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MicroRNA24-2 (miR24-2) is associated with human tumorigenesis; however, its molecular mechanisms are poorly understood. Herein, our findings demonstrate that miR24-2 promotes the proliferation ability in vitro and the tumorigenic ability in vivo in human liver cancer stem cells (hLCSCs). Mechanically, the miR24-2 targets for 3' UTR (2,627-2,648) of protein arginine methyltransferase 7 (PRMT7) inhibit the translational ability of prmt7 gene. Moreover, miR24-2 inhibits the di-/tri-methylation of histone H4 arginine 3 by reducing PRMT7 and then promotes the expression of Nanog via long noncoding RNA HULC. Notably, miR24-2 inhibits histone deacetylase HDAC3 through miR675, which promotes the acetylation of histone H4 at lysine 16. Subsequently, miR24-2 enhances the interaction between LC3 and ATG4 dependent on PI3K and triggers cellular autophagy. Strikingly, miR24-2 inhibits the degradation of pyruvate kinase M1 via autophagosome-P62 in hLCSCs. Furthermore, miR24-2 enhances the activity of Src by promoting the binding of PKM1 to the Src promoter regions in hLCSCs. In particular, our results also indicate that src gene determines the oncogenic functions of miR24-2. These results provided a valuable theoretical basis for the discovery of liver cancer therapeutic targets and diagnosis markers based on miR24-2.
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Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , MicroARNs/genética , Células Madre Neoplásicas/metabolismo , Familia-src Quinasas/genética , Acetilación , Autofagia , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Histonas/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/metabolismo , Metilación , Proteína Homeótica Nanog/genética , Proteína-Arginina N-Metiltransferasas/genética , Interferencia de ARN , Hormonas Tiroideas/metabolismo , Proteínas de Unión a Hormona TiroideRESUMEN
Several microRNAs are associated with carcinogenesis and tumour progression. Herein, our observations suggest both miR24-2 and Pim1 are up-regulated in human liver cancers, and miR24-2 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR24-2 increases the expression of N6-adenosine-methyltransferase METTL3 and thereafter promotes the expression of miR6079 via RNA methylation modification. Furthermore, miR6079 targets JMJD2A and then increased the tri-methylation of histone H3 on the ninth lysine (H3K9me3). Therefore, miR24-2 inhibits JMJD2A by increasing miR6079 and then increases H3K9me3. Strikingly, miR24-2 increases the expression of Pim1 dependent on H3K9me3 and METTL3. Notably, our findings suggest that miR24-2 alters several related genes (pHistone H3, SUZ12, SUV39H1, Nanog, MEKK4, pTyr) and accelerates progression of liver cancer cells through Pim1 activation. In particular, Pim1 is required for the oncogenic action of miR24-2 in liver cancer. This study elucidates a novel mechanism for miR24-2 in liver cancer and suggests that miR24-2 may be used as novel therapeutic targets of liver cancer.
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Progresión de la Enfermedad , Histonas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Lisina/metabolismo , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Animales , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Masculino , Metilación , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Modelos Biológicos , Oncogenes , Proteínas Proto-Oncogénicas c-pim-1/genéticaRESUMEN
OBJECTIVE: To evaluate the correlation of Fast-track extubation ultrasound score (FTEUS) and clinical multi-organ information indicators in post-cardiac surgery patients. METHODS: prospectively recruit post-cardiac surgery patients who were about to extubating from Febuary 2019 to September 2019. A fast-track extubation ultrasound score protocol (FTE-USP) was developed on the basis of the conventional fast-track extubation standard precisely and individualized. Cardiac, pulmonary and inferior vena cava ultrasound examinations were performed by specially trained observers, video data were saved, FTE-USP was used for scoring, Kendall consistency coefficient was used to meature the interobserver consistency. The correlation between the FTEUS and the patients' clinical indicators was evaluated. RESULTS: A total of 207 patients were recruited in the study, including 89 males and 118 females, aged (54.63±11.80) years. The FTEUS was performed at bedside with a mean time of (8.23±2.08) min, Kendall consistency coefficient is 0.941. With the increase of the total score of FTEUS, the incidence of clinical adverse events increased (especially the arrhythmia), and there were significant changes in liver, kidney, heart, lung and other organ function indicators, among which serum creatinine level, serum cystatin C level, serum NT-pro-brain natriuretic peptide, length of stay in intensive care unit, non-invasive mechanical ventilation time after extubation, and incidence of arrhythmia were positively correlated with FTEUS (P < 0.05).With FTEUS increased to 5 points, the incidence of arrhythmia (14/24, 58.3%), cardiopulmonary resuscitation (2/24, 8.3%) and weaning failure (2/24, 8.3%) increased. CONCLUSION: FTE-USP integrates multi-organ informations, can be performed quickly at the bedside and alerts adverse events. It has the potential to be applied to assist clinical decision-making in post-cardiac surgery patients before extubation.
