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1.
Anticancer Res ; 41(1): 175-185, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419811

RESUMEN

BACKGROUND/AIM: Both pediatric glioblastoma (pGB) and adult glioblastoma (aGB) are clinically devastating, and are known to have different molecular pathogenesis. Here, we focused on the role of ZEB2 in pGB and aGB. MATERIALS AND METHODS: Following transfection with ZEB2 siRNA into pGB cells (KNS42) and aGB cells (U87 and U373), cell proliferation, migration and invasion, and cell cycle progression were evaluated. RESULTS: Targeted inhibition of ZEB2 induced up-regulation of E-cadherin expression and down-regulation of vimentin expression. Furthermore, it reduced invasion and migration of both pGB and aGB cells. Interestingly, in pGB cells, but not in aGB cells, silencing of ZEB2 reduced cell proliferation and viability, and affected the cell cycle progression of tumor cells. CONCLUSION: Inhibition of ZEB2 altered the mesenchymal features and reduced the migration and invasive ability of both pGB and aGB cells. ZEB2 effects were different in pGB and aGB cells regarding proliferation and cell cycle progression, suggesting that different underlying molecular mechanisms drive progression in these two types of tumors.


Asunto(s)
Expresión Génica , Glioblastoma/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Adulto , Factores de Edad , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Niño , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/metabolismo , Humanos , Inmunohistoquímica , Inmunofenotipificación , MicroARNs/genética , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo
2.
In Vivo ; 35(1): 131-140, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33402458

RESUMEN

BACKGROUND/AIM: Dual-specificity protein phosphatase 4 (DUSP4) negatively regulates MAPK signaling and is involved in various cellular processes. We herein evaluated the relationship between DUSP4 expression and clinicopathological characteristics in a large series of gastric cancer samples. MATERIALS AND METHODS: DUSP4 expression was examined by immunohistochemistry in 508 gastric cancer samples. Cases were classified according to the TCGA molecular classification and HER2 amplification. Kaplan-Meier plots were used to predict the relationship between mRNA expression of DUSP4 and survival. RESULTS: Low expression of DUSP4 was significantly correlated with larger tumor size, higher pT category, positive nodal status, higher stage, lymphovascular invasion, perineural invasion, worse overall survival, and worse recurrence-free survival. No correlation was observed between DUSP4 expression and molecular characteristics. Bioinformatics analysis showed that low mRNA expression was associated with a poor prognosis. CONCLUSION: Low expression of DUSP4 is associated with aggressive phenotypes of gastric cancer and a poor prognosis.

3.
Clin Cancer Res ; 2020 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-33172897

RESUMEN

PURPOSE: Gastric cancer remains the leading cause of cancer-related deaths in Northeast Asia. Population-based endoscopic screenings in the region have yielded successful results in early detection of gastric tumors. Endoscopic screening rates are continuously increasing, and there is a need for an automatic computerized diagnostic system to reduce the diagnostic burden. In this study, we developed an algorithm to classify gastric epithelial tumors automatically and assessed its performance in a large series of gastric biopsies and its benefits as an assistance tool. EXPERIMENTAL DESIGN: Using 2,434 whole-slide images, we developed an algorithm based on convolutional neural networks to classify a gastric biopsy image into one of three categories: negative for dysplasia (NFD), tubular adenoma, or carcinoma. The performance of the algorithm was evaluated by using 7,440 biopsy specimens collected prospectively. The impact of algorithm-assisted diagnosis was assessed by six pathologists using 150 gastric biopsy cases. RESULTS: Diagnostic performance evaluated by the AUROC curve in the prospective study was 0.9790 for two-tier classification: negative (NFD) versus positive (all cases except NFD). When limited to epithelial tumors, the sensitivity and specificity were 1.000 and 0.9749. Algorithm-assisted digital image viewer (DV) resulted in 47% reduction in review time per image compared with DV only and 58% decrease to microscopy. CONCLUSIONS: Our algorithm has demonstrated high accuracy in classifying epithelial tumors and its benefits as an assistance tool, which can serve as a potential screening aid system in diagnosing gastric biopsy specimens.

