RESUMEN
Radiotherapy resistance is an important and urgent challenge in the clinical management of esophageal squamous carcinoma (ESCC). However, the factors mediating the ESCC resistance to radiotherapy and its underlying molecular mechanisms are not fully clarified. Our previous studies have demonstrated the critical role of DNA polymerase iota (POLI) in ESCC development and progression, here, we aimed to investigate the involvement of POLI in ESCC radiotherapy resistance and elucidate the underlying molecular mechanism. We found that highly expressed POLI was correlated with shorter overall survival of ESCC patients received radiotherapy. Down-regulation of POLI sensitized ESCC to IR, prolonged γH2AX foci in nuclei and comet tails after IR. HR but not NHEJ repair is inhibited in POLI-deficient ESCC cells. POLI stabilizes RAD51 protein via competitively binding with and blocking the interaction between RAD51 and E3 ligase XIAP and XIAP-mediated ubiquitination. Furthermore, loss of POLI leads to the activation of GAS signaling. Our findings provide novel insight into the role of POLI in the development of radioresistance mediated by stabilizing RAD51 protein in ESCC.
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Ionizing radiation (IR) poses a growing threat to human health, and thus ideal radioprotectors with high efficacy and low toxicity still receive widespread attention in radiation medicine. Despite significant progress made in conventional radioprotectants, high toxicity, and low bioavailability still discourage their application. Fortunately, the rapidly evolving nanomaterial technology furnishes reliable tools to address these bottlenecks, opening up the cutting-edge nano-radioprotective medicine, among which the intrinsic nano-radioprotectants characterized by high efficacy, low toxicity, and prolonged blood retention duration, represent the most extensively studied class in this area. Herein, we made the systematic review on this topic, and discussed more specific types of radioprotective nanomaterials and more general clusters of the extensive nano-radioprotectants. In this review, we mainly focused on the development, design innovations, applications, challenges, and prospects of the intrinsic antiradiation nanomedicines, and presented a comprehensive overview, in-depth analysis as well as an updated understanding of the latest advances in this topic. We hope that this review will promote the interdisciplinarity across radiation medicine and nanotechnology and stimulate further valuable studies in this promising field.
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DNA-PKcs is a key regulator of DNA double-strand break repair. Apart from its canonical role in the DNA damage response, DNA-PKcs is involved in the cellular response to oxidative stress (OS), but its exact role remains unclear. Here, we report that DNA-PKcs-deficient human cells display depolarized mitochondria membrane potential (MMP) and reoriented metabolism, supporting a role for DNA-PKcs in oxidative phosphorylation (OXPHOS). DNA-PKcs directly interacts with mitochondria proteins ANT2 and VDAC2, and formation of the DNA-PKcs/ANT2/VDAC2 (DAV) complex supports optimal exchange of ADP and ATP across mitochondrial membranes to energize the cell via OXPHOS and to maintain MMP. Moreover, we demonstrate that the DAV complex temporarily dissociates in response to oxidative stress to attenuate ADP-ATP exchange, a rate-limiting step for OXPHOS. Finally, we found that dissociation of the DAV complex is mediated by phosphorylation of DNA-PKcs at its Thr2609 cluster by ATM kinase. Based on these findings, we propose that the coordination between the DAV complex and ATM serves as a novel oxidative stress checkpoint to decrease ROS production from mitochondrial OXPHOS and to hasten cellular recovery from OS.
