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Papillary thyroid cancer (PTC) is the most common form of thyroid cancer and is characterized by its tendency for lymphatic metastasis, leading to a poor prognosis. Tetraspanin 1 (TSPAN1) is a member of the tetra-transmembrane protein superfamily and has been implicated in tumorigenesis and cancer metastasis in various studies. However, the role of TSPAN1 in PTC tumor development remains unclear. In this study, we aimed to investigate the impact of TSPAN1 on PTC cell behavior. Our results demonstrate that knockdown of TSPAN1 inhibits PTC cell proliferation, migration, and invasion, while overexpression of TSPAN1 has the opposite effect. These findings suggest that TSPAN1 might play a role in the tumorigenesis and invasiveness of PTC. Mechanistically, we found that TSPAN1 activates the ERK pathway by increasing its phosphorylation, subsequently leading to upregulated expression of c-Myc. Additionally, we observed that TSPAN1-ERK-c-Myc axis activation promotes glycolytic activity in PTC cells, as evidenced by the upregulation of glycolytic genes such as LDHA. Taken together, our findings indicate that TSPAN1 acts as an oncogene in PTC by regulating glycolytic metabolism. This discovery highlights the potential of TSPAN1 as a promising therapeutic target for PTC treatment. Further research in this area could provide valuable insights into the development of targeted therapies for PTC patients.
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MicroRNAs , Neoplasias da Glândula Tireoide , Humanos , Linhagem Celular Tumoral , Neoplasias da Glândula Tireoide/patologia , Câncer Papilífero da Tireoide/patologia , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Proliferação de Células/genética , Tetraspaninas/genética , Tetraspaninas/metabolismo , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genéticaRESUMO
Objective: This study aims to evaluate the efficacy of secondary sentinel lymph node (SLN) biopsy in cN1a papillary thyroid carcinoma (PTC) surgery, drawing parallels to strategic approaches akin to those employed by athletic players.Methods: We selected eleven patients diagnosed with suspected cN1a PTC from January 2020 to July 2020. Carbon nanoparticles were utilized to mark lymph nodes, analogous to strategic marking in athletic games, ensuring precise identification during surgery. The secondary SLN biopsy technique was implemented, reflecting the precision and planning seen in athletic strategies.Results: The average tumor size was 12.64±5.63 mm. Notably, 2 patients exhibited extrathyroidal spread, 3 had thyroiditis, and all had neck metastases. The SLN identification rate stood at 100%, mirroring the accuracy expected in athletic performance. Out of the group, 3 patients had sentinel lymph node metastasis, with additional metastasis in non-SLN areas in 1 patient. The detection rate, false-negative rate, and overall accuracy paralleled the high performance and reliability seen in athletic endeavors. A total of 42 lateral SLNs were identified, with the majority being grade IV. This strategic identification is akin to an athlete's ability to focus on key areas during play (AU)
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Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Biópsia de Linfonodo Sentinela , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Carcinoma/diagnóstico , Carcinoma/patologia , AtletasRESUMO
Background: The EBSLN is vulnerable to damage during thyroidectomy, results in voice related complications, negatively affect patient quality of life, routine identification of the EBSLN prior to surgical manipulation is necessary for a complication-free thyroidectomy. We aimed to validate a video-assisted procedure for identifying and preserving the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy and analyze the EBSLN Cernea classification and the localization of the nerve entry point (NEP) from the insertion of the sternothyroid muscle. Methods: A prospective descriptive study was performed; 134 patients, who scheduled for lobectomy with an intraglandular tumor max diameter ≤ 4â cm and without extrathyroidal extension, were randomly divided into the video-assisted surgery (VAS) and conventional open surgery (COS) groups. We used the video-assisted surgical procedure for visually identifying the EBSLN directly, and compared the differences in the visual identification rate and total identification rate of the two groups. We also measured the localization of the NEP using the insertion of the sternothyroid muscle as a reference. Results: There was no statistically significant difference in clinical characteristics between the two groups. The visual identification rate and total identification rate were significantly higher in the VAS group than the COS group (91.04% vs. 77.61%, 100% vs. 89.6%). The EBSLN injury rate was 0 in both groups. The mean vertical distance (VD) of the NEP from the sternal thyroid insertion was 1.18â mm (SD 1.12â mm, range, 0-5â mm), with approximately 88.97% of the results occurring within the 0-2â mm range. The mean horizontal distance (HD) was 9.33â mm (SD 5.03â mm, range, 0-30â mm), with over 92.13% of the results occurring within the 5-15â mm range. Conclusion: Both the visual and total identification rates of the EBSLN were significantly higher in the VAS group. This method provided a good visual exposure rate of the EBSLN, aiding in identifying and protecting the EBSLN during thyroidectomy.
