repertoire of partner proteins. Through an exhaustive exploration of Naa10p's functions, spanning its acetylation activity and acetyltransferase-independent functionalities, this review offers novel insights with implications for targeted therapeutic strategies involving this pivotal protein in the realm of cancer therapeutics.
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Acetiltransferasas , Neoplasias , Humanos , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Procesamiento Proteico-Postraduccional , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
CONTEXT: Recent studies suggest that the clinical characteristics and biological behavior of pituitary tumors (PITs) in patients with multiple endocrine neoplasia type 1 (MEN1) may not be as aggressive as previously reported. Increased imaging of the pituitary as recommended by screening guidelines identifies more tumors, potentially at an earlier stage. However, it is unknown if these tumors have different clinical characteristics in different MEN1 mutations. OBJECTIVE: To assess characteristics of patients with MEN1 with and without PITs, and compare among different MEN1 mutations. METHODS: Data of patients with MEN1 in a tertiary referral center from 2010 to 2023 were retrospectively analyzed. RESULTS: Forty-two patients with MEN1 were included. Twenty-four patients had PITs, 3 of which were invasive and managed with transsphenoidal surgery. One PIT enlarged during follow-up. Patients with PITs had a higher median age at MEN1 diagnosis than those without PITs. MEN1 mutations were identified in 57.1% of patients, including 5 novel mutations. In patients with PITs, those with MEN1 mutations (mutation+/PIT+ group) had more additional MEN1-associated tumors than those without (mutation-/PIT+ group). The mutation+/PIT+ group had a higher incidence of adrenal tumors and a lower median age at initial manifestation of MEN1 than the mutation-/PIT+ group. The most common neuroendocrine neoplasm was nonfunctional in the mutation+/PIT+ group and insulin-secreting in the mutation-/PIT+ group. CONCLUSION: This is the first study comparing characteristics of patients with MEN1 with and without PITs harboring different mutations. Patients without MEN1 mutations tended to have less organ involvement and it might be reasonable for them to receive less intensive follow-up.
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Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Hipofisarias , Humanos , Neoplasia Endocrina Múltiple Tipo 1/patología , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Estudios Retrospectivos , Mutación , Hipófisis/patologíaRESUMEN
BACKGROUND AND AIMS: For EUS-guided fine-needle biopsy sampling (EUS-FNB) of solid pancreatic lesions (SPLs), the role of sampling strategy between targeted biopsy sampling and wide sampling has not been reported. This study aimed to investigate the benefits of the 2 sampling techniques on EUS-FNB using rapid on-site evaluation. METHODS: Patients with SPLs were prospectively enrolled and randomly assigned (1:1) to undergo EUS-FNB using either contrast guidance or the fanning technique. The primary outcome was the total number of passes required to establish a diagnosis, and secondary outcomes were overall diagnostic accuracy and adverse event rates. RESULTS: One hundred eighteen patients were enrolled from February 2019 to January 2021, with 59 patients assigned to each group. There was no significant difference in the total number of passes required to establish a diagnosis between the contrast and fanning groups (median, 1 [interquartile range, 1-1] vs 1 [interquartile range, 1-2], respectively; P = .629). The sensitivity, specificity, and diagnostic accuracy in the contrast group was 100%, 66.7%, and 98.3% and in the fanning group 100%, 100%, and 100%, respectively (P = 1). An SPL <4 cm (odds ratio, 2.47; 95% confidence interval, 1.05-5.81; P = .037) and macroscopic visible core length >1 cm (odds ratio, 2.89; 95% confidence interval, 1.07-7.84; P = .037) were independently associated with increased cytologic and histologic accuracy. CONCLUSIONS: The diagnostic accuracy of EUS-FNB with the fanning technique for SPLs was comparable with the contrast guidance technique. Without additional cost, EUS-FNB with the fanning technique may be preferred for SPLs. (Clinical trial registration number: NCT04924725.).