4.
Laryngoscope ; 2020 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-33002212

RESUMEN

OBJECTIVES/HYPOTHESIS: Ultrasound-guided fine-needle aspiration cytology (US-FNAC) is a well-established procedure performed to establish the diagnosis of Kikuchi-Fujimoto disease (KFD). Ultrasound-guided core needle biopsy (US-CNB) is an alternative diagnostic tool for KFD. However, the efficacy of US-CNB is not well evaluated. This study aimed to evaluate the efficacy of US-CNB and compare it with that of US-FNAC in the diagnosis of KFD. STUDY DESIGN: Retrospective cohort study. METHODS: We analyzed 170 patients who were diagnosed with KFD between January 2009 and May 2019. US-FNAC, US-CNB, and excisional biopsy were performed in 47, 114, and 9 patients, respectively. Diagnostic accuracies of US-FNAC and US-CNB were analyzed and compared. RESULTS: Of the 170 patients, 45 and 125 were men and women, respectively. The mean age was 26.9 ± 9.1 years. The most common symptom was cervical lymphadenopathy, followed by fever, headache, and myalgia. The diagnosis of KFD was established primarily by US-FNAC in 21 (44.7%) of the 47 patients, by US-CNB in 109 (95.6%) of the 114 patients, and by excisional biopsy in all 9 patients. There was no specific major complication related to US-FNAC and US-CNB. CONCLUSION: US-CNB can be considered safe and effective and used as the primary modality for the pathological diagnosis of KFD. LEVEL OF EVIDENCE: 4. Laryngoscope, 2020.

5.
Biomed Opt Express ; 11(5): 2652-2664, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32499950

RESUMEN

Cutaneous radiation injury (CRI) is a skin injury caused by exposure to high dose ionizing radiation (IR). Diagnosis and treatment of CRI is difficult due to its initial clinically latent period and the following inflammatory bursts. Early detection of CRI before clinical symptoms will be helpful for effective treatment, and various optical methods have been applied with limitations. Here we show that optical coherence tomography angiography (OCTA) could detect changes in the skin during the latent period in CRI mouse models non-invasively. CRI was induced on the mouse hindlimb with exposure to various IR doses and the injured skin regions were imaged longitudinally by OCTA until the onset of clinical symptoms. OCTA detected several changes in the skin including the skin thickening, the dilation of large blood vessels, and the irregularity in vessel boundaries. Some of OCTA findings were confirmed by histology. The study results showed that OCTA could be used for early CRI detection.

6.
Mol Cells ; 43(5): 459-468, 2020 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-32299194

RESUMEN

Nuclear receptor subfamily group H member 4 (NR1H4), also known as farnesoid X receptor, has been implicated in several cellular processes in the liver and intestine. Preclinical and clinical studies have suggested a role of NR1H4 in colon cancer development; however, how NR1H4 regulates colon cancer cell growth and survival remains unclear. We generated NR1H4 knockout (KO) colon cancer cells using clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease (CAS9) technology and explored the effects of NR1H4 KO in colon cancer cell proliferation, survival, and apoptosis. Interestingly, NR1H4 KO cells showed impaired cell proliferation, reduced colony formation, and increased apoptotic cell death compared to control colon cancer cells. We identified MYC as an important mediator of the signaling pathway alterations induced by NR1H4 KO. NR1H4 silencing in colon cancer cells resulted in reduced MYC protein levels, while NR1H4 activation using an NR1H4 ligand, chenodeoxycholic acid, resulted in time- and dose-dependent MYC induction. Moreover, NR1H4 KO enhanced the anti-cancer effects of doxorubicin and cisplatin, supporting the role of MYC in the enhanced apoptosis observed in NR1H4 KO cells. Taken together, our findings suggest that modulating NR1H4 activity in colon cancer cells might be a promising alternative approach to treat cancer using MYC-targeting agents.