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Background: Whether patients with unilateral papillary thyroid carcinoma (PTC) with lateral cervical lymph node metastasis (LLNM) require prophylactic central regional lymph node dissection (CLND) remains unclear. Herein, we investigated the independent risk factors associated with contralateral central lymph node metastasis (cCLNM) in unilateral PTC with LLNM and analyzed the optimal extent of lymph node dissection by comparing the 5-year recurrence-free survival rates. Materials and methods: We retrospectively analyzed 695 patients with unilateral papillary thyroid carcinoma and lateral cervical lymph node metastasis. Factors including sex, age, multifocal, location of primary tumor, tumor diameter, capsule invasion, thyroid nodular goiter, Hashimoto thyroiditis, ipsilateral central lymph node metastasis(iCLNM), and lateral cervical lymph node metastasis were analyzed using univariate and multivariate logistic regression analyses to explore the independent risk factors of cCLNM. Propensity scores were matched to compare the 5-year recurrence-free survival rates in patients divided by different lymph node metastases and dissections. Results: Of all patients who underwent bilateral (b)CLND, 52% (149/286) had cCLNM. Receiver operating characteristic (ROC) curve analysis was performed on 286 patients who underwent bCLND, for which a tumor diameter of 20.5 mm and number of LLNM of 3.5 were used as the thresholds for predicting cCLNM. The 5-year recurrence-free survival (RFS) rates in the cCLN-negative and cCLN-positive groups were 98.6% and 91.2%, with statistically significant differences (P=0.034). The 5-year RFS rates showed no significant difference between the ipsilateral (i)CLND and bCLND groups (P=0.235). Multifactorial regression analysis showed that tumor diameter >2 cm, presence of iCLNM, and number of LLNM >3 were independent risk factors of cCLNM.But male sex, young age (<45 years), multifocality, location of primary tumor, capsule invasion, thyroid nodular goiter, and Hashimoto thyroiditis were not associated with cCLNM. Conclusion: Not all unilateral PTC with LLNM require prophylactic cCLND; however, prophylactic cCLND is necessary in cases which display high-risk factors for cCLNM, including primary diameter >2 cm, iCLNM, and number of LLNM >3.
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BACKGROUND: Cervical cancer is a common gynecological cancer among women worldwide. OBJECTIVE: To determine the effects of 6 MV and 10 MV volumetric-modulated arc therapy (VMAT) photon beams on the target volume (TV) planning and critical organs in cases of cervical cancer. METHODS: Fifty patients with carcinoma of the cervix who underwent radiotherapy were selected. The transverse diameter (T) of the cross section of the upper edge of the sacroiliac joint on computerized tomography (CT) images of the patients was measured, and the mean value was calculated as 34 cm. All patients were divided into two groups: Group A (T < 34 cm) and Group B (T > 34 cm). The VMAT plans were generated using 6 MV and 10 MV plans separately. The prescription dose was 47.5 Gy, and the daily dose was 1.9 Gy. RESULTS: In Group A, the planning target volume (PTV) dose assessment parameters of 6 MV and 10 MV plans and their homogeneity and conformity indices were not statistically significantly different. A significant difference was observed between the 6 MV and 10 MV plans for the PTV dose assessment parameters and the homogeneity index of the plans for Group B. The monitor units (MUs) of the 10 MV plans were lower than in the 6 MV plans in both Groups A and B, and the difference was statistically significant. The assessment parameter V40 Gy of both the rectum and bladder in the 6 MV plans was smaller than the corresponding parameter in the 10 MV plans in Group A; in Group B, the assessment parameter V50 Gy of the rectum in the 10 MV plans was smaller than in the 6 MV plans. CONCLUSION: When T < 34 cm, 6 MV energy is more suitable for the external irradiation of cervical cancer. When T > 34 cm, 10 MV energy is more suitable for cervical cancer radiotherapy. Therefore, 10 MV should be considered for patients with a large abdominal size.