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Extubación Traqueal , Procedimientos Quirúrgicos Cardíacos , Adulto , Anciano , Femenino , Humanos , Intubación Intratraqueal , Tiempo de Internación , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
BACKGROUND: Long noncoding RNA HULC is highly up-regulation in human hepatocellular carcinoma (HCC). However, the functions of HULC in hepatocarcinogenesis remains unclear. METHODS: RT-PCR, Western blotting, Chromatin immunoprecipitation (CHIP) assay, RNA Immunoprecipitation (RIP) and tumorignesis test in vitro and in vivo were performed. RESULTS: HULC is negatively associated with expression of PTEN or miR15a in patients of human liver cancer. Moreover, HULC accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, HULC increasesthe expression of P62 via decreasing mature miR15a. On the other hand, excessive HULC increases the expression of LC3 on the level of transcription and then activates LC3 through Sirt1 (a deacetylase). Notably, HULC enhanced the interplay between LC3 and ATG3. Furthermore, HULC also increases the expression of becline-1(autophagy related gene). Therefore, HULC increases the cellular autophagy by increasing LC3II dependent on Sirt1.Noteworthy, excessive HULC reduces the expression of PTEN, ß-catenin and enhances the expression of SAPK/JUNK, PKM2, CDK2, NOTCH1, C-Jun in liver cancer cells. Of significance, our observations also revealed that HULC inhibited PTEN through ubiquitin-proteasome system mediated by autophagy-P62.Ultimately,HULC activates AKT-PI3K-mTOR pathway through inhibiting PTEN in human liver cancer cells. CONCLUSIONS: This study elucidates a novel mechanism that lncRNA HULC produces a vital function during hepatocarcinogenesis.
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Carcinoma Hepatocelular/patología , Proteínas Portadoras/genética , Neoplasias Hepáticas/patología , MicroARNs/genética , ARN Largo no Codificante/genética , Animales , Autofagia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Proteínas Asociadas a Microtúbulos/genética , Trasplante de Neoplasias , Proteínas de Unión al ARN/genética , Transducción de SeñalRESUMEN
Long noncoding RNA CUDR plays an important role during tumorigenesis. Herein, we demonstrate that SET1A cooperates with CUDR to accelerate hepatocarcinogenesis and promote malignant transformation of hepatocyte-like stem cells. Mechanistically, CUDR enhances the phosphorylation of RB1, C-myc expression, and the interplay between the SET1A and pRB1. Notably, CUDR acts as a sponge cushion that shows a link between SET1A and pRB1, producing a activated pRB1-SET1A complex. On the other hand, the pRB1-SET1A complex may carry methyls(me) to occupy the position of H3K4, resulting in specific tri-methylation of forth lysine of histone H3 (H3K4me3). Thereby, the H3K4me3 loads on the TRF2 promoter region which causes the TRF2 overexpression. Ultimately, the excessive TRF2 binds to telomere repeat DNA, prolonging the telomere length. These findings provide the first demonstration that SET1A cooperates with CUDR to play a positive potential role during hepatocarcinogenesis and hepatocyte-like stem cells' malignant transformation epigenetically.