Asunto(s)
Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Receptores Citoplasmáticos y Nucleares/metabolismo , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Ácido Quenodesoxicólico/farmacología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Neoplasias del Colon/terapia , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Terapia Molecular Dirigida , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Transducción de Señal
7.
Sci Rep ; 10(1): 4853, 2020 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-32184420

RESUMEN

Secreted Protein Acidic and Rich in Cysteine (SPARC)-related modular calcium-binding protein-2 (SMOC2), a secreted matricellular protein, is reported to be involved in various processes related to cancer progression such as regulating the cell cycle, angiogenesis, and invasion. However, its expression and prognostic significance in papillary thyroid carcinomas (PTCs) remains unknown. Using immunohistochemistry, we evaluated the expression profile of SMOC2 and its prognostic value in a large cohort of PTCs. Real time-PCR analysis with fresh-frozen tissues showed that SMOC2 mRNA expression in PTCs was substantially lower than the expression in matched non-cancerous thyroid tissues, consistent with the results from thyroid cancer cell lines. Immunohistochemical analysis demonstrated that SMOC2 was normally present in thyroid follicular epithelial cells and the expression level was maintained in nodular hyperplasia. However, SMOC2 expression was significantly lower in lymphocytic thyroiditis and follicular tumors including follicular adenomas and carcinomas. In particular, 38% of PTCs exhibited a complete loss of SMOC2 expression, which was associated with the presence of BRAF (V600E) mutation. Moreover, SMOC2 further declined during lymph node metastasis in PTCs. DNA methylation chip analysis revealed one hypermethylated CpG site in the promoter region of SMOC2 gene, suggesting an epigenetic regulation of SMOC2 in PTCs. Remarkably SMOC2 positivity was associated with improved recurrence-free survival along with female sex, tumor size, and the N stage. However, SMOC2 was not identified as an independent prognostic marker in multivariate analyses. Taken together, SMOC2 expression is significantly down-regulated in PTCs and SMOC2 positivity is closely associated with better clinical outcomes, suggesting that SMOC2 can be a prognostic marker in PTC patients.

8.
Int J Mol Sci ; 21(5)2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-32164317

RESUMEN

Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is one of the major limitations associated with its use. In particular, proctitis is a major clinical complication of pelvic radiotherapy. Recent evidence suggests that endothelial injury significantly affects the initiation of radiation-induced inflammation. The damaged endothelial cells accelerate immune cell recruitment by activating the expression of endothelial adhesive molecules, which participate in the development of tissue damage. Pravastatin, a cholesterol lowering drug, exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells and inhibits the interaction of leukocytes and damaged endothelial cells. Here, we aimed to investigate the effects of pravastatin on radiation-induced endothelial damage in human umbilical vein endothelial cell and a murine proctitis model. Pravastatin attenuated epithelial damage and inflammatory response in irradiated colorectal lesions. In particular, pravastatin improved radiation-induced endothelial damage by regulating thrombomodulin (TM) expression. In addition, exogenous TM inhibited leukocyte adhesion to the irradiated endothelial cells. Thus, pravastatin can inhibit endothelial damage by inducing TM, thereby alleviating radiation proctitis. Therefore, we suggest that pharmacological modulation of endothelial TM may limit intestinal inflammation after irradiation.

