RESUMO
In recent years, the development of bispecific antibodies (bsAbs) has become a major trend in the biopharmaceutical industry. By simultaneously engaging two molecular targets, bsAbs have exhibited unique mechanisms of action that could lead to clinical benefits unattainable by conventional monoclonal antibodies. The type of structure used to construct a bsAb directly influences the distance, angle, degree of freedom, and affinity between the two antibody binding sites and the interaction between the two antigens or the cells where the antigens are located, which have been bound by the antibody. Consequently, the structure of the bsAb is one of the most vital factors affecting its function. Herein, we reported for the first time a novel basic module bsAb format, VFV (Variable domain-Fab-Variable domain). And then, the feasibility of the VFV format was demonstrated by constructing a series of engager-like basic module bsAbs. Next, a series of VFV bsAbs containing Fc (VFV-Ig), Fab (VFV-Fab), or Hinge (VFV-Hinge) were developed based on Hxb module, and all of them had adequate purity and activity. Finally, a T cell engager bsAb with the potential to overcome on-target off-tumor activity was constructed according to the structural characteristics of VFV, which validated that the VFV module can be used as a new brick for the construction of various bsAbs. In a word, the successful construction of this bsAb format for the first time not only enriches the arsenal of the bsAb format, but also provides inspiration for the construction of new bsAbs. Nevertheless, we are fully aware that as a proof-of-concept study, this paper has many shortcomings, and there is still a lot of work to be done to determine whether VFV can serve as a platform for drug development.
Assuntos
Anticorpos Biespecíficos , Neoplasias , Humanos , Anticorpos Monoclonais , Sítios de Ligação de Anticorpos , Linfócitos TRESUMO
The monocyte adhesion to endothelial cells is an early step in chronic inflammation. Interferon-γ (IFN-γ) is regarded as a master regulator of inflammation development. However, the significance and mechanisms of IFN-γ in the monocyte adhesion to endothelial cells remains largely unknown. IFN-γ up-regulates PD-L1 on various types of cells. Here, we performed flow cytometry to examine the contribution of IFN-γ-induced PD-L1 expression on monocyte adhesion to endothelial cells. Up-regulation of PD-L1 by IFN-γ enhanced the adhesion of monocytes to endothelial cells. By immunoprecipitation and lectin blot, PD-L1 in endothelial cells interacted with CD169/Siglec 1 in monocytes depending on the α2,3-sialylation of PD-L1. ST3Gal family (ST3ß-galactoside α-2,3-sialyltransferase) was the major glycosyltransferase responsible for the α2,3-sialylation of membrane proteins. Down-regulation of ST3Gal4 by RNAinterference partially reduced the α2,3-sialylation of PD-L1 and the PD-L1-CD169 interaction. Finally, purified PD-L1 protein with α2,3-sialylation, but not PD-L1 protein without α2,3-sialylation, partially reduced IFN-γ-induced monocyte adhesion to endothelial cells. These findings provide evidence that the interaction between PD-L1 and CD169 promoted monocyte adhesion to endothelial cells and might elucidate a new mechanism of monocyte adhesion to endothelial cells.
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Células Endoteliais , Monócitos , Humanos , Células Endoteliais/metabolismo , Inflamação , Interferon gama/farmacologia , Interferon gama/metabolismo , Monócitos/metabolismo , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Antígeno B7-H1/metabolismoRESUMO
PURPOSE: Sialic acid-bound immunoglobulin-like lectin 15 (Siglec15) has emerged as a novel therapeutic target in tumor immunotherapy. This study is designed to investigate the function and mechanism of Siglec15 in thyroid carcinoma (THCA). MATERIALS AND METHODS: The information on patients with THCA from TGCA and GEO database were used to analyze the expression of Siglec15 in THCA. THCA cells were treated with Siglec15-mFc, a recombinant fusion protein consisting of the extracellular domain of human Siglec15 and murine IgG Fc. THP-1 cells expressing human Siglec15 and its mutant were co-cultured with THCA cells to mimic the contact between Siglec15-expressing tumor-associated macrophages and THCA cells. Wound-healing assay and transwell migration assay were used to examine the migration abilities of BCPAP and C643 cells. Pull-down assay was performed to examine the interaction between Siglec15 and epidermal growth factor receptor (EGFR) on the cancer cells. Cycloheximide (CHX) assay was used to evaluate the stability of the protein. RESULTS: The expression of Siglec15 in thyroid carcinoma tissues is higher than in normal tissues. Siglec15 promotes the migration of THCA cells by binding to EGFR in a sialic acid-dependent manner and increases EGFR protein expression. Inhibition of the EGFR pathway blocks the effect of Siglec15 on the migration of THCA cells. CONCLUSIONS: Our findings reveals that Siglec15 promotes the migration of thyroid carcinoma cells by enhancing the EGFR protein stability.