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Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Unión al ADN , Estrés Oxidativo , Humanos , Adenosina Trifosfato/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Mitocondrias/metabolismo , FosforilaciónRESUMEN
TAB182 (also named TNKS1BP1), a binding protein of tankyrase 1, has been found to participate in DNA repair. Our previous study has revealed the involvement of TAB182 in the radioresistance of esophageal squamous cell carcinoma (ESCC) cells. However, whether TAB182 contributes to the ESCC tumorigenesis and progression remains unclear. In this study, we found that highly expressed TAB182 is closely associated with a poor prognosis of patients with ESCC. TAB182 silencing reduced ESCC cell proliferation and invasion in vitro, tumorigenicity and metastasis in vivo. RNA-seq and IP-MS analysis revealed that TAB182 could affect the ß-catenin signaling pathway via interacting with ß-catenin. Furthermore, TAB182 prevented ß-catenin to be phosphorylated by GSK3ß and recruited four and a half of LIM-only protein 2 (FHL2), which thereby promoted ß-catenin nucleus translocation to result in activation of the downstream targets transcription in ESCC cells. Our findings demonstrate that TAB182 enhances tumorigenesis of esophageal cancer by promoting the activation of the ß-catenin signaling pathway, which provides new insights into the molecular mechanisms by which TAB182 accelerates progression of ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Tanquirasas , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Regulación Neoplásica de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteínas con Homeodominio LIM/genética , Proteínas Musculares/genética , Tanquirasas/genética , Factores de Transcripción/metabolismoRESUMEN
Renal cell carcinoma (RCC) is one of the most aggressive urological malignancies and has a poor prognosis, especially in patients with metastasis. Although RCC is traditionally considered to be radioresistant, radiotherapy (RT) is still a common treatment for palliative management of metastatic RCC. Novel approaches are urgently needed to overcome radioresistance of RCC. Black phosphorus quantum dots (BPQDs) have recently received great attention due to their unique physicochemical properties and good biocompatibility. In the present study, we found that BPQDs enhance ionizing radiation (IR)-induced apoptotic cell death of RCC cells. BPQDs treatment significantly increases IR-induced DNA double-strand breaks (DSBs), as indicated by the neutral comet assay and the DSBs biomarkers γH2AX and 53BP1. Mechanistically, BPQDs can interact with purified DNA-protein kinase catalytic subunit (DNA-PKcs) and promote its kinase activity in vitro. BPQDs impair the autophosphorylation of DNA-PKcs at S2056, and this site phosphorylation is essential for efficient DNA DSBs repair and the release of DNA-PKcs from the damage sites. Consistent with this, BPQDs suppress nonhomologous end-joining (NHEJ) repair and lead to sustained high levels of autophosphorylated DNA-PKcs on the damaged sites. Moreover, animal experiments indicate that the combined approach with both BPQDs and IR displays better efficacy than monotreatment. These findings demonstrate that BPQDs have potential applications in radiosensitizing RCC cells.
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Carcinoma de Células Renales , Neoplasias Renales , Puntos Cuánticos , Animales , Carcinoma de Células Renales/radioterapia , ADN/metabolismo , Reparación del ADN , Humanos , Neoplasias Renales/radioterapia , Fósforo , Polinucleótido 5'-Hidroxil-Quinasa/metabolismo , Tolerancia a RadiaciónRESUMEN
Chromosomal instability (CIN) is a driving force for cancer development. The most common causes of CIN include the dysregulation of the spindle assembly checkpoint (SAC), which is a surveillance mechanism that prevents premature chromosome separation during mitosis by targeting anaphase-promoting complex/cyclosome (APC/C). DAB2IP is frequently silenced in advanced prostate cancer (PCa) and is associated with aggressive phenotypes of PCa. Our previous study showed that DAB2IP activates PLK1 and functions in mitotic regulation. Here, we report the novel mitotic phosphorylation of DAB2IP by Cdks, which mediates DAB2IP's interaction with PLK1 and the activation of the PLK1-Mps1 pathway. DAB2IP interacts with Cdc20 in a phosphorylation-independent manner. However, the phosphorylation of DAB2IP inhibits the ubiquitylation of Cdc20 in response to SAC, and blocks the premature release of the APC/C-MCC. The PLK1-Mps1 pathway plays an important role in mitotic checkpoint complex (MCC) assembly. It is likely that DAB2IP acts as a scaffold to aid PLK1-Mps1 in targeting Cdc20. Depletion or loss of the Cdks-mediated phosphorylation of DAB2IP destabilizes the MCC, impairs the SAC, and increases chromosome missegregation and subsequent CIN, thus contributing to tumorigenesis. Collectively, these results demonstrate the mechanism of DAB2IP in SAC regulation and provide a rationale for targeting the SAC to cause lethal CIN against DAB2IP-deficient aggressive PCa, which exhibits a weak SAC.