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Transformación Celular Neoplásica/genética , Epigénesis Genética , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias Hepáticas/genética , ARN Largo no Codificante/genética , Células Madre/patología , Animales , Transformación Celular Neoplásica/patología , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Ratones , Fosforilación , Regiones Promotoras Genéticas , Proteína de Retinoblastoma/metabolismo , Regulación hacia ArribaRESUMEN
Long noncoding RNA cancer upregulated drug resistant (CUDR) is overexpressed in many tumors and promotes tumorigenesis. Herein, we demonstrate CUDR could enhance the human embryonic stem cells (ESC) differentiation into hepatocyte-like cells by reducing trimethylation on histone H3 twenty-seventh lysine (H3K27me3). On the other hand, excessive CUDR triggers hepatocyte-like cells malignant transformation. Mechanistically, we identify CUDR causes highly upregulated in liver cancer (HULC) and ß-catenin abnormal expression by inhibiting HULC promoter methylation and promoting ß-catenin promoter-enhancer chromatin looping formation mediated by CUDR-ccctc-binding factor (CTCF) complex, which recruits more RNA polII and P300. Strikingly, HULC and ß-catenin activity are crucial for CUDR oncogenic function. These findings provide the first demonstration that CUDR plays a positive potential role in liver cancer stem cell through the cascade of CUDR-HULC/CUDR-ß-catenin signaling, and offer insights into a novel link between long noncoding RNA (lncRNA) and the epigenetic modification in cancer stem cells.
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Diferenciación Celular , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , ARN Largo no Codificante/genética , beta Catenina/metabolismo , Factor de Unión a CCCTC , Línea Celular Tumoral , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Hepatocitos/citología , Hepatocitos/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Hígado/citología , Hígado/metabolismo , Neoplasias Hepáticas/terapia , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal , Regulación hacia Arriba , beta Catenina/genéticaRESUMEN
The laboratory practice "Primary culture and directional differentiation of rat bone marrow mesenchymal stem cells (BMSCs)" is part of a required course for sophomore medical students at Tongji university, which has been conducted since 2012. Blended learning has been widely applied in medical courses. Based on a student-centered teaching philosophy, we reconstructed a comprehensive stem cell laboratory module with blended learning in 2021, aiming to facilitate students in enhancing their understanding of the multi-lineage differentiation potential of stem cells and improve their experimental skills, self-directed learning ability, and innovative thinking. First, we constructed in-depth online study resources, including videos demonstrating laboratory procedures, a PowerPoint slide deck, and published literature on student self-learning before class. In class, students performed a primary culture of BMSCs, freely chose among adipogenic, osteogenic, or chondrogenic differentiation, and used cytochemical or immunofluorescence staining for identification. After class, the extracurricular part involved performing quantitative polymerase chain reaction to examine the expression of multi-lineage differentiation marker genes, which was designed as an elective. After 2 years of practice, positive feedback was obtained from both students and faculty members who achieved, the learning goal as expected. The reconstructed stem cell laboratory module provides comprehensive practice opportunities for students. Students have a better understanding of BMSC at the molecular, cellular, and functional levels and have improved their experimental skills, which forms a basis for scientific research for medical students. Introducing blended learning into other medical laboratory practices thus seems valuable.
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Diferenciación Celular , Células Madre Mesenquimatosas , Estudiantes de Medicina , Humanos , Ratas , Animales , Células Madre Mesenquimatosas/citología , Universidades , Aprendizaje , Laboratorios , Educación de Pregrado en Medicina/métodosRESUMEN
[This retracts the article DOI: 10.1016/j.omtn.2018.03.002.].
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Circular RNA (CircRNA) is a newly identified special class of non-coding RNA (ncRNA) that plays an important regulatory role in the progression of certain diseases. Herein, our results indicate that CircMEG3 is downregulated expression and negatively correlated with the expression of telomerase-related gene Cbf5 in human liver cancer. Moreover, CircMEG3 inhibits the growth of human liver cancer stem cells in vivo and in vitro. CircMEG3 inhibits the expression of m6A methyltransferase METTL3 dependent on HULC. Moreover, CircMEG3 inhibits the expression of Cbf5, a component of telomere synthetase H/ACA ribonucleoprotein (RNP; catalyst RNA pseudouracil modification) through METTL3 dependent on HULC. Thereby, CircMEG3 inhibits telomerase activity and shortens telomere lifespan dependent on HULC and Cbf5 in human liver cancer stem cell. Strikingly, increased Cbf5 abrogates the ability of CircMEG3 to inhibit malignant differentiation of human liver cancer stem cells. In summary, these observations provide important basic information for finding effective liver cancer therapeutic targets.