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Ácido N-Acetilneuramínico , Neoplasias da Glândula Tireoide , Humanos , Animais , Camundongos , Movimento Celular , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Estabilidade ProteicaRESUMO
As a tumor-associated biological molecule, microRNA-143-3p (miR-143-3p) is implicated in the progression of papillary thyroid carcinoma (PTC). We conducted this study to elucidate the effects of miR-143-3p mediated by Musashi RNA binding protein 2 (MSI2) on the biological activities of PTC cells. The K1 cells with the lowest miR-143-3p expression were selected for the experiments. The targeting relationship between miR-143-3p and MSI2 was verified. The biological functions of miR-143-3p and MSI2 with respect to K1 cell proliferation, cycle distribution, apoptosis, invasion, migration, and tumorigenesis were studied using gain- and loss-of-function assays both in vitro and in vivo. MSI2 was verified to be a target gene of miR-143-3p. Cells treated with upregulation of miR-143-3p or silencing of MSI2 exhibited significantly decreased the expression of Bcl-2, PCNA, MCM2, Ki67, MSI2, MMP-2, and MMP-9. This was accompanied by inhibited cell proliferation, cell invasion, and migration, as well as a significant increase in Bax expression, cell cycle arrest, and cell apoptosis. More importantly, the tumor inhibitory effects of upregulated miR-143-3p were also confirmed in the tumor xenografts in nude mice. Our results indicate that upregulation of miR-143-3p suppresses the progression of PTC by impeding cell growth, invasion, and migration via downregulation of MSI2, highlighting the potential of miR-143-3p as a target for future PTC treatment.
Assuntos
Proliferação de Células/genética , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , Câncer Papilífero da Tireoide/genética , Animais , Apoptose , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Masculino , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Câncer Papilífero da Tireoide/patologia , Ativação Transcricional/genéticaRESUMO
BACKGROUND & AIMS: The microenvironment regulates hepatoma stem cell behavior. However, the contributions of lymphatic endothelial cells to the hepatoma stem cell niche remain largely unknown; we aimed to analyze this contribution and elucidate the mechanisms behind it. METHODS: Associations between lymphatic endothelial cells and CD133+ hepatoma stem cells were analyzed by immunofluorescence and adhesion assays; with the effects of their association on IL-17A expression examined using western blot, quantitative reverse transcription PCR and luciferase reporter assay. The effects of IL-17A on the self-renewal and tumorigenesis of hepatoma stem cells were examined using sphere and tumor formation assays. The role of IL-17A in immune escape by hepatoma stem cells was examined using flow cytometry. The expression of IL-17A in hepatoma tissues was examined using immunohistochemistry. RESULTS: CD133+ hepatoma stem cells preferentially interact with lymphatic endothelial cells. The interaction between the mannose receptor and high-mannose type N-glycans mediates the interaction between CD133+ hepatoma stem cells and lymphatic endothelial cells. This interaction activates cytokine IL-17A expression in lymphatic endothelial cells. IL-17A promotes the self-renewal of hepatoma stem cells. It also promotes their immune escape, partly through upregulation of PD-L1. CONCLUSION: Interactions between lymphatic endothelial cells and hepatoma stem cells promote the self-renewal and immune escape of hepatoma stem cells, by activating IL-17A signaling. Thus, inhibiting IL-17A signaling may be a promising approach for hepatoma treatment. LAY SUMMARY: The microenvironment is crucial for the self-renewal and development of hepatoma stem cells, which lead to the development of liver cancer. Lymphatic endothelial cells are an important component of this niche microenvironment, helping hepatoma stem cells to self-renew and escape immune attack, by upregulating IL-17A signaling. Thus, targeting IL-17A signaling is a potential strategy for the treatment of hepatoma.