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Radioterapia de Intensidade Modulada , Neoplasias do Colo do Útero , Humanos , Feminino , Radioterapia de Intensidade Modulada/métodos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Neoplasias do Colo do Útero/radioterapia , Fótons/uso terapêuticoRESUMO
The dysregulation of circular RNAs (circRNAs) facilitates the tumorigenesis of papillary thyroid carcinoma (PTC). This study was targeted at determining the functions and mechanism of circ_0000644 in regulating PTC development. Circ_0000644, microRNA-1205 (miR-1205) and E2F transcription factor 3 (E2F3) expressions were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Actinomycin D (ActD) and Ribonuclease R (RNase R) assays were used to verify the circular characteristic of circ_0000644. After circ_0000644 was knocked down, PTC cell growth, migration, invasion and apoptosis were assessed by cell counting kit-8 (CCK-8) assay, Transwell assay and flow cytometry analysis, respectively. The regulating relationships among circ_0000644, E2F3 and miR-1205 were confirmed through RNA immunoprecipitation (RIP) assay and dual-luciferase reporter assay. Besides, the regulatory effects of circ_0000644 on the protein level of E2F3 was analyzed via Western blot. In PTC, circ_0000644 was highly expressed, and it was located mainly in the cytoplasm, and it had stable structure. The knockdown of circ_0000644 repressed PTC cell growth, migration, and invasion, and facilitated apoptosis. Circ_0000644 could directly interact with miR-1205 to repress the expression of miR-1205, and it served as a miR-1205 sponge to modulate E2F3 expression in PTC cells. Circ_0000644 up-regulates E2F3 expression via sponging miR-1205 to promote PTC progression.
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MicroRNAs , Neoplasias da Glândula Tireoide , Linhagem Celular Tumoral , Proliferação de Células/genética , Fator de Transcrição E2F3/genética , Fator de Transcrição E2F3/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismoRESUMO
PURPOSE: To compare the dosimetric differences between intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) in the treatment of male and female thymoma. MATERIAL AND METHODS: This single-institutional analysis included 20 patients with thymoma treated with RT between January 2017 and December 2020. Twenty patients were retrospectively planned for IMRT (IMRT1 with an average field angle of 216°, 288°, 0°, 72°,and 144°; IMRT2 with fan-shaped field angles of 280°, 320°, 0°, 40°, and 80°) and VMAT (VMAT1 with two arcs ranging form 280° to 80°,clockwise and then counterclockwise; VMAT2 with two 360° arcs). The plans for all investigated RT modalities were optimized for a prescriptional dose of 50Gy and fractional dose of 2.0Gy. Planning target volume (PTV) and organs-at-risk (OARs: heart, breasts, lungs, spinal cord, and esophagus) dosimetric parameters were compared. RESULTS: All plans met the preparation aims for all the included metrics. There was little difference in the median values of PTV parameters (D2%, D98%, Dmean, homogeneity index[HI], and conformity index [CI]). The CI of the VMAT2 plan was the closest to 1 in both therapy groups. The monitor unit (MU) of IMRT2 and the estimated total delivery time of VMAT1 were the lowest in both therapy groups and were statistically significant. In the male group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) for VMAT1 were the lowest and showed statistical significance. In the female group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) and bilateral breast parameters (Dmean, V5Gy, V10Gy, and V20Gy) of IMRT2 were the lowest and showed statistical significance. CONCLUSIONS: In male thymoma patients undergoing postoperative RT (PORT) treatment, the choice of fan-shaped VMAT may be a better option for protecting the lungs. For female thymoma patients receiving PORT, fan-shaped IMRT can better protect the lungs and breasts. The fan-shaped field performed better than the average and the full arc fields in PORT for thymoma.