9.
Exp Dermatol ; 29(2): 158-167, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31560791

RESUMEN

Delayed wound healing after radiation exposure can cause serious cutaneous damage, and its treatment is a major clinical challenge. Although mesenchymal stem cells (MSCs) have emerged as a promising therapeutic agent in regenerative medicine, they alone do not produce satisfactory effects in a combined radiation and wound injury (CRWI) model. Here, we investigated the therapeutic effect of combined umbilical cord blood-derived (UCB)-MSCs and platelet-rich plasma (PRP) treatment on wound healing in a CRWI mouse model. First, we assessed the release of cytokines from UCB-MSCs cultured with PRP and observed changes in the expression of angiogenic factors. The angiogenic paracrine factors from UCB-MSCs cultured with PRP were assessed in human umbilical vein endothelial cells (HUVECs). To assess therapeutic efficacy, UCB-MSCs and PRP were topically implanted into a CRWT mouse model. Vascular endothelial growth factor (VEGF), a pro-angiogenic growth factor, urokinase-type plasminogen activator and contributor to VEGF-induced signalling were more highly expressed in conditioned media of UCB-MSCs cultured with PRP than in that of UCB-MSCs alone. Furthermore, conditioned media of UCB-MSCs cultured with PRP increased the formation of tube-like structures in HUVECs. Co-treatment of UCB-MSCs and PRP in a CRWI mouse model increased the wound closure rate and angiogenesis compared with an untreated irradiated group. Moreover, increased expression of VEGF and CD31 were observed in the wound tissue of co-treated mice compared with untreated irradiated mice. PRP stimulates the release of angiogenic factors from UCB-MSCs, and combined therapy of UCB-MSCs and PRP improves regeneration efficacy by enhancing angiogenesis in a CRWI model.

10.
Mol Cancer Ther ; 19(2): 479-489, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31672764

RESUMEN

Although chemo- or radiotherapy is usually performed in patients with colorectal cancer, the response is highly variable in locally rectal cancer. Therefore, additional studies are needed on predictable markers and the molecular mechanisms of chemo- and radiotherapy. Y box binding protein 1 (YB1) is an oncoprotein that is aberrantly expressed in many cancers, including colorectal cancer. However, to date there are no targeting agents or strategies to inhibit YB1 expression. Here, we investigate the oncogenic function of YB1 in colorectal cancer and methods to control its expression. We observed that YB1 expression level is correlated with colorectal cancer survival rate. Moreover, YB1 overexpression was associated with colorectal cancer lymph node metastasis and invasion. We also found that radiation exposure increased YB1 expression, which led to radioresistant colorectal cancer, mediated through the activation of cancer stem cell marker CD44 and PI3K/AKT/mTOR signaling. This study revealed, by both in vitro and in vivo assays, that depletion of YB1 could reduce cell proliferation and motility in colorectal cancer. We further demonstrated that the PI3K/mTOR inhibitor BEZ235 suppressed YB1 expression and enhanced the cytotoxicity of radiation. In addition, combined treatment with BEZ235 and radiation showed a significant antitumor response in an in vivo mouse xenograft model. Taken together, our results provide evidence that the activation of YB1 is a major factor in radioresistance and suggest that targeting YB1-mediated signaling is a promising therapeutic strategy for colorectal cancer.

11.
Front Pharmacol ; 10: 892, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31474856

RESUMEN

Background and Aims: Radiation-induced intestinal injury occurred in application of radiotherapy for abdominal and pelvic cancers or in nuclear accidents. Radiation-induced enteritis may be considered an ideal model of gastrointestinal inflammation. The endothelium is a crucial component of inflammation, and the endothelial dysfunction following radiation exposure induces the intestinal proinflammatory response and progression of radiation enteritis. Baicalein (5,6,7-trihydroxyflavonoid) is a flavonoid from Scutellaria baicalensis used in oriental herbal medicine. Baicalein has been found to have multiple beneficial properties including antioxidant, anti-inflammatory, anti-allergic, and anti-cancer activities. Here, we investigated the therapeutic effects of baicalein on endothelial dysfunction in radiation-induced intestinal inflammation. Materials and Methods: We performed histological analysis, bacterial translocation, and intestinal permeability assays and also assessed infiltration of leukocytes and inflammatory cytokine expression using a mouse model of radiation-induced enteritis. In addition, to investigate the effect of baicalein in endothelial dysfunction, we analyzed endothelial-derived adherent molecules in human umbilical vein endothelial cells (HUVECs) and irradiated intestinal tissue. Results: Histological damage such as shortening of villi length and impaired intestinal crypt function was observed in the radiation-induced enteritis mouse model. Intestinal damage was attenuated in baicalein-treated groups with improvement of intestinal barrier function. Baicalein inhibited the expression of radiation-induced adherent molecules in HUVECs and intestine of irradiated mouse and decreased leukocyte infiltration in the radiation-induced enteritis. Conclusions: Baicalein could accelerate crypt regeneration via recovery of endothelial damage. Therefore, baicalein has a therapeutic effect on radiation-induced intestinal inflammation by attenuating endothelial damage.