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Puntos de Control del Ciclo Celular/genética , Inestabilidad Cromosómica/genética , Mitosis/genética , Oncogenes/genética , Huso Acromático/metabolismo , Humanos , Fosforilación , Transducción de Señal , TransfecciónRESUMEN
The PI3K/AKT/mTOR signaling pathway is constitutively active in PTEN-deficient cancer cells, and its targeted inhibition has significant anti-tumor effects. However, the efficacy of targeted therapies is often limited due to drug resistance. The relevant signaling pathways in PTEN-deficient cancer cells treated with the PI3K/mTOR inhibitor BEZ235 were screened using a phosphokinase array, and further validated following treatment with multiple PI3K/AKT/mTOR inhibitors or AKT knockdown. The correlation between PTEN expression levels and STAT3 kinase phosphorylation in the tissue microarrays of gastric cancer patients was analyzed by immunohistochemistry. Cell proliferation and clonogenic assays were performed on the suitably treated PTEN-deficient cancer cells. Cytokine arrays, small molecule inhibition and knockdown assays were performed to identify related factors. PTEN-deficient tumor xenografts were established in nude mice that were treated with PI3K/AKT/mTOR and/or STAT3 inhibitors. PTEN deficiency was positively correlated with low STAT3 activity. PI3K/mTOR inhibitors increased the expression and secretion of macrophage migration inhibitory factor (MIF) and activated the JAK1/STAT3 signaling pathway. Both cancer cells and in vivo tumor xenografts showed that the combined inhibition of PI3K/AKT/mTOR and STAT3 activity enhanced the inhibitory effect of BEZ235 on the proliferation of PTEN-deficient cancer cells. Our findings provide a scientific basis for a novel treatment strategy in cancer patients with PTEN deficiency.
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Combining targeted therapeutic agents is an attractive cancer treatment strategy associated with high efficacy and low toxicity. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is an essential factor in DNA damage repair. Studies from us and others have revealed that DNA-PKcs also plays an important role in normal mitosis progression. Histone deacetylase (HDACs) inhibitors commonly lead to mitotic aberration and have been approved for treating various cancers in the clinic. We showed that DNA-PKcs depletion or kinase activity inhibition increases cancer cells' sensitivity to HDACs inhibitors in vitro and in vivo. DNA-PKcs deficiency significantly enhances HDACs inhibitors (HDACi)-induced mitotic arrest and is followed by apoptotic cell death. Mechanistically, we found that DNA-PKcs binds to HDAC6 and facilitates its acetylase activity. HDACi is more likely to impair HDAC6-induced deacetylation of HSP90 and abrogate HSP90's chaperone function on Aurora A, a critical mitotic kinase that regulates centrosome separation and mitotic spindle assembly in DNA-PKcs-deficient cells. Our current work indicates crosstalk between DNA-PKcs and HDACs signaling pathways, and highlights that the combined targeting of DNA-PKcs and HDACs can be used in cancer therapy. Abbreviations: DNA-PKcs, DNA-dependent protein kinase catalytic subunit, HDACs, Histone deacetylases, DSBs, DNA double-strand breaks, ATM, ataxia telangiectasia mutated, ATR, ATM-Rad3-related.
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Proteína Quinasa Activada por ADN/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Histona Desacetilasa 6/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de Ciclo Celular/metabolismo , División del Núcleo Celular/genética , División del Núcleo Celular/fisiología , Daño del ADN/genética , Reparación del ADN/genética , Histona Desacetilasa 6/genética , Humanos , Proteínas Supresoras de Tumor/metabolismoRESUMEN
[This corrects the article DOI: 10.1155/2018/2968252.].