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Radioterapia de Intensidade Modulada , Timoma , Neoplasias do Timo , Feminino , Humanos , Masculino , Órgãos em Risco , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada/efeitos adversos , Estudos Retrospectivos , Timoma/radioterapia , Timoma/cirurgia , Neoplasias do Timo/radioterapia , Neoplasias do Timo/cirurgiaRESUMO
PURPOSE: This study was designed to explore the optimal minimum segment width (MSW) in the intensity-modulated radiotherapy (IMRT) plan for esophageal cancer. PATIENTS AND METHODS: The imaging data of 20 esophageal cancer patients were selected for this study. Four IMRT plans were designed for each patient with MSWs of 0.5, 1.0, 1.5, and 2.0 cm. The conformity index (CI) and homogeneity index (HI) of the planning target volumes (PTV), organs at risk (OARs), control points (CP), monitor units (MU), plan delivery time (DT), and gamma passing rates (GPR) were collected and compared to appraise the treatment plan quality and delivery efficiency. RESULTS: Lower-MSW plans had larger CI and smaller HI values, and lower dose parameters of OARs and PTVs. The HI, CI, and dose parameter of OARs in the 0.5 and 1.0 cm MSW groups were similar and much better than those of the 1.5 and 2.0 cm MSW groups. Meanwhile, the plan in the 0.5 cm MSW group had significantly higher MUs, CPs, and DTs, and a significantly lower relative dose of GPR with a 3% dose difference and 3 mm distance to agreement criteria than the other three groups. CONCLUSION: The 0.5 and 1 cm MSW groups had better dosimetric parameters and IMRT plan quality than the other groups. However, plans with 0.5 cm MSW had worse delivery accuracy and efficiency than the other three groups. Thus, MSW of 1.0 cm was the optimal choice to ensure good quality, delivery accuracy, and treatment efficiency in IMRT plans for esophageal cancer.
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BACKGROUND: Terminal differentiation-induced ncRNA (TINCR) plays an essential role in epidermal differentiation and is involved in the development of various cancers. METHODS: qPCR was used to detect the expression level of TINCR in tissues and cell lines of laryngeal squamous cell carcinoma (LSCC). The potential targets of TINCR were predicted by the bioinformation website. The expression of miR-210 and BTG2 genes were detected by qPCR, and the protein levels of BTG2 and Ki-67 were evaluated by western blot. CCK-8 assay, scratch test, and transwell chamber were used to evaluate the proliferation, invasion, and metastasis ability of LSCC cells. The relationships among TINCR, miR-210, and BTG2 were investigated by bioinformatics software and luciferase reporter assay. The in vivo function of TINCR was accessed on survival rate and tumor growth in nude mice. RESULTS: We used qRT-PCR to detect the expression of TINCR in laryngeal squamous cell carcinoma (LSCC) tissues and cells and found significantly lower levels in cancer tissues compared with adjacent tissues. Additionally, patients with high TINCR expression had a better prognosis. TINCR overexpression was observed to inhibit the proliferation and invasion of LSCC cells. TINCR was shown to exert its antiproliferation and invasion effects by adsorbing miR-210, which significantly promoted the proliferation and invasion of laryngeal squamous cells. Overexpression of miR-210 was determined to reverse the tumour-suppressive effects of TINCR. BTG2 (anti-proliferation factor 2) was identified as the target gene of miR-210, and BTG2 overexpression inhibited the proliferation and invasion of LSCC cells. BTG2 knockdown relieved the inhibitory effects of TINCR on the proliferation and invasion of LSCC. Finally, TINCR upregulation slowed xenograft tumour growth in nude mice and significantly increased survival compared with control mice. CONCLUSION: The results of this study suggest that TINCR inhibits the proliferation and invasion of LSCC by regulating the miR-210/BTG2 pathway, participates in cell cycle regulation, and may become a target for the treatment of LSCC.
