High Mobility Group A1 Protein Research Articles

Let-7d microRNA affects mesenchymal phenotypic properties of lung fibroblasts

MicroRNAs are small noncoding RNAs that inhibit protein expression. We have previously shown that the inhibition of the microRNA let-7d in epithelial cells caused changes consistent with epithelial-to-mesenchymal transition (EMT) both in vitro and in vivo. The aim of this study was to determine whether the introduction of let-7d into fibroblasts alters their mesenchymal properties. Transfection of primary fibroblasts with let-7d caused a decrease in expression of the mesenchymal markers α-smooth muscle actin, N-cadherin, fibroblast-specific protein-1, and fibronectin, as well as an increase in the epithelial markers tight junction protein-1 and keratin 19. Phenotypic changes were also present, including a delay in wound healing, reduced motility, and proliferation of fibroblasts following transfection. In addition, we examined the effects of transfection on fibroblast responsiveness to TGF-β, an important factor in many fibrotic processes such as lung fibrosis and found that let-7d transfection significantly attenuated high-mobility group-A2 protein induction by TGF-β. Our results indicate that administration of the epithelial microRNA let-7d can significantly alter the phenotype of primary fibroblasts.

Role of high mobility group protein A1 in tumor development

High mobility group protein A1 (HMGA1),one of the non-histone chromatin proteins,can regulate the transcription of several tumor related genes by various different ways,thereby effecting the formation and growth of tumor.So HMGA1 can be not only used as a tumor marker,but also as indicator of tumor prognosis and therapeutic target,and then providing new ways for the tumor biological therapies. Key words: HMGA proteins; Neoplasms; Transcription; Prognosis

Overexpression of High Mobility Group A1 Protein in Human Uveal Melanomas: Implication for Prognosis

There is increasing evidence that the high mobility group A1 (HMGA1) protein, which functions as a transcriptional master regulator, plays critical roles in tumor progression. We evaluated HMGA1 expression in 89 primary uveal melanomas (UM) by immunohistochemistry to determine the clinicopathological and prognostic value of HMGA1 in UM after adjusting for other prognostic variables. Nuclear expression of HMGA1 was detected in 44% UMs. High expression levels of HMGA1 were more frequent in UMs with high levels of epithelioid cell pattern, mitoses count, and Ki67 labeling index (P = 0.025, P<0.0001, P = 0.0018; respectively), and HMGA1 expression levels were directly correlated with Ki67 labeling indexes and mitoses counts (R = 0.31, P <0.0001; R = 0.27, P<0.0068; respectively). High expression of HMGA1 was also independently associated with an increased risk of distant metastases as determined using the Cox proportional hazards regression model (multivariate hazard ratio: 3.44; 95% confidence interval: 1.56–7.60; log rank P = 0.0022). Moreover, high HMGA1 expression was associated with shorter UM-specific survival (multivariate hazard ratio: 2.41; 95% confidence interval: 1.10–5.53; log rank P = 0.041). These findings suggest that high levels of HMGA1 are associated with adverse clinical outcomes in UM patients and that further evaluation of HMGA1 as a potential therapeutic target in UM is warranted.

Rb Protein is Essential to the Senescence-Associated Heterochromatic Foci Formation Induced by HMGA2 in Primary WI38 Cells

Cellular senescence is an irreversible form of cell cycle arrest that provides a barrier to neoplastic transformation. The integrity of the Rb (Retinoblastoma) pathway is necessary for the formation of the senescence-associated heterochromatin foci (SAHF) that offers a molecular basis for the stability of the senescent state. Surprisingly, although high mobility group A2 protein (HMGA2) can promote tumorigenesis and inhibit Rb function in tumor cells, high-level expression of HMGA2 is sufficient to induce SAHF formation in primary cells. It therefore becomes significant to determine whether Rb protein is necessary in HMGA2-induced SAHF formation. In this study, we established the cellular senescence and SAHF assembly WI38 cell model by ectopic expression of HMGA2, in which typical senescent markers were seen, including notable upregulation of p53, p21 and p16, and elevated SA-β-galactosidase staining together with downregulation of E2F target genes. We then showed that the Rb pathway inhibitor E7 protein was able to partly abolish the ability of SAHF formation after HMGA2 expression in WI38 cells, indicating that Rb is a crucial factor for HMGA2-induced SAHF formation. However, Rb depletion did not completely rescue the cell growth arrest induced by HMGA2, suggesting that Rb is not an exclusive pathway for HMGA2-induced senescence in WI38 cells.