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BACKGROUND: The functions of HULC have been demonstrated in several cancers. However, its mechanism has not been elucidated in human liver cancer stem cells. METHODS: Liver cancer stem cells were isolated from Huh7 cells; gene infection and tumorigenesis test in vitro and in vivo were performed. RESULTS: We demonstrate that HULC promotes growth of liver cancer stem cells in vitro and in vivo. Mechanistically, HULC enhances the expression of Sirt1 dependent on miR675 and then induces the cellular autophagy through Sirt1. HULC enhances CyclinD1 and thereby increases pRB and inhibited P21 WAF1/CIP 1 via autophagy-miR675-PKM2 pathway in human liver cancer stem cells. Ultimately, our results demonstrate that CyclinD1 is required for the oncogenic functions of HULC in liver cancer stem cells. CONCLUSIONS: It reveals the key molecular signaling pathways for HULC and provides important basic information for finding effective tumor therapeutic targets based on HULC.
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Proteínas Portadoras/metabolismo , Ciclina D1/metabolismo , Neoplasias Hepáticas/patología , Proteínas de la Membrana/metabolismo , MicroARNs/metabolismo , Células Madre Neoplásicas/patología , ARN Largo no Codificante/metabolismo , Hormonas Tiroideas/metabolismo , Animales , Autofagia/fisiología , Línea Celular Tumoral , Xenoinjertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Transfección , Regulación hacia Arriba , Proteínas de Unión a Hormona TiroideRESUMEN
miR-155 is associated with the promotion of tumorigenesis. Herein, we indicate that abnormal miR-155 was negatively correlated with the expression of P21WAF1/Cip1. Our results suggest that miR-155 alters the transcriptome and inhibits the expression of H3F3A in liver cancer cells. Therefore, miR-155 inhibits the methylation modification of histone H3 on the 27th lysine. Notably, on the one hand, miR-155-dependent CTCF loops cause the CDK2 interacting with cyclin E in liver cancer cells; on the other hand, miR-155 promotes the phosphorylation modification of CDK2 by inhibiting H3F3A. Subsequently, miR-155 competitively blocks the binding of RNA polymerase II (RNA Pol II) to the P21WAF1/CIP1 promoter by increasing the phosphorylation of CDK2, inhibiting the transcription and translation of P21WAF1/CIP1. Strikingly, excessive P21WAF1/CIP1 abolishes the cancerous function of miR-155. In conclusion, miR-155 can play a positive role in the development of liver cancer and influence a series of gene expression through epigenetic regulation.
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miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylation on histone H3 36th lysine (H3K36me3). Thereby, the H3K36me3-hMSH6-SKP2 triplex complex is significantly decreased. Notably, the ternary complex's occupancy capacity on chromosome is absolutely reduced, preventing it from DNA damage repair. By virtue of the reductive degradation ability of SKP2 for aging histone H3.3 bound to mismatch DNA, the aging histone H3.3 repair is delayed. Therefore, the mismatch DNA escapes from repair, triggering the abnormal expression of several cell cycle-related genes and causing the malignant transformation of mesenchymal stem cells. These observations strongly suggest understanding the novel functions of miR675 will help in the development of novel therapeutic approaches in a broad range of cancer types.