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Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Neoplasias Pancreáticas , Humanos , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/métodos , Páncreas/patología , Manejo de Especímenes , Neoplasias Pancreáticas/patologíaRESUMEN
N-α-acetyltransferase 10 protein, Naa10p, is involved in various cellular functions impacting tumor progression. Due to its capacity to acetylate a large spectrum of proteins, both oncogenic and tumor-suppressive roles of Naa10p have been documented. Here, we report an oncogenic role of Naa10p in promoting metastasis of esophageal cancer. NAA10 is more highly expressed in esophageal cancer tissues compared to normal tissues. Higher NAA10 expression also correlates with poorer survival of esophageal cancer patients. We found that NAA10 expression was transcriptionally regulated by the critical oncogene c-Myc in esophageal cancer. Furthermore, activation of the c-Myc-Naa10p axis resulted in upregulated cell invasiveness of esophageal cancer. This increased cell invasiveness was also elucidated to depend on the enzymatic activity of Naa10p. Moreover, Naa10p cooperated with Naa15p to interact with the protease inhibitor, PAI1, and prevent its secretion. This inhibition of PAI1 secretion may derive from the N-terminal acetylation effect of the Naa10p/Naa15p complex. Our results establish the significance of Naa10p in driving metastasis in esophageal cancer by coordinating the c-Myc-PAI1 axis, with implications for its potential use as a prognostic biomarker and therapeutic target for esophageal cancer.
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Neoplasias Esofágicas , Humanos , Acetilación , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/fisiopatología , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismoRESUMEN
BACKGROUND AND AIM: The small endoscopic ultrasound (EUS)-suspected gastric gastrointestinal stromal tumors (GISTs), gastric subepithelial tumors at the muscularis propria layer on EUS, are detected frequently. Bite-on-bite forceps biopsy and EUS-guided tissue sampling yield variable results. This study aimed to analyze clinicopathologic features of the small EUS-suspected gastric GISTs 2 cm or less in size and to evaluate the efficacy and safety of the endoscopic incisional biopsy (EIB) for these small tumors. METHODS: This prospective study investigated 70 patients with small EUS-suspected gastric GISTs 2 cm or less in size in two stages. Firstly, 30 patients were recruited for the efficacy and safety evaluation of the EIB. Secondly, 40 patients were randomly assigned to receive either EIB or the bite-on-bite biopsy for comparison of the diagnostic yield, procedure time, and adverse event rate. RESULTS: Combining two study stages, leiomyoma (74%) was diagnosed histologically to outnumber GIST (26%) with a diagnostic rate of 94% for patients receiving EIB. KIT exon 11 mutations (50%) and PDGFRA exon 12 mutations (16%) were detected in the small gastric GISTs. In the direct comparison, the diagnostic yield of EIB and the bite-on-bite biopsy was 85% and 50%, respectively (P = 0.018). There was no statistically significant difference of the mean procedure time or adverse event rate between these two groups. CONCLUSIONS: Leiomyoma is more common than expected among these small tumors. Tissue diagnosis with an effective and safe sampling technique, such as EIB, is necessary for making further clinical decisions.