Effect of silencing of high mobility group A2 gene on gastric cancer MKN-45 cells

To investigate the effect of high mobility group A2 (HMGA2) gene silencing on gastric cancer MKN-45 cells in vitro. HMGA2 short hairpin RNA (shRNA) expression plasmids were constructed, including a pair of random scrambled sequences. Human gastric cancer cell line MKN-45 cells were divided into three groups: blank control group (non-transfected cells), transfected group (cells transfected with HMGA2 shRNA recombinant plasmid) and scrambled sequence group (transfected with random scrambled plasmid). Cells were transfected with HMGA2 shRNA recombinant plasmids and scrambled plasmid in vitro, and the cells transfection efficiency was assayed by fluorescence microscopy. The HMGA2 messenger RNA (mRNA) expression was detected by reverse transcription polymerase chain reaction, gastric cancer cells apoptosis was detected by flow cytometry, cell proliferation was detected by methyl thiazol tetrazolium, and the protein expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), P27, caspase-9 and B-cell leukemia/lymphoma-2 (Bcl-2) were analyzed by Western blotting. Compared with the blank control group and the scrambled sequence group, the levels of HMGA2 mRNA and protein expression in the transfected group were significantly reduced (P < 0.05). The relative HMGA2 mRNA expression levels of the blank control group, transfected group and scrambled sequence group were 0.674 ± 0.129, 0.374 ± 0.048 and 0.689 ± 0.124, respectively. The relative HMGA2 protein expression levels of the blank control group, transfected group and scrambled sequence group were 0.554 ± 0.082, 0.113 ± 0.032 and 0.484 ± 0.123, respectively. Moreover, transfection with the scrambled sequence had no effect on the expression of HMGA2. After being transfected with shRNA for 24, 48 and 72 h, the cell apoptotic rates of the transfected group were 21.65% ± 0.28%, 39.98% ± 1.82% and 24.51% ± 0.93%, respectively, which significantly higher than those of blank control group (4.72% ± 1.34%, 5.83% ± 0.13% and 5.22% ± 1.07%) and scrambled sequence group (4.28% ± 1.33%, 7.87% ± 1.43% and 6.71% ± 0.92%). After 24, 48 and 72 h, the cell proliferation inhibition rates in the transfected group were 31.57% ± 1.17%, 39.45% ± 2.07% and 37.56% ± 2.32%, respectively; the most obvious cell proliferation inhibition appeared at 48 h after transfection. Compared with the blank control group and scrambled sequence group, after transfection of shRNA for 72 h, the protein expression levels of PI3K (0.042 ± 0.005 vs 0.069 ± 0.003, 0.067 ± 0.05), Akt (0.248 ± 0.004 vs 0.489 ± 0.006, 0.496 ± 0.104) and Bcl-2 (0.295 ± 0.084 vs 0.592 ± 0.072, 0.594 ± 0.109) were significantly reduced. The protein expression levels of P27 (0.151 ± 0.010 vs 0.068 ± 0.014, 0.060 ± 0.013) and caspase-9 (0.136 ± 0.042 vs 0.075 ± 0.010, 0.073 ± 0.072) were significantly upregulated. HMGA2 shRNA gene silencing induces apoptosis and suppresses proliferation of MKN-45 cells.

High mobility group A1 protein acts as a new target of Notch1 signaling and regulates cell proliferation in T leukemia cells

Active mutations of Notch1 play pivotal roles during leukemogenesis, but the downstream targets and molecular mechanisms of activated Notch1 signaling have not yet been fully clarified. In this study, we detected the overexpression of the high mobility group A1 (HMGA1) and activation of Notch1 signaling in mouse thymic lymphomas. A direct regulation of Notch1 on HMGA1 transcription was demonstrated and two Notch1/RBPJ cobinding sites of T/CTCCCACA were found in HMGA1 promoter regions. It was the first time demonstrated that HMGA1 was the downstream target of Notch1 signaling. Moreover, knockdown of HMGA1 resulted in significantly impaired cell growth and decreased expressions of cyclin D and cyclin E in human T leukemia cells. The formation of complexes was also observed between HMGA1 and retinoblastoma (RB) protein indicating a mechanism of cell cycle regulation. These findings suggest that activated HMGA1 regulates cell proliferation through the Notch1 signaling pathway, which represents an important molecular pathway leading to leukemogenesis.

HMGA2 regulates the in vitro aging and proliferation of human umbilical cord blood-derived stromal cells through the mTOR/p70S6K signaling pathway

The human high-mobility group protein A2 (HMGA2) protein is an architectural transcription factor that transforms chromatin structure by binding to DNA. Recently, it has been reported that HMGA2 is highly expressed in fetal neural stem cells and has the capacity to promote stemness. However, there is currently no information available on the functional significance and molecular mechanisms of the cellular in vitro aging and proliferation of human umbilical cord blood-derived stromal cells (hUCBSCs). In the present study, we evaluated the direct effects of HMGA2 on the cellular aging and proliferation of hUCBSCs and investigated potential regulatory mechanisms responsible for the corresponding functions. We found that the overexpression of HMGA2 enhanced proliferation and reduced or even reversed the in vitro aging process of hUCBSCs. This effect was accompanied by the increased expression of cyclin E and CDC25A and the significantly decreased expression of cyclin-dependent kinase inhibitors. Furthermore, HMGA2 inhibition compromised cell proliferation and adipogenic differentiation in early-stage hUCBSCs. From the molecular/cellular functional analysis of microarray data, we found that HMGA2 overexpression induced a PI3K/Akt/mTOR/p70S6K cascade, which in turn suppressed the expression of p16INK4A and p21CIP1/WAF1 in hUCBSCs. These results provide novel insights into the mechanism by which HMGA2 regulates the in vitro aging and proliferation of hUCBSCs.