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Maternally expressed gene 3 (MEG3) encodes an lncRNA which is suggested to function as a tumor suppressor and has been showed to involve in a variety of cancers. Herein, our findings demonstrate that MEG3 inhibits the malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, MEG3 promotes the expression and maturition of miR122 which targets PKM2. Therefore, MEG3 decreases the expression and nuclear location of PKM2 dependent on miR122. Furthermore, MEG3 also inhibits CyclinD1 and C-Myc via PKM2 in liver cancer cells. On the other hand, MEG3 promotes ß-catenin degradation through ubiquitin-proteasome system dependent on PTEN. Strikingly, MEG3 inhibits ß-catenin activity through PKM2 reduction and PTEN increase. Significantly, we also found that excessive ß-catenin abrogated the effect of MEG3 in liver cancer. In conclusion, our study for the first time demonstrates that MEG3 acts as a tumor suppressor by negatively regulating the activity of the PKM2 and ß-catenin signaling pathway in hepatocarcinogenesis and could provide potential therapeutic targets for the treatment of liver cancer.
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Proteínas Portadoras/metabolismo , Proliferación Celular , Neoplasias Hepáticas/enzimología , Proteínas de la Membrana/metabolismo , Fosfohidrolasa PTEN/metabolismo , ARN Largo no Codificante/metabolismo , Hormonas Tiroideas/metabolismo , beta Catenina/metabolismo , Animales , Proteínas Portadoras/genética , Línea Celular Tumoral , Estabilidad de Enzimas , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Proteínas de la Membrana/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Fosfohidrolasa PTEN/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , ARN Largo no Codificante/genética , Transducción de Señal , Hormonas Tiroideas/genética , Carga Tumoral , beta Catenina/genética , Proteínas de Unión a Hormona TiroideRESUMEN
Inflammatory and autophagy-related gene P62 is highly expressed in most human tumor tissues. Herein, we demonstrate that P62 promotes human mesenchymal stem cells' malignant transformation via the cascade of P62-tumor necrosis factor alpha (TNF-α)-CUDR-CTCF-insulin growth factor II (IGFII)-H-Ras signaling. Mechanistically, we reveal P62 enhances IGFII transcriptional activity through forming IGFII promoter-enhancer chromatin loop and increasing METTL3 occupancy on IGFII 3' UTR and enhances H-Ras overexpression by harboring inflammation-related factors, e.g., TNFR1, CLYD, EGR1, NFκB, TLR4, and PPARγ. Furthermore, the P62 cooperates with TNF-α to promote malignant transformation of mesenchymal stem cells. These findings, for the first time, provide insight into the positive role that P62 plays in malignant transformation of mesenchymal stem cells and reveal a novel link between P62 and the inflammation factors in mesenchymal stem cells.
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MicroRNAs are known to be involved in carcinogenesis. Recently, microRNA-372 (miR372) has been proven to play a substantial role in several human cancers, but its functions in liver cancer remain unclear. Herein, our results demonstrate that miR372 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR372 enhances expression of Y-box-binding protein 1 (YB-1) by targeting for phosphatase and tensin homolog (PTEN) directly and consequently promotes phosphorylation of YB-1 via HULC looping dependent on ERK1/2 and PTEN. In particular, HULC knockdown or PTEN overexpression abrogated this miR372 action. Moreover, miR372 inhibits the degradation of ß-catenin dependent on phosphorylation of YB-1 and then enhances the expression and activity of pyruvate kinase M2 isoform (PKM2) by ß-catenin-LEF/TCF4 pathway. Furthermore, the loading of LEF/TCF4 on PKM2 promoter region was significantly increased in miR372 overexpressing Hep3B, and thus, glycolytic proton efflux rate (glycoPER) was significantly increased in rLV-miR372 group compared to the rLV group. Moreover, ß-catenin knockdown abrogates this function of miR372. Ultimately, miR372 promotes the expression of erbB-2 through PKM2-pH3T11-acetylation on histone H3 lysine 9 (H3K9Ac) pathway. Of significance, both YB-1 knockdown and erbB-2 knockdown abrogate oncogenic action of miR372. Our observations suggest that miR372 promotes liver cancer cell cycle progress by activating cyclin-dependent kinase 2 (CDK2)-cyclin E-P21/Cip1 complex through miR372-YB-1-ß-catenin-LEF/TCF4-PKM2-erbB-2 axis. This study elucidates a novel mechanism for miR372 in liver cancer cells and suggests that miR372 can be used as a novel therapeutic target of liver cancer.