12.
J Transl Med ; 17(1): 295, 2019 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-31462256

RESUMEN

BACKGROUND: The skin is impacted by every form of external radiation therapy. However, effective therapeutic options for severe, acute radiation-induced skin reactions are limited. Although platelet-rich plasma (PRP) is known to improve cutaneous wound healing, its effects in the context of high-dose irradiation are still poorly understood. METHODS: We investigated the regenerative functions of PRP by subjecting the dorsal skin of mice to local irradiation (40 Gy) and exposing HaCaT cells to gamma rays (5 Gy). The cutaneous benefits of PRP were gauged by wound size, histologic features, immunostains, western blot, and transepithelial water loss (TEWL). To assess the molecular effects of PRP on keratinocytes of healing radiation-induced wounds, we evaluated AKT signaling. RESULTS: Heightened expression of keratin 14 (K14) was documented in irradiated HaCaT cells and skin tissue, although the healing capacity of injured HaCaT cells declined. By applying PRP, this capacity was restored via augmented AKT signaling. In our mouse model, PRP use achieved the following: (1) healing of desquamated skin, acutely injured by radiation; (2) activated AKT signaling, improving migration and proliferation of K14 cells; (3) greater expression of involucrin in keratin 10 cells and sebaceous glands; and (4) reduced TEWL, strengthening the cutaneous barrier function. CONCLUSIONS: Our findings indicate that PRP enhances the functions of K14 cells via AKT signaling, accelerating the regeneration of irradiated skin. These wound-healing benefits may have merit in a clinical setting.


Asunto(s)
Plasma Rico en Plaquetas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Traumatismos por Radiación/complicaciones , Transducción de Señal , Piel/lesiones , Cicatrización de Heridas , Animales , Línea Celular , Proliferación Celular/efectos de la radiación , Modelos Animales de Enfermedad , Humanos , Queratinocitos/patología , Queratinocitos/efectos de la radiación , Queratinas/metabolismo , Ratones , Transducción de Señal/efectos de la radiación , Piel/patología , Piel/efectos de la radiación , Cicatrización de Heridas/efectos de la radiación , Rayos X
13.
Cancer Sci ; 110(9): 2834-2845, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31278880

RESUMEN

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5-fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X-linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor ß receptor 2-mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Metformina/farmacología , Fenformina/farmacología , Neoplasias del Recto/terapia , Transducción de Señal/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Quimioradioterapia/métodos , Colon/patología , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de la radiación , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Humanos , Masculino , Metformina/uso terapéutico , Ratones , Ratones Desnudos , Recurrencia Local de Neoplasia , Fenformina/uso terapéutico , Neoplasias del Recto/patología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de la radiación , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Cancer Sci ; 110(7): 2226-2236, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31102316

RESUMEN

Hyaluronic acid synthase 2 (HAS2) is suggested to play a critical role in malignancy and is abnormally expressed in many carcinomas. However, its role in colorectal cancer (CRC) malignancy and specific signaling mechanisms remain obscure. Here, we report that HAS2 was markedly increased in both CRC tissue and malignant CRC cell lines. Depletion of HAS2 in HCT116 and DLD1 cells, which express high levels of HAS2, critically increased sensitivity of radiation/oxaliplatin-mediated apoptotic cell death. Moreover, downregulation of HAS2 suppressed migration, invasion and metastasis in nude mice. Conversely, ectopic overexpression of HAS2 in SW480 cells, which express low levels of HAS2, showed the opposite effect. Notably, HAS2 loss- and gain-of-function experiments revealed that it regulates CRC malignancy through TGF-ß expression and SMAD2/Snail downstream components. Collectively, our findings suggest that HAS2 contributes to malignant phenotypes of CRC, at least partly, through activation of the TGF-ß signaling pathway, and shed light on the novel mechanisms behind the constitutive activation of HAS2 signaling in CRC, thereby highlighting its potential as a therapeutic target.