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Tumores del Estroma Gastrointestinal , Leiomioma , Neoplasias Gástricas , Biopsia , Endosonografía/métodos , Tumores del Estroma Gastrointestinal/diagnóstico por imagen , Tumores del Estroma Gastrointestinal/patología , Gastroscopía/métodos , Humanos , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: The use of macroscopic on-site evaluation (MOSE) to estimate the adequacy of a specimen for histological diagnosis during endoscopic ultrasound (EUS)-guided fine-needle tissue acquisition (FNTA) has recently been advocated. This study aimed to evaluate the diagnostic yield of MOSE compared with conventional EUS-FNTA without rapid on-site evaluation (ROSE). METHODS: This was an international, multicenter, prospective, randomized controlled study. After providing informed consent, consecutive adult patients referred for EUS-FNTA for solid lesions larger than 2âcm were randomized to a MOSE arm or to a conventional arm without ROSE. A designated cytopathologist from each center performed all cytopathological examinations for that center and was blinded to the randomization results. The primary outcome measure was the diagnostic yield, and the secondary outcomes included sensitivity, specificity, positive predictive value, negative predictive value, diagnostic accuracy, and the rate of procedure-related complications. RESULTS: 244 patients (122 conventional, 122 MOSE) were enrolled during the study period. No significant differences between the two arms were found in procedure time or rate of procedure-related adverse events. The diagnostic yield for the MOSE technique (92.6â%) was similar to that for the conventional technique (89.3â%; P â=â0.37), with significantly fewer passes made (median: conventional 3, MOSE 2; P â<â0.001). CONCLUSIONS: EUS-FNTA with the MOSE technique provided a similar diagnostic yield to conventional EUS-FNTA technique in the absence of ROSE but with fewer passes. This technique can be used when ROSE is not available.
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Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Neoplasias Pancreáticas , Adulto , Endosonografía , Humanos , Agujas , Estudios ProspectivosAsunto(s)
Linfoma de Células B de la Zona Marginal , Linfoma de Células B Grandes Difuso , Antibacterianos/uso terapéutico , Humanos , Tejido Linfoide , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Membrana Mucosa , Estudios ProspectivosRESUMEN
BACKGROUND/OBJECTIVE: The atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) category is one of six diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). In this study, we report the diagnostic distribution of thyroid fine needle aspiration (FNA) cytology and analyze the outcome of AUS/FLUS cases. METHODS: A total of 29,937 thyroid FNA results, reported between April 2012 and December 2016, were retrieved from the database of a medical center. We reviewed the electronic medical records and analyzed the management of these patients. RESULTS: Overall frequency of AUS/FLUS is 3.1% in our laboratory, which is at the lower limit of the recommended range. Of these, 891 reports of AUS/FLUS from 770 patients were identified. Out of the 770 patients, 367 had surgical intervention. In these 367 patients, final surgical pathology yielded 204 (55.6%) malignancies, 12 indeterminateness (3.3%), and 151 (41.1%) benignity. Among these surgical patients, 113 (30.8%) had received a repeat FNA of the thyroid before thyroid resection. The difference between the malignancy rates among patients who directly received surgery after the first AUS/FLUS diagnosis (132 of 254, 52.0%) and patients having a repeat FNA before surgery (72 of 113, 63.7%) was not statistically significant. CONCLUSION: Our results are in agreement with AUS/FLUS diagnoses in less than 7% of specimens, and confirm that it is appropriate to perform either a repeat thyroid FNA or thyroid lobectomy, with the clinical decision being subject to the standardized management protocols of the second edition of TBSRTC in the AUS/FLUS category.
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Biopsia con Aguja Fina , Enfermedades de la Tiroides/diagnóstico , Enfermedades de la Tiroides/patología , Glándula Tiroides/patología , Biopsia con Aguja Fina/estadística & datos numéricos , Humanos , Enfermedades de la Tiroides/epidemiología , Enfermedades de la Tiroides/cirugía , Factores de TiempoRESUMEN
Solid pancreatic or peripancreatic lesions comprise a heterogeneous group of diseases that rely on a multimodality imaging approach for subsequent tissue procurement. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA)/biopsy is an effective and safe method for tissue diagnosis in this region. The failure to obtain adequate tissue for diagnosis under EUS guidance is still a rare but important issue. Percutaneous core needle biopsy (CNB) provides an alternative pathway for adequate specimen acquisition. Because of the deep retroperitoneal location, the percutaneous biopsy of pancreatic or peripancreatic lesions may inevitably pass through visceral organs. The procedure is relatively risky and difficult for general radiologists, particularly beginners, and an adequate knowledge of the abdominal anatomy and biopsy technique is indispensable. In this review, various aspects of percutaneous CNB for solid pancreatic or peripancreatic lesions using different trans-organ approaches are reviewed to increase the chance of successful biopsy.