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Vanillin is a natural compound endowed with antioxidant and anti-mutagenic properties. We previously identified the vanillin derivative VND3207 with strong radio-protective and antioxidant effects and found that VND3207 confers survival benefit and protection against radiation-induced intestinal injury (RIII) in mice. We also observed that VND3207 treatment enhanced the expression level of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) in human lymphoblastoid cells with or without γ-irradiation. DNA-PKcs is a critical component of DNA double strand break repair pathway and also regulates mitotic progression by stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. In the present study, we found that VND3207 protected intestinal epithelial cells in vitro against ionizing radiation by promoting cell proliferation and inhibiting cell apoptosis. In addition, VND3207 promoted DNA-PKcs activity by increasing autophosphorylation at S2056 site. Consistent with this, VND3207 significantly decreased the number of γH2AX foci and mitotic catastrophe after radiation. DNA-PKcs deficiency abolished these VND3207 radio-protective effects, indicating that DNA-PKcs activation is essential for VND3207 activity. In conclusion, VND3207 promoted intestinal repair following radiation injury by regulating the DNA-PKcs pathway.
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Benzaldehídos/farmacología , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/metabolismo , Proteína Quinasa Activada por ADN/metabolismo , Mucosa Intestinal/efectos de los fármacos , Traumatismos Experimentales por Radiación/prevención & control , Protectores contra Radiación/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Proteína Quinasa Activada por ADN/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Células Epiteliales/efectos de la radiación , Rayos gamma/efectos adversos , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de la radiación , Mutación con Pérdida de Función , Masculino , Ratones , Fosforilación/efectos de los fármacos , Traumatismos Experimentales por Radiación/patología , Protectores contra Radiación/uso terapéuticoRESUMEN
As a new kind of two-dimensional nanomaterial, black phosphorus (BP) nanosheets have attracted significant interests in diverse bioapplications due to their unique structure and physicochemical properties. Despite BP nanosheets' advantages in cancer diagnosis and therapy applications, their biosafety issues are still unclear. Herein, we report a systematic study on the In Vitro and In Vivo toxicity of BP nanosheets. In Vitro experiments showed that BP nanosheets decrease the viability of human bronchial epithelial cells in a time- and dose-dependent manner. The mechanism study showed that BP nanosheets interfere with mitochondrial membrane potential, leading to an increase in intracellular ROS. These responses further initiated the activation of the caspase-3 and ultimately dictated cells to undergo apoptosis. Then, the In Vivo experiments of BP nanosheets revealed that single injection of BP nanosheets does not cause toxicity to mice in a short period of time, whereas multiple injections of BP nanosheets exert adverse effects on liver and renal function of mice. Interestingly, the liver and renal function of the mice returned to normal after a recovery period. Our findings provide insights into the rational design of BP nanosheets and guide their applications in biomedical fields.
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Nanoestructuras , Fósforo , Animales , Apoptosis , Ratones , Nanoestructuras/toxicidad , Fósforo/toxicidadRESUMEN
Graphene quantum dots (GQDs) have gained significant attention in various biomedical applications. The physicochemical properties of these nanoparticles, including toxic effects, are largely determined by their surface modifications. Previous studies have demonstrated high in vitro cytotoxicity of the hydroxylated GQDs (OH-GQDs). The focus of this study was on the intestinal toxicity of OH-GQDs. Briefly, C57BL/6J mice were given daily oral gavage of 0.05, 0.5 or 5 mg/kg OH-GQD for 7 days, and the indices of intestinal damage were evaluated. Higher doses of the OH-GQDs caused significant intestinal injuries, such as enhanced intestinal permeability, shortened villi and crypt loss. The number of Lgr5+ intestinal stem cells also decreased dramatically upon OH-GQDs exposure, which also inhibited the Ki67+ proliferative progenitor cells. In addition, an increased number of crypt cells harboring the oxidized DNA base 8-OHdG and γH2AX foci were also detected in the intestines of OH-GQD-treated mice. Mechanistically, the OH-GQDs up-regulated both total and phosphorylated p53. Consistent with this, the average number of TUNEL+ and cleaved caspase-3+ apoptotic intestinal epithelial cells were significantly increased after OH-GQDs treatment. Finally, a 3-dimensional organoid culture was established using isolated crypts, and OH-GQDs treatment significantly reduced the size of the surviving intestinal organoids. Taken together, the intestinal toxicity of the OH-GQDs should be taken into account during biomedical applications.