Asunto(s)
Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , Hialuronano Sintasas/metabolismo , Tolerancia a Radiación , Transducción de Señal , Animales , Línea Celular Tumoral , Movimiento Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Hialuronano Sintasas/genética , Ratones , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Análisis de Matrices Tisulares , Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia Arriba
15.
Cells ; 8(4)2019 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-30935019

RESUMEN

Autophagy is a cellular process that disrupts and uses unnecessary or malfunctioning components for cellular homeostasis. Evidence has shown a role for autophagy in tumor cell survival, but the molecular determinants that define sensitivity against autophagic regulation in cancers are not clear. Importantly, we found that breast cancer cells with low expression levels of a zinc-finger protein, ZNF143 (MCF7 sh-ZNF143), showed better survival than control cells (MCF7 sh-Control) under starvation, which was compromised with chloroquine, an autophagy inhibitor. In addition, there were more autophagic vesicles in MCF7 sh-ZNF143 cells than in MCF7 sh-Control cells, and proteins related with the autophagic process, such as Beclin1, p62, and ATGs, were altered in cells with less ZNF143. ZNF143 knockdown affected the stability of p53, which showed a dependence on MG132, a proteasome inhibitor. Data from proteome profiling in breast cancer cells with less ZNF143 suggest a role of NAD(P)H quinone dehydrogenase 1(NQO1) for p53 stability. Taken together, we showed that a subset of breast cancer cells with low expression of ZNF143 might exhibit better survival via an autophagic process by regulating the p53⁻Beclin1 axis, corroborating the necessity of blocking autophagy for the best therapy.


Asunto(s)
Beclina-1/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Transducción de Señal , Estrés Fisiológico , Transactivadores/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis , Autofagia , Neoplasias de la Mama/ultraestructura , Línea Celular Tumoral , Supervivencia Celular , Supervivencia sin Enfermedad , Femenino , Humanos , Estabilidad Proteica , Vacuolas/metabolismo , Vacuolas/ultraestructura
16.
Int J Mol Sci ; 20(5)2019 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-30841658

RESUMEN

Radiation-induced enteropathy remains a major complication after accidental or therapeutic exposure to ionizing radiation. Recent evidence suggests that intestinal microvascular damage significantly affects the development of radiation enteropathy. Mesenchymal stem cell (MSC) therapy is a promising tool to regenerate various tissues, including skin and intestine. Further, photobiomodulation (PBM), or low-level light therapy, can accelerate wound healing, especially by stimulating angiogenesis, and stem cells are particularly susceptible to PBM. Here, we explored the effect of PBM on the therapeutic potential of MSCs for the management of radiation enteropathy. In vitro, using human umbilical cord blood-derived MSCs, PBM increased proliferation and self-renewal. Intriguingly, the conditioned medium from MSCs treated with PBM attenuated irradiation-induced apoptosis and impaired tube formation in vascular endothelial cells, and these protective effects were associated with the upregulation of several angiogenic factors. In a mouse model of radiation-induced enteropathy, treatment with PBM-preconditioned MSCs alleviated mucosal destruction, improved crypt cell proliferation and epithelial barrier functions, and significantly attenuated the loss of microvascular endothelial cells in the irradiated intestinal mucosa. This treatment also significantly increased angiogenesis in the lamina propria. Together, we suggest that PBM enhances the angiogenic potential of MSCs, leading to improved therapeutic efficacy for the treatment of radiation-induced enteropathy.


