RESUMO
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths and a major health problem. High mobility group box 3 (HMGB3), a member of the high-mobility group box (HMGB) family, was reported to be over-expressed in gastric carcinoma and bladder cancer. However, the function of HMGB3 in CRC remains unclear. Here, we found that HMGB3 was up-regulated in CRC at both mRNA and protein levels. qRT-PCR results showed that high expression of HMGB3 had positive correlation with serosal invasion, lymph metastasis, and tumor-node-metastasis (TNM) stage in CRC patient. Functional experiments showed that HMGB3 can promote CRC cells proliferation and migration in vitro. Moreover, we found HMGB3 can active WNT/ß-catenin pathway to increase the expression level of c-Myc and MMP7. These results may be the reason for HMGB3 oncogene role in CRC. In summary, our data indicated that HMGB3 may serve as an oncoprotein and could be used as a potential prognostic marker in CRC.
Assuntos
Movimento Celular , Neoplasias Colorretais/metabolismo , Proteína HMGB3/fisiologia , Via de Sinalização Wnt , Linhagem Celular Tumoral , Proliferação de Células , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-IdadeRESUMO
Rax/Rx is a paired-type homeodomain-containing transcription factor that is essential for cell proliferation in the developing eye and brain. The molecular mechanisms that regulate cell proliferation by rax, however, are largely unknown. Here, we identify the high mobility group B3 gene (hmgb3) as a downstream target of Xenopus rax (Xrax/XRx1). Overexpression of Xhmgb3 results in an increase in eye and brain sizes due to promoted cell proliferation, while morpholino-oligo-mediated knock down of Xhmgb3 reduces eye and brain sizes. In addition, ChIP assays showed that Xhmgb3 is recruited around the promoter region of c-myc to enhance c-myc transcription. We also found that XOptx2 requires rax for its initial expression. Furthermore, we show that Xhmgb3 and XOptx2 are required for retinal development mainly at different developmental stages. Our findings reveal a novel aspect of progenitor cell proliferation during embryonic central nervous system (CNS) development.
Assuntos
Encéfalo/embriologia , Olho/embriologia , Proteína HMGB3/fisiologia , Proteínas de Homeodomínio/fisiologia , Xenopus laevis/embriologia , Animais , Encéfalo/citologia , Proliferação de Células , Olho/citologia , Genes myc , Proteína HMGB3/genética , Proteínas de Homeodomínio/genética , Células-Tronco/fisiologia , Transativadores/genética , Transcrição Gênica , Proteínas de Xenopus/genéticaRESUMO
Hmgb3 is an X-linked member of a family of sequence-independent chromatin-binding proteins that is preferentially expressed in hematopoietic stem cells (HSC). Hmgb3-deficient mice (Hmgb3(-/Y)) contain normal numbers of HSCs, capable of self-renewal and hematopoietic repopulation, but fewer common lymphoid (CLP) and common myeloid progenitors (CMP). In this study, we tested the hypothesis that Hmgb3(-/Y) HSCs are biased toward self-renewal at the expense of progenitor production. Wild-type and Hmgb3(-/Y) CLPs and CMPs proliferate and differentiate equally in vitro, indicating that CLP and CMP function normally in Hmgb3(-/Y) mice. Hmgb3(-/Y) HSCs exhibit constitutive activation of the canonical Wnt signaling pathway, which regulates stem cell self-renewal. Increased Wnt signaling in Hmgb3(-/Y) HSCs corresponds to increased expression of Dvl1, a positive regulator of the canonical Wnt pathway. To induce hematopoietic stress and a subsequent response from HSCs, we treated Hmgb3(-/Y) mice with 5-fluorouracil. Hmgb3(-/Y) mice exhibit a faster recovery of functional HSCs after administration of 5-fluorouracil compared with wild-type mice, which may be due to the increased Wnt signaling. Furthermore, the recovery of HSC number in Hmgb3(-/Y) mice occurs more rapidly than CLP and CMP recovery. From these data, we propose a model in which Hmgb3 is required for the proper balance between HSC self-renewal and differentiation.
Assuntos
Diferenciação Celular , Proteína HMGB3/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Regeneração/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ciclo Celular/genética , Proteínas Desgrenhadas , Fluoruracila/farmacologia , Proteína HMGB3/genética , Células-Tronco Hematopoéticas/efeitos dos fármacos , Camundongos , Camundongos Mutantes , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ativação Transcricional , Proteínas Wnt/metabolismoRESUMO
Hmgb3 is a member of a family of chromatin-binding proteins that can alter DNA structure to facilitate transcription factor binding. We identified the Hmgb3 cDNA in a subtractive hybridization screen for transcripts that are preferentially expressed in hematopoietic stem cells. We inserted an internal ribosomal entry site-green fluorescence protein cassette into the 3' untranslated region of the X-linked Hmgb3 locus to identify Hmgb3-expressing cells. In adult mice, Hmgb3 mRNA is detected in bone marrow cells, primitive Lin-, c-kit+, Sca-1+, IL-7Ralpha- cells, and Ter119+ erythroid cells. We observed that long-term repopulating ability is entirely contained in the subpopulation of Lin-, c-kitHI cells that express Hmgb3. Most common lymphoid and myeloid progenitors express Hmgb3. Introduction of a retrovirus containing the Hmgb3 cDNA into mouse bone marrow stem cells demonstrated that enforced expression of Hmgb3 inhibited B-cell and myeloid differentiation. We conclude that down-regulation of Hmgb3 protein levels is an important step for myeloid and B-cell differentiation.