Assuntos
Antígeno AC133/imunologia , Antígeno B7-H1/imunologia , Carcinoma Hepatocelular , Células Endoteliais , Interleucina-17/imunologia , Neoplasias Hepáticas , Células-Tronco Neoplásicas/metabolismo , Carcinogênese/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Transdução de Sinais , Evasão Tumoral , Microambiente Tumoral , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
CD133+ cancer stem cells are responsible for thyroid cancer initiation. The regulatory pathways essential for sustaining the self-renewal of thyroid cancer stem cells remain largely unknown. Glutamate signaling regulates the self-renewal ability of stem cells. In the present study, we found that the level of glutamate was higher in CD133+ thyroid cancer cells than in CD133- thyroid cancer cells. The transcriptional level of glutamate aspartate transporter SLC1A3 was high in CD133+ thyroid cancer cells. Activation of NF-κB signaling by CD133 was responsible for SLC1A3 high transcription level in CD133+ thyroid cancer cells. Knock down of SLC1A3 significantly reduced the level of glutamate and inhibited the self-renewal activity and tumorigenicity of CD133+ thyroid cancer cells. Overexpression of SLC1A3 rescued the negative effect of CD133 knockdown on the self-renewal capability of CD133+ thyroid cancer cells. Taken together, CD133 promotes the self-renewal capacity of CD133+ thyroid cancer cells at least partly through activation of SLC1A3 expression.
Assuntos
Antígeno AC133/metabolismo , Autorrenovação Celular , Transportador 1 de Aminoácido Excitatório/genética , Células-Tronco Neoplásicas/citologia , Neoplasias da Glândula Tireoide/genética , Linhagem Celular Tumoral , Transportador 1 de Aminoácido Excitatório/metabolismo , Regulação Neoplásica da Expressão Gênica , Ácido Glutâmico/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Accumulating evidences indicate that long non-coding RNAs (lncRNAs) play an important role in initiation and development of thyroid cancer. However, the underlying molecular mechanism remains elusive. METHODS: To explore potential oncogenic and tumor suppressive lncRNAs in papillary thyroid cancer (PTC), we performed RNA sequencing to discover differentially expression lncRNAs between PTC tissues and matched normal tissues. RT-qPCR was used to validate differentially expressed lncRNAs. Bioinformatic analysis was performed to predicted potential miRNA and gene which might be regulated by MIAT. Cell proliferation, invasion and cycle assay were conducted to study the function of MIAT and LASP1 in PTC. RESULTS: Through analysis of RNA sequencing, we observed that lncRNA-MIAT was overexpressed in PTC tissues. The upregulation of MIAT was further confirmed in 40 pairs of PTC tissues and normal tissues we collected. In the function assays, results suggested that MIAT silencing led to inhibition of cell proliferation, invasion and disruption of cell cycle progression in PTC cells. Mechanistically, MIAT directly bound to miR-324-3p and upregulated LASP1 expression in PTC cells. In addition, expression of MIAT was positively correlated with LASP1 mRNA expression in samples collected from patients with PTC. More importantly, transfection of recombinant LASP1 attenuated MIAT silencing induced inhibition of cell proliferation, invasion and disruption of cell cycle progression in PTC cells. CONCLUSIONS: In conclusion, the findings suggest that lncRNA-MIAT may promote PTC proliferation and invasion through physically binding miR-324-3p and upregulation of LASP1.
RESUMO
CD133, a widely known cancer stem cell marker, has been proved to promote tumor metastasis. However, the mechanism by which CD133 regulates metastasis remains largely unknown. Here, we report that CD133 knockdown inhibits cancer cell migration, and CD133 overexpression promotes cell migration. CD133 expression is beneficial to activate the Src-focal adhesion kinase (FAK) signaling pathway. Further studies show that CD133 could interact with Src, and the region between amino acids 845 and 857 in the CD133 C-terminal domain is indispensable for its interaction with Src. The interaction activates Src to phosphorylate its substrate FAK and to promote cell migration. Likewise, a Src binding-deficient CD133 mutant loses the abilities to increase Src and FAK phosphorylation and to promote cell migration. Inhibition of Src activity by PP2, a known Src activity inhibitor, could block the activation of FAK phosphorylation and cell migration induced by CD133. In summary, our data suggest that activation of FAK by the interaction between CD133 and Src promotes cell migration, providing clues to understand the migratory mechanism of CD133(+) tumor cells.
