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Highly activated aerobic glycolysis provides the metabolic requirements for tumor cell growth and proliferation. Erianin, a natural product isolated from Dendrobium chrysotoxum Lindl, has been reported to exert antitumor activity in multiple cancers. However, whether Erianin exerts inhibitory effects on aerobic glycolysis and the inherent mechanism remain poorly defined in non-small cell lung cancer (NSCLC). Here, we showed that Erianin inhibited the cell viability and proliferation, and induced apoptosis in NSCLC cells. Moreover, Erianin overtly suppressed aerobic glycolysis via decreasing HK2 expression. Mechanistically, Erianin dose-dependently curbed the Akt-GSK3ß signaling pathway phosphorylation activation, which afterwards downregulated HK2 expression. Meanwhile, Erianin inhibited HCC827 tumor growth in vivo. Taken together, our results suggest that the natural product Erianin can suppress aerobic glycolysis and exert potent anticancer effects via the Akt-GSK3ß signaling pathway in NSCLC cells.
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Human malignancies exhibit elevated levels of survivin, and have been linked to poor prognosis. Targeting survivin expression is a promising therapeutic strategy against cancer cells. Natural compounds have become a hot topic in research due to their non-toxic, non-invasive, and efficient treatment of multiple diseases. In this current investigation, it was discovered that Dioscin, as a natural compound, exerted profound antitumor activity against NSCLC cell lines, inhibiting NSCLC cell viability and promoting apoptosis. Further mechanistic studies showed that Dioscin promoted ubiquitination-mediated survivin degradation via strengthening the interaction between survivin and the E3 ubiquitin ligase Fbxl7. Furthermore, Dioscin exhibited a strong tumor suppressive effect in xenograft tumor models, and Dioscin treatment led to a notable decrease in tumor volume and weight. Based on our findings, Dioscin is expected to be a potential antitumor agent for non-small cell lung cancer treatment.
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Aerobic glycolysis is a typical metabolic rearrangement for tumorigenesis. Arecoline is of explicit carcinogenicity, numerous works demonstrate its mutagenicity, genotoxicity, and cytotoxicity. However, the effects of arecoline on aerobic glycolysis of esophageal epithelial cells remain unclear. In the present study, 5 µM arecoline efficiently increased HK2 expression to induce aerobic glycolysis in Het-1A-Are and NE2-Are cells. The mechanistic analysis showed that arecoline activated the Akt-c-Myc signaling pathway and reduced the GSK3ß-mediated phosphorylation of c-Myc on Thr58 to prevent its ubiquitination and destruction, subsequently promoting HK2 transcription and expression. Taken together, these results suggest that arecoline can induce aerobic glycolysis of esophageal epithelial cells and further confirm that arecoline is a carcinogen harmful to human health.
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Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Humanos , Arecolina , Línea Celular Tumoral , Células Epiteliales/metabolismo , Glucólisis , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx. Despite continuous improvement in treatment strategies, recurrence or persistence of cancer after radiotherapy is still inevitable, highlighting the need to identify therapeutic resistance factors and develop effective methods for NPC treatment. Herein, we found that TRAF4 is overexpressed in NPC cells and tissues. Knockdown TRAF4 significantly increased the radiosensitivity of NPC cells, possibly by inhibiting the Akt/Wee1/CDK1 axis, thereby suppressing survivin phosphorylation and promoting its degradation by FBXL7. TRAF4 is positively correlated with p-Akt and survivin in NPC tissues. High protein levels of TRAF4 were observed in acquired radioresistant NPC cells, and knockdown of TRAF4 overcomes radioresistant in vitro and the xenograft mouse model. Altogether, our study highlights the TRAF4-survivin axis as a potential therapeutic target for radiosensitization in NPC.
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Carcinoma , Neoplasias Nasofaríngeas , Humanos , Animales , Ratones , Carcinoma/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Survivin/genética , Survivin/metabolismo , Factor 4 Asociado a Receptor de TNF/metabolismo , Transducción de Señal , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Ubiquitinación/genéticaRESUMEN
The oncoprotein survivin plays a pivotal role in controlling cell division and preventing apoptosis by inhibiting caspase activation. Its significant contribution to tumorigenesis and therapeutic resistance has been well established. Isoliquiritigenin (ISL), a natural compound, has been recognized for its powerful inhibitory effects against various tumors. However, whether ISL exerts regulatory effects on survivin and its underlying mechanism in oral squamous cell carcinoma (OSCC) remains unclear. Here, we found that ISL inhibited the viability and colony formation of OSCC, and promoted their apoptosis. The immunoblotting data showed that ISL treatment significantly decreased survivin expression. Mechanistically, ISL suppressed survivin phosphorylation on Thr34 by deregulating Akt-Wee1-CDK1 signaling, which facilitated survivin for ubiquitination degradation. ISL inhibited CAL27 tumor growth and decreased p-Akt and survivin expression in vivo. Meanwhile, survivin overexpression caused cisplatin resistance of OSCC cells. ISL alone or combined with cisplatin overcame chemoresistance in OSCC cells. Overall, our results revealed that ISL exerted potent inhibitory effects via inducing Akt-dependent survivin ubiquitination in OSCC cells.