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Endosonografía/métodos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/patología , Biopsia con Aguja Fina , Sistema Digestivo/diagnóstico por imagen , Sistema Digestivo/patología , Neoplasias del Sistema Digestivo , Humanos , Páncreas/diagnóstico por imagen , Páncreas/patologíaRESUMEN
Gastric neuroendocrine tumors (GNETs) are a heterogeneous group of neoplasm with varying biological characteristics. This study aimed to investigate the clinical features and outcomes of GNET patients after endoscopic diagnosis and treatment in a multicenter registry. Patients with GNETs confirmed histologically were recruited from 17 hospitals between January 2010 and April 2016 in Taiwan. Clinical, laboratory, radiological, endoscopic, pathological data, treatment strategies, follow-up periods, and survivals were collected retrospectively. Totally 187 (107 female, 80 male) patients were recruited. Mean (â±âstandard deviation [SD]) age and size of tumors were 63.2-year-old (â±â14.6) and 2.3-cm (â±â3.0). World Health Organization (WHO) grading were 93 (49.7%) G1, 26 (13.9%) G2, 40 (21.4%) G3, and 28 (15.0%) unknown. G3 patients were older (meanâ±âSD, 71.6â±â12.4 vs. 60.9â±â14.3/56.7â±â15.4 years), larger (6.1â±â4.0 vs.1.2â±â1.3/2.4â±â2.5âcm), more distally located (35.0% vs. 7.6%/15.4%), lower proportion of superficial lesions (17.5% vs. 61.9%/53.8%) and higher rates of lymphovascular invasion (32.5% vs. 3.2%/7.7%) than G1/G2. There was no nodal or distant organ metastases despite different grading of lesionsâ¦10âmm and those <20âmm limited to mucosa and submucosa layers. GNETs larger than 20âmm with G1, G2, and G3 had lymph node (LN) metastatic rates of 21.4%, 30.0%, and 59.3%, respectively. Survivals were different between grading for those >20âmm (log-rank test Pâ=â.02). Male gender (Pâ=â.01), deeper invasion (Pâ=â.0001), nodal (Pâ<â.0001), and distant organ metastases (Pâ=â.0001) were associated with worse outcome. In conclusion, treatment strategies for GNET should be decided by grading, size, invasiveness, and LN metastasis risk. Curative endoscopic resection is feasible for G1/2 lesions less than 20âmm and limited to mucosa/submucosa layers without lymphovascular invasion.
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Endoscopía Gastrointestinal/métodos , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/cirugía , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Femenino , Mucosa Gástrica/patología , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Pronóstico , Estudios Retrospectivos , Factores Socioeconómicos , Taiwán/epidemiología , Adulto JovenRESUMEN
The aim of the present study was to evaluate the clinical utility of plasma chromogranin A (CgA) in patients diagnosed with early-stage pancreatic neuroendocrine tumors (PNETs) in terms of diagnostic value and treatment response. A total of 35 patients with PNETs were prospectively enrolled from August 2010 to April 2014. Demographic and clinicopathological data were collected, and serial plasma CgA levels were measured. Tumor responses were defined by the Response Evaluation Criteria In Solid Tumors criteria. Pearson's χ2 test was used for the analysis of the association between the plasma CgA level and various factors. Plasma CgA level was significantly associated with the size (P=0.03), metastasis (P=0.02) and tumor stage (P=0.03) of the PNETs. Using 126 U/l as the optimal cutoff value, the sensitivity and specificity were 87.5 and 81.5%, respectively. For localized tumors, the sensitivity of CgA for diagnosing PNETs was relatively low, even following a lowering of the cutoff values (29.6-51.9%). Plasma CgA level was correlated with therapeutic response in those patients with high baseline CgA levels (P=0.025), but not in the patients with low baseline CgA levels (P=0.587). In conclusion, plasma CgA level was associated with tumor size, metastasis and tumor stage in patients with PNET. For early-stage PNETs, CgA exhibited a limited role in diagnosis and treatment response evaluation in the population of the present study.