Assuntos
Antígeno AC133/metabolismo , Movimento Celular , Quinase 1 de Adesão Focal/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Antígeno AC133/genética , Linhagem Celular Tumoral , Quinase 1 de Adesão Focal/genética , Humanos , Células-Tronco Neoplásicas/patologia , Fosforilação , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/genéticaRESUMO
Several genome-wide association studies on thyroid cancer (TC) have reported similar findings of a new susceptibility locus, 14q13.3. After that, a number of studies reported that rs944289 polymorphism at chromosome 14q13.3 has been implicated in TC risk. However, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 12 studies involving a total of 7,598 TC cases, 53,613 controls, and 239 nuclear families for 14q13.3-rs944289 polymorphism to evaluate its effect on genetic susceptibility for TC. An overall random-effect per-allele OR of 1.30 (95 % CI 1.21-1.40, P < 10(-5)) was found for the polymorphism. Significant results were also observed for under dominant and recessive genetic models. In the subgroup analysis by ethnicity, we found similar significant results for both Caucasians (T allele: OR 1.29, 95 % CI 1.17-1.42, P < 10(-5)) and East Asians (T allele: OR 1.33, 95 % CI 1.18-1.49, P < 10(-5)). Further in stratified analyses according to study design and sample size, evidence of gene-disease association was also obtained. In addition, we found that rs944289 confers its risk, for both papillary thyroid carcinoma and follicular thyroid carcinoma when stratified by histological types of TC. Furthermore, our results on stratified analysis according to radiation exposure status showed an increased sporadic TC risk, while no associations were detected among radiation-related TCs for rs944289 polymorphism. Our result demonstrated that rs944289 polymorphism on 14q13.3 is a low penetrant risk factor for developing TC.
Assuntos
Cromossomos Humanos Par 14/genética , Variação Genética , Polimorfismo Genético , Neoplasias da Glândula Tireoide/genética , Alelos , Povo Asiático/genética , Carcinoma/genética , Carcinoma Papilar , Estudos de Casos e Controles , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Viés de Publicação , Fatores de Risco , Câncer Papilífero da Tireoide , População Branca/genéticaRESUMO
Due to the important role in the DNA repair pathways, numerous studies have been carried out to explore the relationship between the polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene and thyroid cancer risk. But previous reports have produced conflicting results. Thus, we performed an updated comprehensive meta-analysis to better investigate the association of the XRCC1 polymorphisms with thyroid cancer risk. There were a total of nine studies included with 1,621 cases and 3,669 controls examining the effects of the XRCC1 Arg280His, Arg399Gln, and Arg194Trp polymorphisms on the susceptibility of thyroid cancer. In our study, the XRCC1 Arg280His polymorphism was found to be associated with an increased thyroid cancer risk in the Caucasian population [allelic contrast: odds ratio (OR) = 1.38, 95% CI = 1.05-1.80, P(Z) = 0.02, P(Q) = 0.61; dominant model: OR = 1.43, 95% CI = 1.08-1.89, P(Z) = 0.01, P(Q) = 0.57]. The Arg399Gln polymorphism was associated with a significant decreased risk [allelic contrast: OR = 0.73, 95% CI = 0.59-0.92, P(Z) = 0.006, P(Q) = 0.31; dominant model: OR = 0.73, 95% CI = 0.55-0.97, P(Z) = 0.03, P(Q) = 0.33; recessive model: OR = 0.56, 95% CI = 0.34-0.93, P(Z) = 0.02, P(Q) = 0.59], while the Arg194Trp SNP conferred an increased risk for thyroid cancer in the mixed populations [allelic contrast: OR = 1.49, 95% CI = 1.02-2.17, P(Z) = 0.04]. To conclude, the present meta-analysis demonstrated that the polymorphisms in the XRCC1 gene may be associated with developing of thyroid cancer.
Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Glândula Tireoide/genética , Humanos , Risco , Neoplasias da Glândula Tireoide/etnologia , Neoplasias da Glândula Tireoide/etiologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
BACKGROUND: A rare syndrome of watery diarrhea, hypokalemia and achlorhydria (WDHA) is usually caused by pancreatic endocrine tumors that secrete excessive vasoactive intestinal polypeptide (VIP). Here we report a rare case of WDHA caused by a pheochromocytoma. CASE PRESENTATION: A 45-year old male presented with persistent and progressive watery diarrhea for half a year, and was treated with dialysis due to azotemia, hypokalemia, hypercalcemia and metabolic acidosis. A right adrenal mass was found by ultrasonography, and Positron Emission Tomography-Computed Tomography (PET-CT) showed the tumor was hyper-metabolic. Levels of plasma normetanephrine (NMN) and serum chromogranin A (CgA) were significantly elevated. Immunohistochemistry analysis of the adrenal tumor was strongly positive for CgA, synaptophysin and VIP. The patient fully recovered from WDHA syndrome soon after surgery, as reflected in that diarrhea stopped, levels of plasma NMN, serum CgA, and electrolytes returned to normal thus no dialysis was needed. The patient remained disease free in a 12-months follow-up period. CONCLUSION: We report an extremely rare case of pheochromocytoma causing WDHA syndrome and uremia, which the patient completely recovered from after tumor resection.
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Acloridria/etiologia , Neoplasias das Glândulas Suprarrenais/patologia , Diarreia/etiologia , Hipopotassemia/etiologia , Feocromocitoma/patologia , Acloridria/sangue , Neoplasias das Glândulas Suprarrenais/cirurgia , Diálise , Diarreia/sangue , Intervalo Livre de Doença , Humanos , Hipopotassemia/sangue , Masculino , Pessoa de Meia-Idade , Feocromocitoma/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: The association of thyroid hormone sensitivity with papillary thyroid carcinoma (PTC) is unclear. This study investigated the relationship between the thyroid hormone sensitivity indices and the risk of PTC and the influence of thyroid hormone sensitivity on the aggressive clinicopathologic features of PTC. METHODS: This retrospective study recruited 1225 PTC patients and 369 patients with benign nodules undergoing surgery in Zhongshan Hospital in 2020. The thyroid hormone sensitivity indices were thyroid feedback quantile-based index (TFQI), TSH index (TSHI) and thyrotropin thyroxine resistance index (TT4RI). We employed logistic regression models to explore the correlation between the thyroid hormone sensitivity indices and the risk of PTC and its cervical lymph node metastasis (LNM). RESULTS: PTC patients had significantly higher levels of TSH, TFQI, TSHI and TT4RI compared to the patients with benign nodules, but thyroid hormone levels did not differ significantly between the two groups. Logistic regression analysis revealed that the higher levels of TFQI, TSHI, and TT4RI were associated with an increased risk of PTC after adjustment for multiple risk factors (TFQI: OR = 1.92, 95% CI: 1.39-2.65, P < 0.001; TSHI: OR = 2.33, 95% CI:1.67-3.26, P < 0.001; TT4RI: OR = 2.41, 95% CI:1.73-3.36, P < 0.001). In addition, patients with decreased thyroid hormone sensitivity had a higher risk of cervical LNM in multiple logistic regression analysis (TFQI: OR = 1.38, 95% CI:1.03-1.86, P = 0.03; TSHI: OR = 1.37, 95% CI:1.02-1.84, P = 0.04; TT4RI: OR = 1.41, 95% CI:1.05-1.89, P = 0.02). CONCLUSION: Impaired sensitivity to thyroid hormone was associated with an increased risk of PTC, and it is also associated with a higher risk of cervical LNM in PTC patients.