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Carcinoma de Células Escamosas , Chalconas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Survivin/farmacología , Survivin/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos , Apoptosis , Chalconas/farmacología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Línea Celular Tumoral , Proliferación CelularRESUMEN
Apoptosis alteration is responsible for tumorigenesis and tumor resistance to therapies. The natural product Tanshinone IIA (Tan IIA) exhibits potent inhibitory effects against various tumors. However, the effect of Tan IIA on apoptosis and its underlying mechanism remains elusive in oral squamous cell carcinoma (OSCC). Here, we demonstrated that Tan IIA dose-dependently suppressed cell viability and colony formation in CAL27, SCC4, and SCC25 cells. Moreover, Tan IIA inhibited Akt activation from inducing Foxo3a dephosphorylation and PUMA-mediated apoptosis. PUMA or Foxo3a knockdown compromised the inhibitory effect of Tan IIA on OSCC cells. Tan IIA administration inhibited CAL27-deprived xenograft tumor growth and increased PUMA expression in vivo. Tan IIA synergistically intensified the efficacy of CDDP/5-FU-based chemotherapy on OSCC cells. Overall, our results revealed that Tan IIA exerted potent antitumor effects via promoting PUMA-mediated apoptosis in OSCC cells.
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Survivin is a bifunctional protein that plays crucial roles in tumorigenesis. In the present study, we discovered that the natural product gastrodin suppressed the cell viability and colony formation of non-small cell lung cancer (NSCLC) cell lines A549, HCC827, and H460 in a dose-dependent manner. In addition, gastrodin enhanced the protein levels of cleaved-caspase 3 by activating the endogenous mitochondrial apoptosis pathway. Gastrodin inhibits protein kinase B (Akt)/WEE1/cyclin-dependent kinase 1 (CDK1) signaling to downregulate survivin Thr34 phosphorylation. Survivin Thr34 dephosphorylation caused by gastrodin interfered with the binding of ubiquitin-specific protease 19 (USP19), which eventually destabilized survivin. We revealed that the growth of NSCLC xenograft tumors was markedly suppressed by gastrodin in vivo. Furthermore, gastrodin overcomes pemetrexed resistance in vivo or in vitro. Our results suggest that gastrodin is a potential antitumor agent by reducing survivin in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Survivin/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Pemetrexed/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , EndopeptidasasRESUMEN
PURPOSE: Chemoresistance is a primary factor for treatment failure and tumor recurrence in non-small cell lung cancer (NSCLC) patients. The oncoprotein survivin is commonly upregulated in human malignancies and is associated with poor prognosis, but its effect on carcinogenesis and chemoresistance in NSCLC is not yet evident, and to explore an effective inhibitor targeting survivin expression is urgently needed. METHODS: The protumor characteristics of survivin and antitumor activities of bergenin in NSCLC cells were examined by MTS, colony formation assays, immunoblot, immunohistochemistry, and in vivo xenograft development. RESULTS: Survivin was upregulated in non-small cell lung cancer (NSCLC) tissues, while its depletion inhibited NSCLC tumorigenesis. The current study focused on bergenin, identifying its effective antitumor effect on NSCLC cells both in vivo and in vitro. The results showed that bergenin could inhibit cell proliferation and induce the intrinsic pathway of apoptosis via downregulating survivin. Mechanistically, bergenin reduced the phosphorylation of survivin via inhibiting the Akt/Wee1/CDK1 signaling pathway, thus resulting in enhanced interaction between survivin and E3 ligase Fbxl7 to promote survivin ubiquitination and degradation. Furthermore, bergenin promoted chemoresistance in NSCLC cells re-sensitized to pemetrexed treatment. CONCLUSIONS: Survivin overexpression is required for maintaining multiple malignant phenotypes of NSCLC cells. Bergenin exerts a potent antitumor effect on NSCLC via targeting survivin, rendering it a promising agent for the treatment of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Survivin , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Pemetrexed/farmacología , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Apoptosis , Proliferación Celular , Línea Celular TumoralRESUMEN