Asunto(s)
Síndrome de Radiación Aguda/terapia , Mucosa Intestinal/patología , Terapia por Luz de Baja Intensidad/métodos , Trasplante de Células Madre Mesenquimatosas/métodos , Neovascularización Fisiológica , Proteínas Angiogénicas/genética , Proteínas Angiogénicas/metabolismo , Animales , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de la radiación , Humanos , Mucosa Intestinal/irrigación sanguínea , Mucosa Intestinal/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL
17.
Cell Commun Signal ; 17(1): 12, 2019 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-30760304

RESUMEN

BACKGROUND: The existence of differentiated thyroid cells is critical to respond radioactive iodide treatment strategy in thyroid cancer, and loss of the differentiated phenotype is a trademark of iodide-refractive thyroid disease. While high-dose therapy has been beneficial to several cancer patients, many studies have indicated this clinical benefit was limited to patients having BRAF mutation. BRAF-targeted paired box gene-8 (PAX8), a thyroid-specific transcription factor, generally dysregulated in BRAF-mutated thyroid cancer. METHODS: In this study, thyroid iodine-metabolizing gene levels were detected in BRAF-transformed thyroid cells after low and high dose of ionizing radiation. Also, an mRNA-targeted approach was used to figure out the underlying mechanism of low (0.01Gyx10 or 0.1Gy) and high (2Gy) radiation function on thyroid cancer cells after BRAFV600E mutation. RESULTS: Low dose radiation (LDR)-induced PAX8 upregulation restores not only BRAF-suppressive sodium/iodide symporter (NIS) expression, one of the major protein necessary for iodine uptake in healthy thyroid, on plasma membrane but also regulate other thyroid metabolizing genes levels. Importantly, LDR-induced PAX8 results in decreased cellular transformation in BRAF-mutated thyroid cells. CONCLUSION: The present findings provide evidence that LDR-induced PAX8 acts as an important regulator for suppression of thyroid carcinogenesis through novel STAT3/miR-330-5p pathway in thyroid cancers.


Asunto(s)
Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/efectos de la radiación , Proteínas Proto-Oncogénicas B-raf/metabolismo , Glándula Tiroides/patología , Glándula Tiroides/efectos de la radiación , Animales , Carcinogénesis/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta en la Radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Hipotiroidismo/patología , Yodo/metabolismo , Ratones Mutantes , MicroARNs/genética , MicroARNs/metabolismo , Modelos Biológicos , Mutación/genética , Factor de Transcripción PAX8/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/radioterapia , Regulación hacia Arriba/genética , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Tuberc Respir Dis (Seoul) ; 82(1): 62-70, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29926551

RESUMEN

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancers have emerged as key predictive biomarkers in EGFR tyrosine kinase inhibitor (TKI) treatment. However, a few patients with wild-type EGFR also respond to EGFR TKIs. This study investigated the factors predicting successful EGFR TKI treatment in lung adenocarcinoma patients with wild-type EGFR. METHODS: We examined 66 patients diagnosed with lung adenocarcinoma carrying wide-type EGFR who were treated with EGFR TKIs. The EGFR gene copy number was assessed by silver in situ hybridization (SISH). We evaluated the clinical factors and EGFR gene copy numbers that are associated with a favorable clinical response to EGFR TKIs. RESULTS: The objective response rate was 12.1%, while the disease control rate was 40.9%. EGFR SISH analysis was feasible in 23 cases. Twelve patients tested EGFR SISH-positive, and 11 were EGFR SISH-negative, with no significant difference in tumor response and survival between EGFR SISH-positive and -negative patients. The overall median progression-free survival (PFS) and overall survival (OS) of 66 patients were 2.1 months and 9.7 months, respectively. Female sex and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 were independent predictors of PFS. ECOG PS 0-1 and a low tumor burden of extrathoracic metastasis were independent predictors of good OS. CONCLUSION: Factors such as good PS, female sex, and low tumor burden may predict favorable outcomes following EGFR TKI therapy in patients with EGFR wild-type lung adenocarcinoma. However, EGFR gene copy number was not predictive of survival.