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Carcinoma Papilar , Hipotireoidismo Congênito , Receptores da Tireotropina/deficiência , Síndrome da Resistência aos Hormônios Tireóideos , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Metástase Linfática/patologia , Estudos Retrospectivos , Carcinoma Papilar/patologia , Linfonodos/patologia , Hormônios Tireóideos , TireotropinaRESUMO
OBJECTIVE: The objective of the study was to evaluate the efficacy of prophylactic neck dissection in the treatment of papillary thyroid cancer and to provide guidelines for clinical practice. METHOD: Relevant clinical trials on prophylactic neck dissection in the treatment of papillary thyroid cancer were retrieved using PubMed, MEDLINE, EMBASE and Cochrane Controlled Trials Register until August 2012. Information was extracted according to the Cochrane systematic review methods. RevMan 5.0 was used for meta-analysis. RESULTS: Nine controlled clinical trials were included in this meta-analysis. Compared with patients who underwent thyroidectomy alone (control group), patients who underwent thyroidectomy plus prophylactic neck dissection (experimental group) showed a higher incidence of transient hypocalcemia (P = 0.02), but no significant changes were observed in the incidence of neck lymph node recurrence (P = 0.69), central neck lymph node recurrence (P = 0.61), lateral neck lymph node recurrence (P = 0.70), permanent hypocalcemia (P = 0.44), transient vocal cord paralysis (P = 0.13), permanent vocal cord paralysis (P = 0.26) and hematoma incidence (P = 0.39). CONCLUSIONS: Combined thyroidectomy and prophylactic neck dissection may be effective in the treatment of patients with papillary thyroid cancer, without more complications compared with thyroidectomy alone.
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Carcinoma Papilar/cirurgia , Carcinoma/cirurgia , Linfonodos/patologia , Esvaziamento Cervical , Recidiva Local de Neoplasia/prevenção & controle , Prevenção Secundária/métodos , Neoplasias da Glândula Tireoide/cirurgia , Carcinoma/complicações , Carcinoma Papilar/complicações , Carcinoma Papilar/patologia , Humanos , Hipocalcemia/complicações , Hipocalcemia/etiologia , Linfonodos/cirurgia , Metástase Linfática , Pescoço/patologia , Pescoço/cirurgia , Esvaziamento Cervical/efeitos adversos , Esvaziamento Cervical/métodos , Recidiva Local de Neoplasia/cirurgia , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/complicações , Tireoidectomia/efeitos adversos , Tireoidectomia/métodos , Resultado do Tratamento , Paralisia das Pregas Vocais/etiologiaRESUMO
Objective: This study aimed to evaluate the effectiveness and safety of carbon nanoparticles-guided lymph node dissection during thyroidectomy in patients with papillary thyroid cancer(PTC). Methods: Clinical trials consisted of two subgroups: unilateral lobectomy (UL; n=283) and total thyroidectomy (TT; n=286). From each subgroup, the patients were randomly assigned to two groups: the carbon nanoparticle group and control group. Primary endpoints included parathyroid hormone (PTH) levels, number of lymph nodes (LNs) detected, number of tiny lymph nodes detected, and recognition and retention of the parathyroid glands. Secondary endpoint was recognition and protection of the recurrent laryngeal nerve. Results: A total of 569 patients with PTC were recruited. There were no statistically significant differences in demographics between the carbon nanoparticles and control groups (P > 0.05). In the UL subgroup, there were no significant differences in PTH levels between the two groups at preoperative, intraoperative, and postoperative day one, and postoperative month one (P>0.05). There was no significant difference in the serum Ca2+ levels between the two groups preoperatively and at postoperative month one (P>0.05). The number of lymph nodes dissected in the carbon nanoparticles group was significantly higher than that in the control group (P<0.0001). The detection rate of tiny lymph nodes in the carbon nanoparticles group was higher than that in the control group (P=0.0268). In the TT subgroup, there was no significant difference in PTH levels between the two groups at preoperative, intraoperative, and postoperative day one (P>0.05). However, the mean PTH level in the carbon nanoparticles group was significantly higher than that of the control group at postoperative month one (P=0.0368). There was no significant difference in the serum Ca2+ levels between the two groups preoperatively and at postoperative month one (P>0.05). There were no significant differences between the two groups in the number of dissected LNs (P>0.05) or the detection rate of tiny lymph nodes (P>0.05). No drug-related AE and complications due to the injection of carbon nanoparticles were recorded in this study. There were no significant differences between the two groups in terms of parathyroid preserved in situ and recurrent laryngeal nerve injury in the UL and TT subgroups. Conclusions: Carbon nanoparticles demonstrated efficacy and safety in thyroidectomy. The application of carbon nanoparticles could significantly facilitate the identification and clearance of LNs and the optimum preservation of parathyroid function. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2300068502.