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MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Carcinoma de Células Escamosas , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Laríngeas/patologia , Camundongos , Camundongos Nus , TransfecçãoRESUMO
Osteosarcoma (OS) that mainly occurs during childhood and adolescence is a devastating disease with poor prognosis presented by extreme metastases. Recent studies have revealed that liver receptor homolog 1 (LRH-1) plays a vital role in the metastasis of several human cancers, but its role is unknown in the metastasis of OS. In this study, Gene Ontology (GO) enrichment analyses based on high-throughput RNA-seq data revealed that LRH-1 acted a pivotal part in the positive regulation of cell migration, motility, and angiogenesis. Consistently, LRH-1 knockdown inhibited the migration of human OS cells, which was concurrent with the downregulation of mesenchymal markers and the upregulation of epithelial markers. In addition, short hairpin RNAs (shRNAs) targeting LRH-1 inactivated transforming growth factor beta (TGF-ß) signaling pathway. LRH-1 knockdown inhibited human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation. Vascular endothelial growth factor A (VEGFA) expression was also downregulated after LRH-1 knockdown. Immunohistochemistry (IHC) revealed that the expression of LRH-1 protein was significantly higher in tumor tissues than in normal bone tissues. We found that high LRH-1 expression was associated with poor differentiation and advanced TNM stage in OS patients using IHC. Based on The Cancer Genome Atlas (TCGA) database, high LRH-1 expression predicts poor survival in lung squamous cell carcinoma (LUSC), kidney renal papillary cell carcinoma (KIRP), and pancreatic adenocarcinoma (PAAD). The downregulation of LRH-1 significantly hindered the migration and motility of LUSC cells. Using multi-omic bioinformatics, the positive correlation between LRH-1- and EMT-related genes was found across these three cancer types. GO analysis indicated that LRH-1 played a vital role in "blood vessel morphogenesis" or "vasculogenesis" in KIRP. Our results indicated that LRH-1 plays a tumor-promoting role in human OS, could predict the early metastatic potential, and may serve as a potential target for cancer therapy.
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Aims: Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown. It is widely acknowledged that the TGFß1 signaling axis plays a major role in liver fibrosis. Therefore, the aims of this study were to elucidate the underlying mechanism of liver regeneration during ALPPS with or without fibrosis, specifically focusing on TGFß1 signaling. Approach: ALPPS was performed in rat models with N-diethylnitrosamine-induced liver fibrosis and no fibrosis. Functional liver remnant regeneration and expression of TGFß1 were analyzed during the ALPPS procedures. Adeno-associated virus-shTGFß1 and the small molecule inhibitor LY2157299 (galunisertib) were used separately or in combination to inhibit TGFß1 signaling in fibrotic rats. Results: Liver regeneration following ALPPS was lower in fibrotic rats than non-fibrotic rats. TGFß1 was a key mediator of postoperative regeneration in fibrotic liver. Interestingly, AAV-shTGFß1 accelerated the regeneration of fibrotic functional liver remnant and improved fibrosis, while LY2157299 only enhanced liver regeneration. Moreover, combination treatment elicited a stronger effect. Conclusions: Inhibition of TGFß1 accelerated regeneration of fibrotic liver, ameliorated liver fibrosis, and improved liver function following ALPPS. Therefore, TGFß1 is a promising therapeutic target in ALPPS to improve fibrotic liver reserve function and prognosis.