HMGA2 Elicits EMT by Activating the Wnt/β-catenin Pathway in Gastric Cancer

The high mobility group protein A2 (HMGA2) is an architectural transcription factor that plays an important role in the development and progression of many malignant neoplasms. High expression of HMGA2 in gastric cancer correlates with invasiveness of cancer and is an independent prognostic factor. The reason for this might be HMGA2 promoting epithelial-mesenchymal transitions (EMT), which is the key process of metastasis for some underlying mechanisms. This study was designed to test whether HMGA2 participates in the EMT and to further understand the underlying mechanisms of EMT promoted by HMGA2. We examined the cell biology and molecular biology changes after overexpression and knockdown HMGA2 of gastric cancer cells in vitro and vivo. To further understand the underlying mechanisms of EMT promoted by HMGA2, based on our previous study, we examined the changes of target genes of HMGA2 after overexpression and knockdown HMGA2 of gastric cancer cells. The results indicated that overexpressing HMGA2 enabled enhancing the oncogenic properties of gastric epithelial origin cell in vitro and in vivo. Furthermore, our study showed that HMGA2 was able to elicit EMT and regulate several genes which are closely related to the Wnt/β-catenin pathway by directly binding to their promoter thereby activating the Wnt/β-catenin pathway. The Wnt/β-catenin pathway activated by HMGA2 might be the underlying mechanism of EMT in gastric cancer cells.

The Wnt/β‐catenin/T‐cell factor 4 pathway up‐regulates high‐mobility group A1 expression in colon cancer

High-mobility group A1 (HMGA1) encodes proteins that act as mediators in viral integration, modification of chromatin structure, neoplastic transformation and metastatic progression. Because HMGA1 is overexpressed in most cancers and has transcriptional relationships with several Wnt-responsive genes, we explored the involvement of HMGA1 in Wnt/β-catenin/TCF-4 signalling. In adenomatous polyposis coli (APC(Min/+)) mice, we observed significant up-regulation of HMGA1 mRNA and protein in intestinal tumours when compared with normal intestinal mucosa. Conversely, restoration of Wnt signalling by the zinc induction of wild-type APC resulted in HMGA1 down-regulation in HT-29 cells. Because APC mutations are associated with mobilization of the β-catenin/TCF-4 transcriptional complex and subsequent activation of downstream oncogenic targets, we analyzed the 5'-flanking sequence of HMGA1 for putative TCF-4 binding elements. We identified two regions that specifically bind the β-catenin/TCF-4 complex in vitro and in vivo, identifying HMGA1 as an immediate target of the β-catenin/TCF-4 signalling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/β-catenin/TCF-4 signalling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/β-catenin/TCF-4 signalling.

The expression of the high-mobility group A2 protein in colorectal cancer and surrounding fibroblasts is linked to tumor invasiveness

Tumor staging of colorectal cancer is typically based on conventional TNM and Dukes classifications. However, additional information could be useful, and there is a significant interest in identifying molecular markers that are related to genetic or epigenetic processes. Using immunohistochemistry, we analyzed the expression of the high-mobility group A2 (previously high-mobility group 1-C [HMGI-C]) protein in 103 colorectal cancer cases to determine its use as a biomarker in colorectal cancer to integrate morphological staging. We found a progressive increase of the high-mobility group A2 protein expression in colorectal cancer tumor samples from cases in which all of the tumor cells were negative up to cases in which all of the tumor cells stained positive. Increased high-mobility group A2 expression is strongly associated with an increase in tumor invasiveness, which was measured through both budding and vascular invasion (P < .0001). Kaplan-Meier estimates showed a decrease in overall survival when vascular invasion is present (P = .023). Moreover, a fraction of the analyzed samples showed high-mobility group A2-positive stromal fibroblasts. Although high-mobility group A2-positive tumors were associated with cell invasiveness, high-mobility group A2-positive stromal fibroblasts were correlated with less invasive tumors. High-mobility group A2 protein expression could be used as a prognostic marker to provide prospective information on patient outcome, complementing the data obtained using conventional pathologic staging systems.