Hexokinase 2 (HK2), the first glycolytic rate-limiting enzyme, is closely correlated with the occurrence and progression of tumors. Effective therapeutic agents targeting HK2 are urgently needed. Bergenin has exhibited various pharmacological activities, such as antitumor properties. However, the effects of bergenin on the abnormal glucose metabolism of cancer cells are yet unclear. In this study, HK2 was overexpressed in OSCC tissues, and the depletion of HK2 inhibited the growth of OSCC cells in vitro and in vivo. Moreover, these results showed that the natural compound, bergenin, exerted a robust antitumor effect on OSCC cells. Bergenin inhibited cancer cell proliferation, suppressed glycolysis, and induced intrinsic apoptosis in OSCC cells by downregulating HK2. Notably, bergenin restored the antitumor efficacy of irradiation in the radioresistant OSCC cells. A mechanistic study revealed that bergenin upregulated the protein level of phosphatase and the tensin homolog deleted on chromosome 10 (PTEN) by enhancing the interaction between PTEN and ubiquitin-specific protease 13 (USP13) and stabilizing PTEN; this eventually inhibited AKT phosphorylation and HK2 expression. Bergenin was identified as a novel therapeutic agent against glycolysis to inhibit OSCC and overcome radioresistance. Targeting PTEN/AKT/HK2 signaling could be a promising option for clinical OSCC treatment.
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Neoplasias , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Glucólisis/genética , Línea Celular Tumoral , Proliferación Celular , Proteasas Ubiquitina-Específicas/metabolismo , Proteasas Ubiquitina-Específicas/farmacologíaRESUMEN
Myeloid leukemia 1 (Mcl-1) is frequently overexpressed in human malignancies and emerged as a promising drug target. In this study, we verified the inhibitory effect of bergenin on colorectal cancer cells both in vivo and in vitro. In an in vitro setting, bergenin significantly reduced the viability and colony formation and promoted apoptosis of CRC cells dose-dependently. Bergenin decreased the activity of Akt/GSK3ß signaling and enhanced the interaction between FBW7 and Mcl-1, which eventually induced Mcl-1 ubiquitination and degradation. Using the HA-Ub K48R mutant, we demonstrated that bergenin promotes Mcl-1 K48-linked polyubiquitination and degradation. In vivo studies showed that bergenin significantly reduced tumor size and weight without toxicity to vital organs in mice. Overall, our results support the role of bergenin in inhibiting CRC cells via inducing Mcl-1 destruction, suggesting that targeting Mcl-1 ubiquitination could be an alternative strategy for antitumor therapy.
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Colorectal cancer (CRC) is the third most common cancer worldwide. The main obstacle in treating advanced CRC is tumor recurrence and metastasis due to chemoresistance. S-phase kinase associated protein 2 (Skp2), an E3 ligase, is highly associated with tumor resistance and a poor prognosis. The results of immunoblotting, immunohistochemical staining, ubiquitination analysis, and co-immunoprecipitation (co-IP) assay revealed that the plant curcuma, curcumol, is a novel Skp2 inhibitor for CRC treatment. Curcumol inhibits aerobic glycolysis in CRC by inducing Skp2 degradation. Co-immunoprecipitation results showed that curcumol enhanced the interaction between cadherin-1 (Cdh1) and Skp2 and led to the ubiquitination and degradation of Skp2. Curcumol exhibited significant antitumor effects against CRC, such as increased intrinsic apoptosis and decreased tumorigenic properties, both in vivo and in vitro. Furthermore, curcumol overcame 5-fluorouracil (5-Fu) resistance in CRC and induced apoptosis in 5-Fu-resistant CRC cells. The present data revealed a novel antitumor mechanism of glycolytic regulation by curcumol, suggesting that curcumol may be a potential chemical candidate for treating 5-Fu-resistant CRC.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Humanos , Proteínas Quinasas Asociadas a Fase-S/genética , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Línea Celular Tumoral , Ubiquitinación , Fluorouracilo/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Cadherinas/metabolismo , Glucólisis , Antígenos CD/metabolismoRESUMEN