19.
Hum Pathol ; 81: 176-183, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30026037

RESUMEN

PIN2/TERF1 interacting telomerase inhibitor 1 (PINX1) is a telomerase inhibitor located on human chromosome 8p23 and also acts as a tumor suppressor in several types of cancers, including breast, gastric, ovarian, and bladder cancer. However, the role of PINX1 expression in papillary thyroid carcinoma (PTC) has not been defined. Therefore, we investigated the role of PINX1 expression in PTC by analyzing the correlation between PINX1 expression and various clinicopathological factors. Immunohistochemistry for PINX1 was performed using a tissue microarray of samples taken from the 160 patients with PTC. We also assessed mRNA and protein expression for PINX1 via quantitative real-time polymerase chain reaction and immunohistochemical analysis. Positive staining for PINX1 was found in 16.3% of PTC cases. PINX1 expression was significantly associated with tumor size, lymph node metastasis, telomerase reverse transcriptase, promoter mutation and recurrence. PINX1 mRNA expression was more pronounced in the recurrent group than in the nonrecurrent group. In addition, results of the binary logistic regression model showed that PINX1 protein expression had a significant influence on recurrence. We concluded that PINX1 expression was associated with several clinicopathological factors and had a significant influence on recurrence in patients with PTC. Therefore, PINX1 expression could be a useful prognostic marker in PTC patients.


Asunto(s)
Biomarcadores de Tumor/análisis , Cáncer Papilar Tiroideo/química , Neoplasias de la Tiroides/química , Proteínas Supresoras de Tumor/análisis , Adulto , Anciano , Biomarcadores de Tumor/genética , Proteínas de Ciclo Celular , Femenino , Humanos , Inmunohistoquímica , Escisión del Ganglio Linfático , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/secundario , Cáncer Papilar Tiroideo/terapia , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Tiroidectomía , Análisis de Matrices Tisulares , Resultado del Tratamiento , Carga Tumoral , Proteínas Supresoras de Tumor/genética , Adulto Joven
20.
Sci Rep ; 8(1): 9277, 2018 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-29915190

RESUMEN

Radiation exposure severely damages the hematopoietic system. Although several radio-protectors have been proposed to prevent radiation-induced damage, most agents have limited efficacy. In the present study, we investigated whether mesenchymal stem cells (MSCs) could contribute to the expansion of hematopoietic cells and mitigate radiation-induced hematopoietic injury in vitro and in vivo. We found that co-culture with MSCs promoted hematopoietic progenitor/stem cell (HPSCs) maintenance by providing a bone marrow-like microenvironment. In addition, we showed that MSCs prevented radiation-induced damage to HPSCs, as evidenced by the lack of DNA damage and apoptosis. Intravenously injected MSCs rapidly migrated to the bone marrow (BM) and prevented loss of BM cellularity, which reduced lethality and ameliorated pancytopenia in the BM of whole body-irradiated mice. We demonstrated that MSC-derived Jagged1 attenuated radiation-induced cytotoxicity of HPSCs, and that this was mediated by Notch signaling and expression of downstream proteins Bcl2 and p63 in HPSCs. In addition, Notch2 depletion significantly reduced the MSC-mediated radio-protective effect in human- and mouse-derived HPSCs. Collectively, our data show that activation of Notch and its associated downstream signaling pathways prevent radiation-induced hematopoietic injury. Therefore, enhancing Jagged1-Notch2 signaling could provide therapeutic benefit by protecting the hematopoietic system against damage after radiation.


Asunto(s)
Células Madre Hematopoyéticas/patología , Células Madre Mesenquimatosas/metabolismo , Traumatismos por Radiación/patología , Receptor Notch2/metabolismo , Animales , Apoptosis/efectos de la radiación , Médula Ósea/patología , Médula Ósea/efectos de la radiación , Células Madre Hematopoyéticas/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Traumatismos por Radiación/metabolismo , Radiación Ionizante , Proteínas Serrate-Jagged/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Cordón Umbilical/citología
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