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Cancer cells encounter metabolic stresses such as hypoxia and nutrient limitations because they grow and divide more quickly than their normal counterparts. In response to glucose restriction, we found that nuclear translocation of the glycolic enzyme, pyruvate kinase M2 (PKM2), helped cancer cells survive under the metabolic stress. Restriction of glucose stimulated AMPK activation and resulted in co-translocation of AMPK and PKM2 through Ran-mediated nuclear transport. Nuclear PKM2 subsequently bound to Oct4 and promoted the expression of cancer stemness-related genes, which might enrich the cancer stem cell population under the metabolic stress. Nuclear PKM2 was also capable of promoting cancer metastasis in an orthotopic xenograft model. In summary, we found that cytosolic AMPK helped PKM2 carry out its nonmetabolic functions in the nucleus under glucose restriction and that nuclear PKM2 promoted cancer stemness and metastasis. These findings suggested a potential new targeting pathway for cancer therapy in the future.
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Adaptación Fisiológica/fisiología , Adenilato Quinasa/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de la Membrana/metabolismo , Células Madre Neoplásicas/metabolismo , Estrés Fisiológico/fisiología , Hormonas Tiroideas/metabolismo , Transporte Activo de Núcleo Celular/fisiología , Animales , Línea Celular Tumoral , Núcleo Celular/metabolismo , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas de Unión a Hormona TiroideRESUMEN
Pyruvate kinase muscle isozymes (PKMs) have crucial roles in regulating metabolic changes during carcinogenesis. A switch from PKM1 to PKM2 isoform was thought to lead to aerobic glycolysis promoting carcinogenesis, and was considered as one of the cancer signatures. However, recent evidence has argued against the existence of PKM isoform switch and related metabolic effects during cancer progression. We compared the effects of PKM1 and PKM2 in cell invasiveness and metastasis of pancreatic ductal adenocarcinoma (PDAC). Both PKM1 and PKM2 expression affected cell migration and invasion abilities of PDAC cells, but only knockdown of PKM2 suppressed metastasis in a xenograft model. By comparing the established PKM2 mutants in the regulation of cell invasion, we found that PKM2 may control cell mobility through its protein kinase and phopho-peptide binding abilities. Further survey for PKM2-associated proteins identified PAK2 as a possible phosphorylation target in PDAC. In vitro binding and kinase assays revealed that PKM2 directly phosphorylated PAK2 at Ser20, Ser141, and Ser192/197. Knockdown of PKM2 decreased PAK2 protein half-life by increasing ubiquitin-dependent proteasomal degradation. Moreover, we identified PAK2 as an HSP90 client protein and the mutation at Ser192/197 of PAK2 reduced PAK2-HSP90 association. Knockdown of PAK2 diminished in vitro cell mobility and in vivo metastatic ability of PKM2 overexpressed PDAC cells. PKM2 and PAK2 protein expression also positively correlated with each other in PDAC tissues. Our findings indicate that PKM2-PAK2 regulation is critical for developing metastasis in PDAC, and suggest that targeting the PKM2/HSP90/PAK2 complex has a potential therapeutic value in this deadly disease.