Dysfunction of epidermal growth factor receptor (EGFR) signaling plays a critical role in the tumorigenesis of oral squamous cell carcinoma (OSCC). In the present study, the data analysis results of immunohistochemistry and the TCGA database verified that the expression of EGFR is significantly upregulated in OSCC tumor tissues, and depletion of EGFR inhibits the growth of OSCC cells in vitro and in vivo. Moreover, these results showed that the natural compound, curcumol, exhibited a profound antitumor effect on OSCC cells. Western blotting, MTS, and immunofluorescent staining assays indicated that curcumol inhibited cell proliferation and induced intrinsic apoptosis in OSCC cells via downregulating myeloid cell leukemia 1 (Mcl-1). A mechanistic study revealed that curcumol inhibited the EGFR-Akt signal pathway, which activated GSK-3[Formula: see text]-mediated Mcl-1 phosphorylation. Further research showed that curcumol-induced Mcl-1 Ser159 phosphorylation is required to disrupt the interaction between deubiquitinase JOSD1 and Mcl-1 and eventually induce Mcl-1 ubiquitination and degradation. In addition, curcumol administration can effectively inhibit CAL27 and SCC25 xenograft tumor growth and is well-tolerated in vivo. Finally, we demonstrated that Mcl-1 is upregulated and positively correlates with p-EGFR and p-Akt in OSCC tumor tissues. Collectively, the present results provide new insights into the antitumor mechanism of curcumol, identifying it as an attractive therapeutic agent that reduces Mcl-1 expression and inhibits OSCC growth. Targeting EGFR/Akt/Mcl-1 signaling could be a promising option in the clinical treatment of OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Proteínas Proto-Oncogénicas c-akt , Glucógeno Sintasa Quinasa 3 , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/genética , Receptores ErbB/genética , Carcinoma de Células Escamosas de Cabeza y Cuello , Proliferación Celular , Transducción de Señal , Línea Celular Tumoral , ApoptosisRESUMEN
The E3 ligase TNF receptor-associated factor 4 (TRAF4) is frequently overexpressed and closely related to poor prognosis in human malignancies. However, its effect on carcinogenesis and radiosensitivity in oral squamous cell carcinoma (OSCC) remains unclear. The present study found that TRAF4 was significantly upregulated in primary and relapsed OSCC tumor tissues. Depletion of TRAF4 markedly improved the sensitivity of OSCC cells to irradiation (IR) treatment, showing that tumor cell proliferation, colony formation and xenograft tumor growth were reduced. Mechanistically, IR promoted the interaction between TRAF4 and Akt to induce Akt K63-mediated ubiquitination and activation. TRAF4 knockout inhibited the phosphorylation of Akt and upregulated GSK3ß activity, resulting in increased myeloid cell leukemia-1 (MCL-1) S159 phosphorylation, which disrupted the interaction of MCL-1 with Josephin domain containing 1 (JOSD1), and ultimately induced MCL-1 ubiquitination and degradation. Moreover, TRAF4 was positively correlated with MCL-1 in primary and in radiotherapy-treated, relapsed tumor tissues. An MCL-1 inhibitor overcame radioresistance in vitro and in vivo. Altogether, the present findings suggest that TRAF4 confers radioresistance in OSCC by stabilizing MCL-1 through Akt signaling, and that targeting TRAF4 may be a promising therapeutic strategy to overcome radioresistance in OSCC.
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Neoplasias de la Boca , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Tolerancia a Radiación , Carcinoma de Células Escamosas de Cabeza y Cuello , Factor 4 Asociado a Receptor de TNF , Humanos , Línea Celular Tumoral , Neoplasias de la Boca/genética , Neoplasias de la Boca/radioterapia , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Factor 4 Asociado a Receptor de TNF/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Ubiquitination is vital for multiple cellular processes via dynamic modulation of proteins related to cell growth, proliferation, and survival. Of the ubiquitination system components, E3 ubiquitin ligases and deubiquitinases have the most prominent roles in modulating tumor metastasis. This review will briefly summarize the observations and underlying mechanisms of multiple E3 ubiquitin ligases and deubiquitinases to regulate tumor metastasis. Further, we will discuss the relationship and importance between ubiquitination components and tumor progression.