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OBJECTIVE@#To investigate the status quo of recognition and management of renal colic among urological surgeons in China.@*METHODS@#From November 2021 to March 2022, 725 urological surgeons in China were surveyed in the form of a questionnaire, including their province, hospital grade, professional title, the number of patients with renal colic treated per week, the preferred drugs and the cognition of the disease. This study was approved by the Medical Ethics Committee of Peking University People's Hospital, and all respondents completed informed consent online.@*RESULTS@#During November 2021 and March 2022, urological surgeons across China were surveyed in the form of a questionnaire, and the reliability and validity of the questionnaire were verified before the study was carried out. In the study, 720 valid questionnaires were collected (accounting for 99.31% of the total number), in which 42.4% of the doctors' preferred drugs were non-steroidal anti-inflammatory drugs (NSAIDs), and 40.0% of the doctors' preferred antispasmodic drugs. Opioids were the first choice of 11.0% of the physicians and other treatments were preferred by 6.6% of physicians. In addition, 61.1% of the doctors thought that the mechanism of renal colic was elevated prostaglandin, 32.2% thought it was ureteral spasm, 5.0% thought it was calculi irritation, and 1.7% thought the mechanism was unclear. The doctor of the cognition of the generation mechanism of renal colic pain had a significant influence on the preferred treatment option (χ2=54.399, P < 0.001) that the "elevated prostaglandins" doctor more often preferred NSAIDs than the doctor who thought cramps and ureter stones caused renal colic (51.6% vs. 28.0%, χ2=34.356, P < 0.001;51.6% vs. 19.4%, χ2=13.759, P < 0.001). In addition, hospital class, physician title, and the number of weekly consultations by physicians influenced the choice of medications for renal colic (P < 0.05), tertiary hospitals, middle and senior professional titles and weekly patients with renal colic > 8 cases generally preferred NSAIDs.@*CONCLUSION@#There are deficiencies in the cognition and drug treatment of renal colic among urological surgeons in China. The choice of the preferred drug was related to the doctor's cognition of the disease, the grade of the hospital, the doctor's professional title and the weekly treatment volume.
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Humanos , Cólico Renal/tratamiento farmacológico , Urólogos , Pueblos del Este de Asia , Reproducibilidad de los Resultados , Antiinflamatorios no Esteroideos , Encuestas y CuestionariosRESUMEN
Changes in histone lysine methylation status have been observed during cancer formation. JMJD2A protein is a demethylase that is overexpressed in several tumors. Herein, our results demonstrate that JMJD2A accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, JMJD2A promoted the expression and mature of pre-miR372 epigenetically. Notably, miR372 blocks the editing of 13th exon-introns-14th exon and forms a novel transcript( JMJD2AΔ) of JMJD2A. In particular, JMJD2A inhibited P21(WAF1/Cip1) expression by decreasing H3K9me3 dependent on JMJD2AΔ. Thereby, JMJD2A could enhance Pim1 transcription by suppressing P21(WAF1/Cip1). Furthermore, through increasing the expression of Pim1, JMJD2A could facilitate the interaction among pRB, CDK2 and CyclinE which prompts the transcription and translation of oncogenic C-myc. Strikingly, JMJD2A may trigger the demethylation of Pim1. On the other hand, Pim1 knockdown and P21(WAF1/Cip1) overexpression fully abrogated the oncogenic function of JMJD2A. Our observations suggest that JMJD2A promotes liver cancer cell cycle progress through JMJD2A-miR372-JMJD2AΔ-P21WAF1/Cip1-Pim1-pRB-CDK2-CyclinE-C-myc axis. This study elucidates a novel mechanism for JMJD2A in liver cancer cells and suggests that JMJD2A can be used as a novel therapeutic targets of liver cancer.