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Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Piruvato Quinasa/fisiología , Quinasas p21 Activadas/metabolismo , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Movimiento Celular/genética , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosforilación/genética , Procesamiento Proteico-Postraduccional/genética , Estabilidad Proteica , Piruvato Quinasa/genética , Quinasas p21 Activadas/genéticaRESUMEN
KH-type splicing regulatory protein (KSRP) is a single-strand RNA binding protein which regulates mRNA stability either by binding to AU-rich elements (AREs) of mRNA 3'UTR or by facilitating miRNA biogenesis to target mRNA. Unlike its well-characterized function at the molecular level in maintaining RNA homeostasis, the role of KSRP in cancer progression remains largely unknown. Here we investigate the role of KSRP in non-small cell lung cancer (NSCLC). We first examined KSRP expression by immunohistochemistry in a cohort containing 196 NSCLC patients and observed a strong positive correlation between KSRP expression and survival of NSCLC patients. Multivariate analysis further identified KSRP as an independent prognostic factor. Manipulating KSRP expression significantly affected in vitro cell mobility and in vivo metastatic ability of NSCLC cells. Microarray analysis identified an ARE-containing gene, EGR3, as a downstream effector of KSRP in NSCLC. Interestingly, we found that KSRP decreased EGR3 mRNA stability in an ARE-independent manner. By screening KSRP-regulated miRNAs in NSCLC cells, we further found that miR-23a directly binds to EGR3 3'UTR, reducing EGR3 expression and thereby inhibiting NSCLC cell mobility. Our findings implicate a targetable KSRP/miR-23a/EGR3 signaling axis in advanced tumor phenotypes.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteína 3 de la Respuesta de Crecimiento Precoz/metabolismo , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , Estabilidad del ARN , ARN Neoplásico/metabolismo , Proteínas de Unión al ARN/metabolismo , Transactivadores/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/genética , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , ARN Neoplásico/genética , Proteínas de Unión al ARN/genética , Transactivadores/genéticaRESUMEN
Carbonic anhydrase IX (CA9) expression level has been considered as a poor prognostic factor in hepatocellular carcinoma (HCC) patients. However, the judging criteria of CA9 level is hard to define for potential clinical applications. Unlike CA9 expression level, CA9 polymorphism is poorly documented in HCC. Here, we found that people carry A allele at CA9 rs1048638, a 3'UTR SNP, has higher risk of HCC. rs1048638-CA correlates with advanced stages, larger tumor sizes, more vascular invasion, and shorter survival of HCC patients. A allele at CA9 rs1048638 impairs miR-34a, a tumor suppressor miRNA in HCC, binding to CA9 3'UTR and desensitizes CA9 mRNA to miR-34a-dependent RNA degradation. CA9 expression levels were also correlated with miR-34a levels and rs1048638 genotypes in HCC patients. rs1048638 influences HCC risk and progression through effects on miR-34a-targeted CA9 expression in HCC. In conclusion, genetic variations of the CA9 3'UTR play important roles in regulating CA9 expression and cancer progression, which is a novel determinant and target for HCC metastasis and prognosis.
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Regiones no Traducidas 3' , Anhidrasa Carbónica IX/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , Polimorfismo de Nucleótido Simple , Interferencia de ARN , Alelos , Biomarcadores de Tumor , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Oportunidad Relativa , PronósticoRESUMEN
Hepatocellular carcinoma (HCC) relies on angiogenesis for growth and metastasis. Leukocyte cell-derived chemotaxin 2 (LECT2) is a cytokine and preferentially expressed in the liver. Previous studies have found that LECT2 targets to both immune and tumor cells to suppress HCC development and vascular invasion. Although LECT2 did not affect HCC cells growth in vitro, it still suppressed HCC xenografts growth in immune-deficient mice, suggesting other cells such as stroma cells may also be targeted by LECT2. Here, we sought to determine the role of LECT2 in tumor angiogenesis in HCC patients. We found that LECT2 expression inhibited tumor growth via angiogenesis in the HCC xenograft model. Specifically, we demonstrated that recombinant human LECT2 protein selectively suppressed vascular endothelial growth factor (VEGF)165-induced endothelial cell proliferation, migration, and tube formation in vitro and in vivo. Mechanistically, LECT2 reduced VEGF receptor 2 tyrosine phosphorylation and its downstream extracellular signal-regulated kinase and AKT phosphorylation. Furthermore, LECT2 gene expression correlated negatively with angiogenesis in HCC patients. Taken together, our findings demonstrate that LECT2 inhibits VEGF165-induced HCC angiogenesis through directly binding to VEGFR2 and has broad applications in treating VEGF-mediated solid tumors.
