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Study of HMGB1on the Differentiation and Apoptosis of Leukemic Cells and Effects of Key Mechanism

Author: ZhangWen
Tutor: JiangGuoSheng
School: Jinan University
Course: Immunology
Keywords: High mobility group protein1 Leukemia All-trans retinoic acid arsenic trioxide acute promyelocytic leukemia
CLC: R733.7
Type: Master's thesis
Year: 2013
Downloads: 10
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Abstract


BackgroundLeukemia is one of the most common malignant tumors in China. It is ahematopoietic stem cell malignant cloning disease that serious threaten to childrenand young adults survival. Therefore, to reveal the pathogenesis of leukemia, lookingfor new targets for therapeutic intervention, has very important significance forprevention and treatment of leukemia.The academic circles agree that the occurrenceof leukemia is result of multiple factors and mechanisms (including proliferation,apoptosis, differentiation defect hindered), which involves the activation of oncogeneand the inactivation of tumor suppressor gene. Among them, induction differentiationtherapy of leukemia is the application of certain chemicals that reversal of immatureand malignant cells to normal cells.High mobility group protein1is a relatively small protein of215amino acidresidues. Named because of the high migration speed in polyacrylamide gelelectrophoresis. The protein molecular weight is about29kD. In the nucleus, HMGB1is a nonhistone DNA-binding protein and serves as a structural component to facilitatethe assembly of nucleoprotein complexes. Extracellular HMGB1is an importantpro-inflammatory mediator and chemotactic factor, involved in the pathogenesis ofinfectious diseases. Development of HMGB1involved in cancer is complex,cytosolic/nuclear and extracellular HMGB1with tumor occurrence, development,metastasis and chemotherapy response are closely related. HMGB1is highlyexpressed in a variety of solid tumors, including malignant melanoma, colon cancer,prostate cancer, pancreatic cancer, breast cancer. It is more important that the invasion and metastasis of HMGB1is correlated with tumor. Although the research describedabove, but the role of HMGB1in leukemia is not clear.ObjectiveThis study intends to establish the expression of HMGB1spectrum in differenttypes of leukemia. By detecting the expression of HMGB1in the differentiationinduced model to analyze its correlation with leukemia. To explore the biologicaleffect of HMGB1in the differentiation of leukemia cells. To elucidate the possiblemechanism and the structural basis of HMGB1mediated differentiation of leukemiacells. Open up a new field for the study of cell differentiation. Provide ideas andexperimental new clues for leukemia treatment.MethodsIt has trained nine different types of leukemia cells to the logarithmic growthphase. By reverse transcription polymerase chain reaction (RT-RCR) and Western blotmethod to detect the expression of HMGB1in the level of mRNA and protein in ninehuman leukemia cells. By positioning the immunohistochemistry qualitative andquantitative detection of HMGB1in clinical specimens in the expression of variousleukemia. The logarithmic growth phase of acute promyelocytic leukemia cells(HL-60) induced differentiation model, according to the different drugs into normalcontrol group, all trans retinoic acid (ATRA) and arsenic trioxide (As2O3) group, toobserve the morphology of HL-60cells by Wright-Gimesa staining, cell proliferationwas measured by CCK8assay, cell cycle and the expression of detection of HL-60cell differentiation antigen CD11b by flow cytometry, the detection of RT-PCR andWestern blot methods of acute promyelocytic leukemia (HL-60) with all trans retinoicacid (ATRA) and arsenic trioxide (As2O3) HMGB1expression at mRNA and proteinlevel of24h,48h,72h,96h after induction. We built the expression of the small-signalmodel of HMGB1interference.ResultsEffect of1μmol/L ATRA and1μmol/L As2O3in HL-60cells can significantlyinhibit the proliferation, differentiation into mature myeloid cells were observed under inverted microscope cell morphology, expression of cell surface differentiationantigen CD11b flow cytometry was significantly increased (p<0.05), Annexin V/PIdouble staining was used to detect apoptosis of As2O3group showed0to4days theapoptosis rate from3.35±0.31%to25.75±8.39%elevated (p<0.05), RT-PCR andWestern blot results showed that HMGB1had high expression in various types ofleukemia, including acute promyelocytic leukemia cells in the highest expression,clinical bone marrow pathology immunohistochemical results also support the aboveconclusion HMGB1is mainly expressed in the nucleus, and in HL-60cells byall-trans retinoic acid (ATRA) induced to granulocyte differentiation at the same time,HMGB1was expressed at mRNA and protein level decreased, the difference wasstatistically significant (p<0.05), HL-60cells (As2O3) induced by arsenic trioxide inthe myeloid differentiation, apoptosis appeared as part of a cell, HMGB1in mRNAthe expression with time increased, the difference was statistically significant(p<0.05). Small interference model establishment failure.ConclusionsThe HMGB1expression is higher in various leukemia cells, in acutepromyelocytic leukemia (M3) of high expression of HMGB1cells, and expressedmainly in the nucleus. With all-trans retinoic acid treatment time prolongs, theexpression of HMGB1in acute promyelocytic leukemia cells gradually decreased, thelevel of transcription and translation, a downward trend. Negatively correlated withdifferentiation degree and the degree of HMGB1expression in HL-60cells. With theeffect of arsenic trioxide time increasing, the expression of HMGB1in acutepromyelocytic leukemia cells gradually increased, the level of transcription andtranslation, is upward trend. Related expression level of HMGB1and HL-60apoptosis positive.

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CLC: > Medicine, health > Oncology > Hematopoietic and lymphoid neoplasms > Leukemia
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