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Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Grafito/toxicidad , Mucosa Intestinal/efectos de los fármacos , Puntos Cuánticos/toxicidad , Células Madre/efectos de los fármacos , Administración Oral , Animales , Apoptosis/genética , Proliferación Celular/genética , Daño del ADN , Grafito/química , Hidroxilación , Mucosa Intestinal/patología , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Permeabilidad , Puntos Cuánticos/química , Células Madre/patología , Propiedades de Superficie , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The intestine is a highly radiosensitive tissue that is susceptible to structural and functional damage due to systemic as well as localized radiation exposure. Unfortunately, no effective prophylactic or therapeutic agents are available at present to manage radiation-induced intestinal injuries. We observed that the vanillin derivative VND3207 improved the survival of lethally irradiated mice by promoting intestinal regeneration and increasing the number of surviving crypts. Pre-treatment with VND3207 significantly increased the number of Lgr5+ intestinal stem cells (ISCs) and their daughter cells, the transient Ki67+ proliferating cells. Mechanistically, VND3207 decreased oxidative DNA damage and lipid peroxidation and maintained endogenous antioxidant status by increasing the level of superoxide dismutase and total antioxidant capacity. In addition, VND3207 maintained appropriate levels of activated p53 that triggered cell cycle arrest but were not sufficient to induce NOXA-mediated apoptosis, thus ensuring DNA damage repair in the irradiated small intestinal crypt cells. Furthermore, VND3207 treatment restores the intestinal bacterial flora structures altered by TBI exposure. In conclusion, VND3207 promoted intestinal repair following radiation injury by reducing reactive oxygen species-induced DNA damage and modulating appropriate levels of activated p53 in intestinal epithelial cells.
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Benzaldehídos/farmacología , Microbioma Gastrointestinal/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Receptores Acoplados a Proteínas G/genética , Proteína p53 Supresora de Tumor/genética , Animales , Antioxidantes/farmacología , Benzaldehídos/química , Linaje de la Célula/efectos de los fármacos , Linaje de la Célula/efectos de la radiación , Microbioma Gastrointestinal/efectos de la radiación , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Intestinos/efectos de los fármacos , Ratones , Estrés Oxidativo/efectos de los fármacos , Exposición a la Radiación/efectos adversos , Traumatismos por Radiación/genética , Traumatismos por Radiación/prevención & control , Tolerancia a Radiación/genética , Transducción de Señal/efectos de la radiación , Células Madre/efectos de los fármacosRESUMEN
The E3 ubiquitin ligase RAD18 has been identified as an oncoprotein that exhibits prometastatic properties in various types of cancer; however, the role of RAD18 in cervical cancer (CC) remains unclear. In the present study, it was revealed that increased expression of RAD18 was associated with worse prognosis of patients with CC. Knockdown of endogenous RAD18 suppressed the motility and invasiveness of CC cells, as evaluated by Transwell assays. mRNA sequencing revealed that silencing RAD18 altered the expression profile of proinflammatory mediators, such as interleukin1ß (IL1ß). Furthermore, exogenous IL1ß treatment rescued RAD18mediated CC cell invasion. These findings indicated an underlying mechanism via which RAD18 promotes CC progression, suggesting that RAD18 may be a potential biomarker and therapeutic target for malignant CC.