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Hepatectomia/métodos , Hepatócitos/metabolismo , Cirrose Hepática/metabolismo , Regeneração Hepática/fisiologia , Fígado/fisiologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Dietilnitrosamina/toxicidade , Células Estreladas do Fígado/metabolismo , Ligadura , Fígado/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Regeneração Hepática/efeitos dos fármacos , Veia Porta/cirurgia , Cultura Primária de Células , Pirazóis/farmacologia , Quinolinas/farmacologia , Ratos , Transdução de Sinais , Fator de Crescimento Transformador beta1/antagonistas & inibidoresRESUMO
BACKGROUND: ATP binding cassette subfamily A member 8 (ABCA8) belongs to the ATP binding cassette (ABC) transporter superfamily. ABCA8 is a transmembrane transporter responsible for the transport of organics, such as cholesterol, and drug efflux. Some members of the ABC subfamily, such as ABCA1, may inhibit cancer development. However, the mechanism of ABCA8 in the process of cancer activation is still ambiguous. METHODS: The expression of ABCA8 in human hepatocellular carcinoma (HCC) tissues and cell lines was examined using qPCR, immunoblotting, and immunohistochemical staining. The effects of ABCA8 on the proliferation and metastasis of HCC were examined using in vitro and in vivo functional tests. A luciferase reporter assay was performed to explore the binding between microRNA-374b-5p (miR-374b-5p) and the ABCA8 3'-untranslated region (UTR). RESULTS: ABCA8 was frequently down-regulated in HCC and this down-regulation was negatively correlated with prognosis. The overexpression of ABCA8 inhibited growth and metastasis in HCC, whereas the knockdown of ABCA8 exerted the antithetical effects both in vivo and in vitro. ABCA8 was down-regulated by miR-374b-5p; this down-regulation can induce epithelial transformation to mesenchyme via the ERK/ZEB1 signaling pathway and promote HCC progression. CONCLUSION: We exposed the prognostic value of ABCA8 in HCC, and illuminated a novel pathway in ABCA8-regulated inhibition of HCC tumorigenesis and metastasis. These findings may lead to a new targeted therapy for HCC through the regulation of ABCA8, and miR-374b-5p.
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Transportadores de Cassetes de Ligação de ATP/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Transportadores de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Metástase Neoplásica , TransfecçãoRESUMO
Tumor cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect, but the involvement of Warburg effect in liver cancer cell metastasis is not well understood. In present study, our results indicate a positive correlation between glucose metabolism level and metastatic potential of hepatocellular carcinoma (HCC). We also observed that a long noncoding RNA-SOX2OT (lncRNA-SOX2OT) can not only increase the metastatic potential of HCC but also promote a pyruvate kinase M2 (PKM2)-mediated activation of glucose metabolism. Inhibition of PKM2 in HCC cells greatly compromises lncRNA-SOX2OT in promoting Warburg effect and metastasis. Furthermore, miR-122-5p was found being a direct target of lncRNA-SOX2OT in regulating PKM2 expression. Thus, our findings reveal that lncRNA-SOX2OT, a regulator of PKM2, could predispose HCC patients to metastases and may serve as a candidate for metastatic prediction and therapies in HCC patients.
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Triiodothyronine (T3), the biologically active form of thyroid hormone, was reported to protect myocardium from ischemia/reperfusion (I/R) injury when given before sustained ischemia, but its cardioprotective effects when given at the onset of reperfusion (postconditioning), a protocol with more clinical impact is unknown. Therefore, the present study was designed to determine whether T3 postconditioning (THPostC) is able to protect the heart from reperfusion injury and its underlying mechanisms. Isolated Sprague-Dawley rat hearts were subjected to 30â¯min ischemia/45â¯min reperfusion, triiodothyronine was delivered at the first 5â¯min of reperfusion. Our data shown that T3 from 1 to 10 µM during the first 5-min of reperfusion concentration-dependently improved post-ischemic myocardial function. A similar protection was observed in isolated rat cardiomyocytes characterized by the alleviation of I/R-induced loss of mitochondrial membrane potential and exacerbated cell death. Moreover, mitophagy (selectively recognize and remove damaged mitochondria) was significantly stimulated by myocardial I/R, which was enhanced with THPostC. Meanwhile, we found that THPostC stimulated PINK1/Parkin pathway, a critical regulator for mitophagy. Then, adenoviral knockdown of PINK1 and Parkin conformed its roles in the THPostC-mediated cardioprotection. Our results suggest that THPostC confers cardioprotection against I/R injury at least in part by reinforcing PINK1-dependent mitophagy. These findings reveal new roles and mechanisms of triiodothyronine in the cardioprotection against I/R injury.