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Nanopartículas , Neoplasias da Glândula Tireoide , Humanos , Tireoidectomia/efeitos adversos , Câncer Papilífero da Tireoide/cirurgia , Estudos Prospectivos , Excisão de Linfonodo/efeitos adversos , Carbono , Neoplasias da Glândula Tireoide/cirurgiaRESUMO
Introduction: The overdiagnosing of papillary thyroid carcinoma (PTC) in China necessitates the development of an evidence-based diagnosis and prognosis strategy in line with precision medicine. A landscape of PTC in Chinese cohorts is needed to provide comprehensiveness. Methods: 6 paired PTC samples were employed for whole-exome sequencing, RNA sequencing, and data-dependent acquisition mass spectrum analysis. Weighted gene co-expression network analysis and protein-protein interactions networks were used to screen for hub genes. Moreover, we verified the hub genes' diagnostic and prognostic potential using online databases. Logistic regression was employed to construct a diagnostic model, and we evaluated its efficacy and specificity based on TCGA-THCA and GEO datasets. Results: The basic multiomics landscape of PTC among local patients were drawn. The similarities and differences were compared between the Chinese cohort and TCGA-THCA cohorts, including the identification of PNPLA5 as a driver gene in addition to BRAF mutation. Besides, we found 572 differentially expressed genes and 79 differentially expressed proteins. Through integrative analysis, we identified 17 hub genes for prognosis and diagnosis of PTC. Four of these genes, ABR, AHNAK2, GPX1, and TPO, were used to construct a diagnostic model with high accuracy, explicitly targeting PTC (AUC=0.969/0.959 in training/test sets). Discussion: Multiomics analysis of the Chinese cohort demonstrated significant distinctions compared to TCGA-THCA cohorts, highlighting the unique genetic characteristics of Chinese individuals with PTC. The novel biomarkers, holding potential for diagnosis and prognosis of PTC, were identified. Furthermore, these biomarkers provide a valuable tool for precise medicine, especially for immunotherapeutic or nanomedicine based cancer therapy.
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Exosomes are nanosized extracellular vesicles that can be released from cancer cells. It has been shown that cancer cellderived exosomes may be associated with carcinogenesis by transferring signaling proteins from malignant to neighboring nonmalignant cells. In addition, annexin A1 (ANXA1) is a wellknown oncogene, that can be released from extracellular vesicles by cancer cells. However, the role of exosomal ANXA1 in the celltocell communication of thyroid cancer and thyroid follicular epithelial cells remains unclear. In the present study, the protein expression levels of ANXA1 in thyroid cancer cells and thyroid cancer cellderived exosomes were analyzed using western blot analysis. In addition, Cell Counting Kit8 and Transwell assays were used to determine cell viability and invasion, respectively. The protein expression levels of ANXA1 were increased in thyroid cancer tissues and thyroid cancer cell lines. In addition, overexpression of ANXA1 significantly increased the proliferation and invasion of the SW579 cells, while knockdown of ANXA1 expression exerted the opposite results. Furthermore, ANXA1 was transferred from the SW579 cells to the Nthyori31 cells via exosomes. Exosomal ANXA1 markedly promoted the proliferation, invasion and epithelialtomesenchymal transition of the Nthyori31 cells. In addition, SW579 cellderived exosomal ANXA1 promoted tumor growth in a xenograft mouse model. Collectively, these findings indicated that SW579 cellderived exosomal ANXA1 promoted thyroid cancer development and Nthyori31 cell malignant transformation. Therefore, these findings may aid in the development of effective treatment methods for thyroid cancer.