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Regulación Neoplásica de la Expresión Génica , Histona Demetilasas con Dominio de Jumonji/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroARNs/genética , Animales , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Modelos Animales de Enfermedad , Epigénesis Genética , Proteínas Fúngicas/metabolismo , Xenoinjertos , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Modelos Biológicos , Regiones Promotoras Genéticas , Proteínas de Unión a Retinoblastoma/metabolismo , Transducción de Señal , Activación Transcripcional , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Inflammatory cytokines and lncRNAs are closely associated with tumorigenesis. Herein, we reveal inflammatory cytokines IL6 cooperates with long noncoding RNA CUDR to trigger the malignant transformation of human embryonic stem cells-derived hepatocyte-like stem cells. Mechanistically, IL6 cooperates with CUDR to cause MELLT3 to interact with SUV39h1 mRNA3'UTR and promote SUV39h1 expression. Moreover, the excessive SUV39h1 also increases tri-methylation of histone H3 on nineth lysine (H3K9me3). Intriguingly, under inflammatory conditions, H3K9me3 promotes the excessive expression and phosphorylation of NF-κB, and in turn, phorsphorylated NF-κB promotes the expression and phosphorylation of Stat3. Furthermore, that the phosphorylated Stat3 loads onto the promoter region of miRs and lncRNAs. Ultimately, the abnormal expression of miRs and lncRNAs increased telomerase activity, telomere length and microsatellite instability (MSI), leading to malignant transformation of hepatocyte-like stem cells.
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Transformación Celular Neoplásica , Interleucina-6/fisiología , Neoplasias Hepáticas Experimentales/patología , ARN Largo no Codificante/fisiología , Animales , Línea Celular , Regulación Neoplásica de la Expresión Génica , Hepatocitos/patología , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Hígado/metabolismo , Hígado/patología , Metiltransferasas/metabolismo , Ratones Endogámicos BALB C , MicroARNs/metabolismo , Inestabilidad de Microsatélites , FN-kappa B/metabolismo , Fosforilación , Procesamiento Proteico-Postraduccional , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Células Madre/patología , Telomerasa/metabolismo , Homeostasis del TelómeroRESUMEN
Cancer stem cells are associated with tumor recurrence. IKK is a protein kinase that is composed of IKKα, IKKß, IKKγ. Herein, we demonstrate that IKKα plus IKKß promoted and IKKγ inhibited liver cancer stem cell growth in vitro and in vivo. Mechanistically, IKKα plus IKKß enhanced and IKKγ inhibited the interplay among HP1α, HP1ß and HP1γ that competes for the interaction among HP1α, SUZ12, HEZ2. Therefore, IKKα plus IKKß inhibited and IKKγ enhanced the activity of H3K27 methyltransferase SUZ12 and EZH2, which methylates H3K27 immediately sites on HOTAIR promoter region. Therefore, IKKα plus IKKß increased and IKKγ decreased the HOTAIR expression. Strikingly, IKKα plus IKKß decreases and IKKγ increases the HP1α interplays with DNA methyltransferase DNMT3b, which increases or decreases TERRA promoter DNA methylation. Thus IKKα plus IKKß reduces and IKKγ increases to recruit TRF1 and RNA polymerase II deposition and elongation on the TERRA promoter locus, which increases or decreases TERRA expression. Furthermore, IKKα plus IKKß decreases/increases and IKKγ increases/decreases the interplay between TERT and TRRRA/between TERT and TREC. Ultimately, IKKα plus IKKß increases and IKKγ decreases the telomerase activity. On the other hand, at the telomere locus, IKKα plus IKKß increases/drcreases and IKKγ decreases/increases TRF2, POT1, pPOT1, Exo1, pExo1, SNM1B, pSNM1B/CST-AAF binding, which keep active telomere regulatory genes and poised for telomere length. Strikingly, HOTAIR is required for IKKα plus IKKß and IKKγ to control telomerase activity and telomere length. These observations suggest that HOTAIR operates the action of IKKα, IKKß, IKKγ in liver cancer stem cells. This study provides a novel basis to elucidate the oncogenic action of IKKα, IKKß, IKKγ and prompts that IKKα, IKKß, IKKγ cooperate to HOTAR to be used as a novel therapeutic targets for liver cancer.