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Mitofagia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Hormônios Tireóideos/uso terapêutico , Animais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Inativação Gênica , Ventrículos do Coração/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitofagia/efeitos dos fármacos , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Quinases/metabolismo , Ratos Sprague-Dawley , Análise de Sobrevida , Hormônios Tireóideos/farmacologia , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly fatal malignant cancer worldwide. Elucidating the underlying molecular mechanism of HCC progression is critical for the identification of new therapeutic targets for HCC. This study aimed to determine the role of Non-SMC condensin II complex subunit G2 (NCAPG2) in HCC proliferation and metastasis. METHODS: We detected NCAPG2 expression in tissues using immunohistochemistry, western blotting and real-time PCR. The effects of NCAPG2 on cell proliferation and metastasis were evaluated both in vitro and in vivo. Immunocytochemistry, enzyme linked immunosorbent assay, co-immunoprecipitation and luciferase reporter assay were performed to uncover the underlying mechanisms. FINDINGS: We found that NCAPG2 is frequently upregulated in HCC tumour tissues and predicts a poor prognosis. NCAPG2 overexpression promotes HCC proliferation, migration, and invasion through activating STAT3 and NF-κB signalling pathways. Moreover, NCAPG2 is a direct target of miR-188-3p. We demonstrated the existence of a positive feedback loop between NCAPG2 and p-STAT3 and a negative feedback loop between NCAPG2 and miR-188-3p. INTERPRETATION: Our study indicates that NCAPG2 overexpression could drive HCC proliferation and metastasis through activation of the STAT3 and NF-κB/miR-188-3p pathways. These findings may contribute to the identification of novel biomarkers and therapeutic targets for HCC. FUND: National Key Program for Science and Technology Research and Development (Grant No. 2016YFC0905902); the National Natural Scientific Foundation of China (Nos. 81772588, 81602058, 81773194); University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province (Grant No. UNPYSCT-2016200); the Innovative Research Program for Graduate of Harbin Medical University (Grant Nos. YJSCX2017-38HYD, YJSCX2016-18HYD).
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas Cromossômicas não Histona/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Sítios de Ligação , Biomarcadores Tumorais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas Cromossômicas não Histona/metabolismo , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Camundongos , Modelos Biológicos , Metástase Neoplásica , Dinâmica Populacional , Prognóstico , Regiões Promotoras Genéticas , Ligação Proteica , Interferência de RNA , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: As a main rate-limiting subunit of the 2-oxoglutarate dehydrogenase multienzyme complex, oxoglutarate dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. EXPERIMENTAL DESIGN: The expression and functional analysis of OGDHL, miR-214, and TWIST1 in human pancreatic cancer tissues, cell lines, and xenograft tumor model were investigated. The correlations between OGDHL and those markers were analyzed. RESULTS: OGDHL was downregulated in human pancreatic cancer and predicted poor prognosis. OGDHL overexpression inhibited migration and invasion of pancreatic cancer cells and suppressed pancreatic cancer tumor growth. OGDHL was shown to be negatively regulated by miR-214. TWIST1 upregulation induced miR-214 expression in pancreatic cancer. OGDHL suppressed TWIST1 expression through promoting ubiquitin-mediated proteasomal degradation of HIF1α and regulating AKT pathways. A combination of OGDHL downregulation and TWIST1 and miR-214 overexpression predicted worse prognosis in patients with pancreatic cancer. CONCLUSIONS: We demonstrated the prognostic value of OGDHL, miR-214, and TWIST1 in pancreatic cancer, and elucidated a novel pathway in OGDHL-regulated inhibition of pancreatic cancer tumorigenesis and metastasis. These findings may lead to new targeted therapy for pancreatic cancer through regulating OGDHL, miR-214, and TWIST1.