Assuntos
Adenocarcinoma Folicular/patologia , Anexina A1/metabolismo , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/patologia , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/metabolismo , Idoso , Animais , Anexina A1/genética , Apoptose , Biomarcadores Tumorais/genética , Comunicação Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transição Epitelial-Mesenquimal , Exossomos/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIM: Papillary thyroid cancer (PTC) is the most common type of thyroid cancer with an increasing morbidity. MicroRNAs (miRNAs) play the pivotal roles in PTC occurrence and development. The aim of this study was to investigate the biological functions of miR-873-5p and its underlying molecular mechanisms in PTC. METHODS: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was performed to detect miR-873-5p expressions in PTC tissues and cell lines. The target gene of miR-873-5p was predicted by TargetScan and confirmed by dual-luciferase reporter assay. Furthermore, cell proliferation, migration and invasion were assessed by CCK-8, wound healing assay and transwell assay, respectively. Additionally, the expressions of CXCL16, MMP1, MMP9 and MMP13 were measured by RT-qPCR and Western blot methods, and p65, Rel-B and their phosphorylation levels were examined by Western blot. RESULTS: We found that miR-873-5p expression was downregulated in PTC tissues and cell lines. Moreover, CXCL16 was identified as a target of miR-873-5p, and its expression was upregulated in PTC tissues and cells at both mRNA and protein levels. Functionally, overexpression of miR-873-5p inhibited PTC cell proliferation, migration and invasion, while co-transfection of CXCL16 overexpression plasmid reversed the anti-tumor behaviors induced by miR-873-5p. In addition, miR-873-5p overexpression suppressed the phosphorylation of p65 and Rel-B, and decreased the mRNA and protein expression of MMP1, MMP9 and MMP13, while overexpression of CXCL16 partially abrogated the effects of miR-873-5p. CONCLUSION: MiR-873-5p functions as a tumor suppressor in PTC by inhibiting the proliferation, migration and invasion of the PTC cells via targeting CXCL16. These findings might provide a potential novel target for the therapy of PTC.
RESUMO
Nerves infiltrate the tumor microenvironment and stimulate the growth of cancer cells through the secretion of neurotransmitters. However, the contributions of nerves to the self-renewal capacity of cancer stem cells (CSCs) remain largely unknown. In this study, we found that CD133+ cancer cells were responsible for the initiation of thyroid cancer. Neurons were juxtaposed with CD133+ cells in thyroid cancer tissues. Acetylcholine, one of the most abundant neurotransmitters, promoted CD133 Y828 phosphorylation, and subsequently increased the interaction between CD133 and PI3K regulatory subunit p85, resulting in the activation of the PI3K-Akt pathway. Acetylcholine increased the self-renewal ability of CD133+ thyroid cancer cells through activation of CD133-Akt pathway. Furthermore, acetylcholine promoted the expression of the immune regulator PD-L1 through the activation of the CD133-Akt pathway, resulting in the resistance of CD133+ thyroid cancer cells to CD8+ T cells. However, acetylcholine receptor antagonist 4-DAMP blocked the positive effects of acetylcholine on the self-renewal and immune escape of CD133+ thyroid cancer cells. Taken together, these data suggest that acetylcholine increases the self-renewal and immune escape abilities of CD133+ thyroid cancer cells through the activation of the CD133-Akt pathway.
Assuntos
Antígeno AC133/imunologia , Acetilcolina/farmacologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Neoplasias da Glândula Tireoide/imunologia , Evasão Tumoral/efeitos dos fármacos , Antígeno AC133/metabolismo , Animais , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Xenoenxertos , Humanos , Camundongos , Proteínas Associadas aos Microtúbulos/biossíntese , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Evasão Tumoral/imunologiaRESUMO
Thyroid cancer results from unregulated expansion of a self-renewing tumor-initiating cell population. The regulatory pathways essential for sustaining the self-renewal of tumor-initiating cells remain largely unknown. Reactive oxygen species (ROS) play a vital role in tumor initiation and progression. In the present study, we found that the level of ROS was higher in CD133 + thyroid cancer cells than in CD133- thyroid cancer cells. The transcriptional level of ROS-generating oxidase NADPH oxidase 1 (NOX1) is high in CD133 + thyroid cancer cells. Activation of STAT3 through phosphorylation is responsible for high activation of NOX1 transcription in CD133 + thyroid cancer cells. Knock down of NOX1 obviously reduced the level of ROS and inhibited the self-renewal activity and tumorigenicity of CD133 + thyroid cancer cells. Furthermore, knock down of NOX1 reduced the activity of PI3K/Akt pathway. Overexpression of active form of Akt rescued the negative effect of NOX1 knockdown on the self-renewal capability of CD133 + thyroid cancer cells. Together, NOX1 promotes the self-renewal property of CD133 + thyroid cancer cells at least partly through activation of the Akt signaling.