microRNA-4701-5p protects against interleukin-1ß induced human chondrocyte CHON-001 cells injury via modulating HMGA1.

BACKGROUND: miRNA-4701-5p has been reported to be a vital regulator in many diseases, including rheumatoid arthritis, and miRNA-4701-5p is evidenced to be participated in synovial invasion and joint destruction. In our report, we investigated the roles of miRNA-4701-5p in osteoarthritis (OA) and analyzed the molecular mechanism. METHODS: Interleukin-1ß (IL-1ß) was applied for stimulating human chondrocyte CHON-001 cells to establish an OA injury model. mRNA levels and protein expression were measured using qRT-PCR and western blot assay, respectively. The proliferation ability and cytotoxicity of CHON-001 cells were checked using MTT assay and lactate dehydrogenase activity. The inflammation of chondrocytes was accessed by the secretion levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-α. The apoptosis of chondrocytes was determined by flow cytometry assay. Bioinformatics software Starbase v2.0 analyzed the functional binding sites between miRNA-4701-5p and HMGA1 and the interaction was further confirmed using dual luciferase reporter analysis. RESULTS: miRNA-4701-5p was down-regulated in the IL-1ß-stimulated chondrocytes and HMGA1 directly targeted miRNA-4701-5p. Up-regulation of miRNA-4701-5p could alleviate IL-1ß-treated CHON-001 cells inflammation and apoptosis, and reversed the cell proliferation decrease and cytotoxicity increase after IL-1ß treatment. Nevertheless, all the roles of miRNA-4701-5p overexpression in CHON-001 cells could be reversed by HMGA1 up-regulation. CONCLUSIONS: miRNA-4701-5p could alleviate the inflammatory injury of IL-1ß-treated CHON-001 cells via down-regulating HMGA1, indicating that miRNA-4701-5p/HMGA1 is a promising therapeutic target for OA.

High mobility group HMGI(Y) protein expression in head and neck squamous cell carcinoma.

CONCLUSION: We conclude that increased expression level of the high mobility group I (HMGI(Y)) is closely associated with malignant transformation in head and neck squamous cell carcinomas (HNSCCs), and the measurement of HMGI(Y) levels in HNSCCs may be useful as a prognostic marker. OBJECTIVES: To investigate whether HMGI overexpression is observed in HNSCCs, and its value as a prognostic marker in HNSCCs. MATERIALS AND METHODS: HMGI(Y) expression was determined at the protein level by immunohistochemisty using a HMGI(Y)-specific antibody and RT-PCR in 10 surgically resected specimens of non-neoplastic tissue (normal palatal tissue) and 40 HNSCCs. We also evaluated the association of HMGI(Y) overexpression within clinicopathologic parameters, i.e. clinical stage, pathologic grade, status of cervical lymph node metastasis, recurrence rate. RESULTS: Expression of HMGI(Y) by immunohistochemical staining was observed in 35 of 40 (87.5%) HNSCC samples, whereas normal mucosa and/or the mucosa adjacent to the tumor tissue showed negative or weakly positive staining (p<0.05). Semi-quantification of HMGI(Y) by RT-PCR was 2.98+/-2.24 in cancer and 0.47+/-0.25 in normal tissue (p<0.001). High expression of HMGI(Y) was observed in recurrent cases, compared with non-recurrent cases (p<0.05). However, no significant correlation was observed between the levels of HMGI(Y) expression and other clinical factors such as clinical stage, pathologic grade, and status of cervical lymph node metastasis.

Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice.

The HMGA1 protein is a major factor in chromatin architecture and gene control. It plays a critical role in neoplastic transformation. In fact, blockage of HMGA1 synthesis prevents rat thyroid cell transformation by murine transforming retroviruses, and an adenovirus carrying the HMGA1 gene in the antisense orientation induces apoptotic cell death in anaplastic human thyroid carcinoma cell lines, but not in normal thyroid cells. Moreover, both in vitro and in vivo studies have established the oncogenic role of the HMGA1 gene. In this study, to define HMGA1 function in vivo, we examined the consequences of disrupting the Hmga1 gene in mice. Both heterozygous and homozygous mice for the Hmga1-null allele show cardiac hypertrophy due to the direct role of HMGA1 on cardiomyocytic cell growth regulation. These mice also developed hematologic malignancies, including B cell lymphoma and myeloid granuloerythroblastic leukemia. The B cell expansion and the increased expression of the RAG1/2 endonuclease, observed in HMGA1-knockout spleen tissues, might be responsible for the high rate of abnormal IgH rearrangements observed in these neoplasias. Therefore, the data reported here indicate the critical role of HMGA1 in heart development and growth, and reveal an unsuspected antioncogenic potential for this gene in hematologic malignancies.

High-mobility group-I/Y proteins: potential role in the pathophysiology of critical illnesses.

High-mobility group (HMG) proteins are architectural factors that have been shown to play a role in the transcriptional regulation of various mammalian genes. One family of HMG proteins, HMG-I/Y, is known to facilitate the initiation of gene transcription by modifying the conformation of DNA and recruiting transcription factors into an organized complex on transcriptional regulatory regions of specific genes. In many circumstances, the nuclear factor-kappa B family of transcription factors is involved in gene regulation that is mediated by HMG-I/Y. We will review the mechanisms by which HMG-I/Y proteins regulate gene transcription, give an overview of selected genes regulated by HMG-I/Y, summarize the potential roles of these genes in critical illnesses, and provide more detailed information about the role of HMG-I/Y in the regulation of nitric oxide synthase-2 during an inflammatory response, such as endotoxemia/sepsis.

The HMG I proteins: dynamic roles in gene activation, development, and tumorigenesis.

The high mobility group I, Y, and I-C proteins are low-molecular-weight, nonhistone chromosomal proteins that play a general role modulating gene expression during development and the immune response. Consistent with their role in early development, all three proteins are expressed at high levels during embryogenesis, and their expression is markedly diminished in differentiated cells. Exceptions to the general repression of these genes in adult tissues involve (1) A burst of synthesis of the HMG I protein during the immune response (during lymphocyte activation and preceding cytokine/adhesion molecule gene expression), (2) A constitutive expression of the HMG I and Y proteins in photoreceptor cells, and (3) Derepression of HMG I, Y, and often I-C expression in neoplastic cells. Work from several laboratories has now uncovered how these proteins participate in gene activation: (1) By altering the chromatin structure around an inducible gene-and thus influencing accessibility of the locus to regulatory proteins-(2) By facilitating the loading of transcription factors onto the promoters, and (3) By bridging adjacent transcription factors on a promoter via protein/protein interactions. Despite the similar structures and biochemical properties of the three proteins, the work has also provided clues to a division of labor between these proteins. HMG I and Y have demonstrable roles in enhanceosome formation, whereas HMG I-C has a specific role in adipogenesis. C-terminal truncations of HMG I-C and wild-type HMG Y appear to function in a manner analogous to oncogenes, as assessed by cellular transforation assays and transgenic mice. Future work should clearly define the similarities and differences in the biological roles of the three proteins, and should evolve to include attempts at pharmaceutical intervention in disease, based upon structural information concerning HMG I interactions with DNA and with regulatory proteins.