Assuntos
Complexo Cetoglutarato Desidrogenase/metabolismo , MicroRNAs/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Complexo Cetoglutarato Desidrogenase/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Prognóstico , Transdução de Sinais , Proteína 1 Relacionada a Twist/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cystatin SN, a specific cysteine protease inhibitor, is thought to be involved in various malignant tumors. Therefore, we evaluated the role of cystatin SN in hepatocellular carcinoma (HCC). Notably, cystatin SN was elevated in tumorous samples and cells. Moreover, overexpression of cystatin SN was correlated with tumor diameter and TNM stage. Cox multivariate analysis displayed that cystatin SN was an independent prognosis indicator and that high cystatin SN level was associated with a dismal prognosis. Moreover, cystatin SN enhancement facilitated the proliferation, migratory, and invasive potential of Huh7 and HCCLM3 cells, whereas cystatin SN knockdown caused the opposite effect. Cystatin SN also modulated the epithelial-mesenchymal transition progression through the PI3K/AKT pathway. In vivo cystatin SN promoted HCCLM3 cell growth and metastasis in xenograft mice model. Thus, cystatin SN was involved in HCC progression and could be a latent target for HCC treatment.
Assuntos
Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Hepáticas/metabolismo , Cistatinas Salivares/metabolismo , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Experimentais , Fosfatidilinositol 3-Quinases , Prognóstico , Proteínas Proto-Oncogênicas c-akt , Cistatinas Salivares/genética , Regulação para CimaRESUMO
The incidence of papillary thyroid cancer (PTC) has been rapidly increasing in recent years. PTC is prone to lymph node metastasization, which further increases the recurrence rate and mortality of thyroid cancer. However, the underlying mechanisms of this process remain elusive. Several reports have shown that the microRNA miR-215 plays an important role in cancer metastasis. Here, we investigated, for the first time, the potential association between miR-215 and metastasis in PTC. The results of qPCR analysis demonstrated that miR-215 was downregulated in PTC cell lines and tissues, and lower levels of miR-215 correlated with lymph node metastasis of PTC. In vitro and in vivo assays revealed that restoration of miR-215 dramatically inhibited PTC cell proliferation and metastasis. We identified ADP ribosylation factor guanine nucleotide-exchange factor 1 (ARFGEF1) as the target, which mediated the function of miR-215. The expression of ARFGEF1 was inhibited by miR-215, and the effects of miR-215 were abrogated by re-expression of ARFGEF1. Moreover, we found that miR-215 suppressed PTC metastasis by modulating the epithelial-mesenchymal transition via the AKT/GSK-3ß/Snail signaling. In summary, our study proves that miR-215 inhibits PTC proliferation and metastasis by targeting ARFGEF1 and indicates miR-215 as a biomarker for PTC prognosis.
Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , MicroRNAs/metabolismo , Transdução de Sinais/genética , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/secundário , Neoplasias da Glândula Tireoide/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação para Baixo/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Metástase Linfática/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Transplante HeterólogoRESUMO
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. The poor survival may be due to a high proportions of tumor recurrence and metastasis. Kinesin family member C1 (KIFC1) is highly expressed in a variety of neoplasms and is a potential marker for non-small cell lung cancer or ovarian adenocarcinoma metastasis. Nevertheless, the role of KIFC1 in HCC metastasis remains obscure. We investigated this in the present study using HCC cell lines and clinical specimens. Our results indicated that increased levels of KIFC1 were associated with poor prognosis and metastasis in HCC. In addition, KIFC1 induced epithelial-to-mesenchymal transition (EMT) and HCC metastasis both in vitro and in vivo. This tumorigenic effect depended on gankyrin; inhibiting gankyrin activity reversed EMT via activation of protein kinase B (AKT)/Twist family BHLH transcription factor 1 (AKT/TWIST1). We also found that KIFC1 was directly regulated by the microRNA miR-532-3p, whose downregulation was associated with metastatic progression in HCC. These results denote that a decrease in miR-532-3p levels results in increased KIFC1 expression in HCC, leading to metastasis via activation of the gankyrin/AKT/TWIST1 signaling pathway.