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Inhibidores de la Angiogénesis/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/farmacología , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Neoplasias Hepáticas/metabolismo , Ratones , Fosforilación/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Aorta Torácica/diagnóstico por imagen , Secuestro Broncopulmonar/sangre , Antígeno CA-19-9/sangre , Aorta Torácica/anomalías , Secuestro Broncopulmonar/diagnóstico por imagen , Secuestro Broncopulmonar/patología , Secuestro Broncopulmonar/cirugía , Femenino , Humanos , Angiografía por Resonancia Magnética , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND AND STUDY AIMS: Two 22G needles with similar designs, apart from the absence (A) or presence of a side port (B), are available for endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA). The side port was designed to increase diagnostic yield but this advantage was unproven. This study evaluated the difference in diagnostic yield between both needles in pancreatic masses. PATIENTS AND METHODS: This was a prospective multicenter randomized cross-over study. Patients with pancreatic masses were randomized to one needle for the first two passes, followed by the other for the next two passes. A pathologist blinded to the needle assessed each puncture for cellularity and morphology. The diagnostic yield between both needles was compared. RESULTS: In total, 30 patients were recruited (mean lesion size: 3.5âcm, range: 1.2â-â6.3). Comparison of cellularity adequacy: first pass: A vs. B: 26/30 vs. 24/30 (Pâ=â0.488): 2nd pass: A vs. B: 25/30 vs. 26/30 (Pâ=â0.718). Comparison of diagnostic accuracy: first pass: A vs. B: 22/30 vs. 23/30 (Pâ=â0.766); after two passes: A vs. B: 26/30 vs. 26/30 (Pâ=â1.0). When all four passes were assessed, adequate cellularity was obtained in 29/30 and the correct diagnosis was obtained in 28/30 patients. There were no procedural complications. CONCLUSIONS: There was no significant difference in diagnostic yield between EUSFNA needles with or without a side port for pancreatic masses. STUDY REGISTRATION: NCT02092519.
RESUMEN
PURPOSE: Kelch-like ECH-associated protein 1 (Keap1) is an E3 ligase participated in the cellular defense response against oxidative stress through nuclear factor erythroid-2-related factor 2 (Nrf2). However, the role of Keap1 in regulating cancer motility is still controversial. We investigated the contribution of the Keap1-Nrf2 axis in the progression of non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: The expression of Keap1 and Nrf2 was examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of NSCLC tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of the Keap1-Nrf2 axis in lung cancer mobility and progression. RESULTS: Keap1 expression was decreased in specimens from NSCLC patients with lymph node metastasis compared with patients without metastasis. Higher Keap1 expression levels were correlated with the survival of NSCLC patients. Moreover, manipulation of Keap1 expression affected cell migration/invasion abilities. Depletion of Nrf2 relieved the migration promotion imposed by Keap1 suppression. Mechanistic investigations found that S100P was downregulated in both Keap1-overexpressing and Nrf2-knockdown NSCLC cells. Overexpression of Keap1 and knockdown of Nrf2 both suppressed S100P expression in NSCLC cells. Knockdown of S100P inhibited cell migration in highly invasive NSCLC cells and also relieved the migration promotion imposed by Keap1 suppression in weakly invasive NSCLC cells. CONCLUSIONS: Our findings suggest that Keap1 functions as a suppressor of tumor metastasis by targeting the Nrf2/S100P pathway in NSCLC cells. In addition, overexpression of Keap1 may be a novel NSCLC treatment strategy and/or useful biomarker for predicting NSCLC progression.