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Movimiento Celular , Proteínas de Unión al ADN/metabolismo , Interleucina-1beta/metabolismo , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias del Cuello Uterino/patologíaRESUMEN
The p53-inducible gene 3 (PIG3) is one of the p53-induced genes at the onset of apoptosis, which plays an important role in cell apoptosis and DNA damage response. Our previous study reported an oncogenic role of PIG3 associated with tumor progression and metastasis in non-small cell lung cancer (NSCLC). In this study, we further analyzed PIG3 mRNA expression in 504 lung adenocarcinoma (LUAD) and 501 lung squamous cell carcinoma (LUSC) tissues from The Cancer Genome Atlas database and we found that PIG3 expression was significantly higher in LUAD with lymph node metastasis than those without, while no difference was observed between samples with and without lymph node metastasis in LUSC. Gain and loss of function experiments were performed to confirm the metastatic role of PIG3 in vitro and to explore the mechanism involved in its oncogenic role in NSCLC metastasis. The results showed that PIG3 knockdown significantly inhibited the migration and invasion ability of NSCLC cells, and decreased paxillin, phospho-focal adhesion kinase (FAK) and phospho-Src kinase expression, while its overexpression resulted in the opposite effects. Blocking FAK with its inhibitor reverses PIG3 overexpression-induced cell motility in NSCLC cells, indicating that PIG3 increased cell metastasis through the FAK/Src/paxillin pathway. Furthermore, PIG3 silencing sensitized NSCLC cells to FAK inhibitor. In conclusion, our data revealed a role for PIG3 in inducing LUAD metastasis, and its role as a new FAK regulator, suggesting that it could be considered as a novel prognostic biomarker or therapeutic target in the treatment of LUAD metastasis.
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Adenocarcinoma del Pulmón/genética , Carcinoma de Células Escamosas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas/genética , Transducción de Señal , Regulación hacia Arriba , Células A549 , Adenocarcinoma del Pulmón/metabolismo , Adulto , Anciano , Animales , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Femenino , Quinasa 1 de Adhesión Focal/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Metástasis Linfática , Masculino , Ratones , Persona de Mediana Edad , Invasividad Neoplásica , Trasplante de Neoplasias , Fosforilación , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismoRESUMEN
DAB2IP (DOC2/DAB2 interactive protein) is downregulated in several cancer types, and its downregulation is involved in tumor cell proliferation, apoptosis, metastasis, and epithelial-mesenchymal transition (EMT). We aimed to investigate the potential role of DAB2IP in the development and progression of gastric cancer. DAB2IP levels were analyzed in human gastric cancer and adjacent normal tissues by Western blots and immunohistochemistry. Potential roles of DAB2IP in regulating gastric cancer cell growth and metastasis were examined by genetic manipulation in vitro. The molecular signaling was determined to understand the mechanisms of observed DAB2IP effects. DAB2IP level is lower in gastric cancer tissues as compared to paired normal tissues. Knockdown of DAB2IP enhanced gastric cancer cell growth and metastasis in vitro and promoted EMT progress at both protein and mRNA levels. Silencing DAB2IP activated extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, and the enhanced proliferation and migration ability induced by DAB2IP knockdown were reduced after incubation with U0126 in SGC7901 gastric cancer cells. Inhibition of DAB2IP enhances gastric cancer cell growth and metastasis through targeting the ERK1/2 signaling, indicating that it may serve as a potential target for treatment of gastric cancer.
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Graphene quantum dots (GQDs) have attracted significant interests due to their unique chemical and physical properties. In this study, we investigated the potential effects of hydroxyl-modified GQDs (OH-GQDs) on the human esophageal epithelial cell line HET-1A. Our data revealed significant cytotoxicity of OH-GQDs which decreased the viability of HET-1A in a dose and time-dependent manner. The moderate concentration (25 or 50 µg/ml) of OH-GQDs significantly blocked HET-1A cells in G0/G1 cell cycle phase. An increased percentage of γH2AX-positive and genomically unstable cells were also detected in cells treated with different doses of OH-GQDs (25, 50, and 100 µg/ml). Microarray data revealed that OH-GQDs treatment down-regulated genes related to DNA damage repair, cell cycle regulation and cytoskeleton signal pathways indicating a novel role of OH-GQDs. Consistent with the microarray data, OH-GQDs disrupted microtubule structure and inhibited microtubule regrowth around centrosomes in HET-1A cells. In conclusion, our findings provide important evidence for considering the application of OH-GQDs in biomedical fields.