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Neoplasias , Ubiquitina-Proteína Ligasas , Enzimas Desubicuitinizantes/metabolismo , Humanos , Neoplasias/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
Met proto-oncogene (MET) amplification and tyrosine-protein kinase Met (c-Met) overexpression confer gefitinib resistance in non-small cell lung cancer (NSCLC). The natural product Licochalcone A (Lico A) exhibits a broad range of inhibitory effects against various tumors. However, the effects of Lico A on c-Met signaling and gefitinib resistance in NSCLC remain unclear. In the present study, Lico A efficiently overcame gefitinib-acquired resistance in NSCLC cells by suppressing c-Met signaling. Lico A decreased cell viability and colony formation dose-dependently and impaired in vivo tumorigenesis of gefitinib-resistant HCC827 and PC-9 cells. Furthermore, Lico A induced intrinsic apoptosis and upregulated the protein expression levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3. Lico A promoted the interaction between c-Met and E3 ligase c-Casitas B-lineage lymphoma (Cbl), which enhanced c-Cbl-mediated c-Met ubiquitination and degradation. Depletion of c-Cbl compromised Lico A-induced c-Met ubiquitination and its inhibitory efficacy in gefitinib-resistant NSCLC cells. Taken together, the results suggest that Lico A is a promising antitumor agent that might be used to overcome c-Met overexpression-mediated gefitinib resistance in NSCLC cells.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Chalconas , Resistencia a Antineoplásicos , Receptores ErbB/genética , Gefitinib/farmacología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , UbiquitinaciónRESUMEN
Tumor-associated macrophages (TAMs), the most abundant inflammatory cell group in the tumor microenvironment, play an essential role in tumor immune regulation. The infiltration degree of TAMs in the tumor microenvironment is closely related to tumor growth and metastasis, and TAMs have become a promising target in tumor immunotherapy. Molecular imaging is a new interdisciplinary subject that combines medical imaging technology with molecular biology, nuclear medicine, radiation medicine, and computer science. The latest progress in molecular imaging allows the biological processes of cells to be visualized in vivo, which makes it possible to better understand the density and distribution of macrophages in the tumor microenvironment. This review mainly discusses the application of targeting TAM in tumor immunotherapy and the imaging characteristics and progress of targeting TAM molecular probes using various imaging techniques.
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Cancer is a major medical problem worldwide. Due to its high heterogeneity, the use of the same drugs or surgical methods in patients with the same tumor may have different curative effects, leading to the need for more accurate treatment methods for tumors and personalized treatments for patients. The precise treatment of tumors is essential, which renders obtaining an in-depth understanding of the changes that tumors undergo urgent, including changes in their genes, proteins and cancer cell phenotypes, in order to develop targeted treatment strategies for patients. Artificial intelligence (AI) based on big data can extract the hidden patterns, important information, and corresponding knowledge behind the enormous amount of data. For example, the ML and deep learning of subsets of AI can be used to mine the deep-level information in genomics, transcriptomics, proteomics, radiomics, digital pathological images, and other data, which can make clinicians synthetically and comprehensively understand tumors. In addition, AI can find new biomarkers from data to assist tumor screening, detection, diagnosis, treatment and prognosis prediction, so as to providing the best treatment for individual patients and improving their clinical outcomes.
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BACKGROUND: Microexons are a particular kind of exon of less than 30 nucleotides in length. More than 60% of annotated human microexons were found to have high levels of sequence conservation, suggesting their potential functions. There is thus a need to develop a method for predicting functional microexons. RESULTS: Given the lack of a publicly available functional label for microexons, we employed a transfer learning skill called Transfer Component Analysis (TCA) to transfer the knowledge obtained from feature mapping for the prediction of functional microexons. To provide reference knowledge, microindels were chosen because of their similarities to microexons. Then, Support Vector Machine (SVM) was used to train a classification model in the newly built feature space for the functional microindels. With the trained model, functional microexons were predicted. We also built a tool based on this model to predict other functional microexons. We then used this tool to predict a total of 19 functional microexons reported in the literature. This approach successfully predicted 16 out of 19 samples, giving accuracy greater than 80%. CONCLUSIONS: In this study, we proposed a method for predicting functional microexons and applied it, with the predictive results being largely consistent with records in the literature.
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Máquina de Vectores de Soporte , Exones , HumanosRESUMEN
Aurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. In human oral squamous cell carcinoma (OSCC), the high protein level of Aurora B is required for maintaining of malignant phenotypes, including in vitro cell growth, colony formation, and in vivo tumor development. By molecular modeling screening of 74 commercially available natural products, we identified that Tanshinone IIA (Tan IIA), as a potential Aurora B kinase inhibitor. The in silico docking study indicates that Tan IIA docks into the ATP-binding pocket of Aurora B, which is further confirmed by in vitro kinase assay, ex vivo pull-down, and ATP competitive binding assay. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Taken together, our data indicate that Tan IIA is an Aurora B kinase inhibitor with therapeutic potentials for cancer treatment.