High-mobility group A1 protein inhibits p53-mediated intrinsic apoptosis by interacting with Bcl-2 at mitochondria

The high-mobility group A (HMGA) proteins are a family of non-histone chromatin factors, encoded by the HMGA1 and HMGA2 genes. Several studies demonstrate that HMGA proteins have a critical role in neoplastic transformation, and their overexpression is mainly associated with a highly malignant phenotype, also representing a poor prognostic index. Even though a cytoplasmic localization of these proteins has been previously reported in some highly malignant neoplasias, a clear role for this localization has not been defined. Here, we first confirm the localization of the HMGA1 proteins in the cytoplasm of cancer cells, and then we report a novel mechanism through which HMGA1 inhibits p53-mitochondrial apoptosis by counteracting the binding of p53 to the anti-apoptotic factor Bcl-2. Indeed, we demonstrate a physical and functional interaction between HMGA1 and Bcl-2 proteins. This interaction occurs at mitochondria interfering with the ability of p53 protein to bind Bcl-2, thus counteracting p53-mediated mitochondrial apoptosis. This effect is associated with the inhibition of cytochrome c release and activation of caspases. Consistent with this mechanism, a strong correlation between HMGA1 cytoplasmic localization and a more aggressive histotype of thyroid, breast and colon carcinomas has been observed. Therefore, cytoplasmic localization of HMGA1 proteins in malignant tissues is a novel mechanism of inactivation of p53 apoptotic function.

The β‐Catenin/Tcf‐4 Pathway Regulates High Mobility Group A1 (hmga1) Expression in Colorectal Cancers

High Mobility Group A1 (HMGA1) encodes proteins that act as mediators in viral integration, chromatin modification, neoplastic transformation, and metastatic progression. Because hmga1 expression is overexpressed in most cancers and has known interactions with several Wnt/β‐catenin‐responsive genes, we explored the involvement of HMGA1 in colorectal cancer. Apc mutations occur in most colorectal cancers and are associated with the mobilization of the β‐catenin/Tcf‐4 transcriptional complex. In adenomatous polyposis coli (Apc)(Min/+) mice expressing truncated Apc, we observed 9‐fold greater HMGA1 mRNA levels relative to mice bearing wild‐type Apc. HMGA1 protein levels were also significantly elevated in Apc(Min/+)intestinal tumors. Sequence analysis of the 5′‐flanking sequence of hmga1 identified a functional Tcf‐4 binding element (TBEs) that specifically binds Tcf‐4 in vitro and in vivo suggesting that hmga1 is a downstream target of the β‐catenin/Tcf‐4 signaling pathway. These findings will be further substantiated by transcription assays to evaluate the impact of Tcf‐4 and β‐catenin expression on hmga1 promoter activity. The results confirm previous work identifying hmga1 as a downstream target of the β‐catenin/Tcf‐4 complex and provide a new target for the development of therapies aimed at treating colorectal cancer. This research is supported by NIH 2P20 RR016461‐05, 1R15CA137520‐01 and NSF MCB055810542242.

HMGA1 and HMGA2 protein expression correlates with advanced tumour grade and lymph node metastasis in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma follows a multistep model of progression through precursor lesions called pancreatic intraepithelial neoplasia (PanIN). The high mobility group A1 (HMGA1) and high mobility group A2 (HMGA2) proteins are architectural transcription factors that have been implicated in the pathogenesis and progression of malignant tumours, including pancreatic cancer. The aim of this study was to explore the role of HMGA1 and HMGA2 in pancreatic carcinogenesis. HMGA1 and HMGA2 expression was examined in 210 ductal pancreatic adenocarcinomas from resection specimens, combined on a tissue microarray also including 40 examples of PanIN and 40 normal controls. The results were correlated with the clinicopathological parameters of the tumours and the outcome of the patients. The percentage of tumour cells showing HMGA1 and HMGA2 nuclear immunoreactivity correlated positively with increasing malignancy grade and lymph node metastasis. Moreover, HMGA1 and HMGA2 expression was significantly higher in invasive carcinomas than in PanINs. No, or very low, expression was found in normal pancreatic tissue. Our results suggest that HMGA1 and HMGA2 are implicated in pancreatic carcinogenesis and may play a role in tumour progression towards a more malignant phenotype.

Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells

High mobility group protein A2 (HMGA2) is an architectural transcription factor that plays an important role in development and progression of malignant neoplasias. Recently, some studies reported that HMGA2 is also implicated in epithelial-mesenchymal transitions (EMT) and cancer stem cells. But the underlying mechanisms of these conditions are poorly understood. Therefore, we established an EMT model of gastric carcinoma cells by overexpressing HMGA2 in vitro, then global mapping of HMGA2 potential transcription factor binding sites was identified by promoter microarray in these cells, and the date obtained from the microarrays were validated via chromatin immunoprecipitation-PCR (ChIP-PCR) and real-time PCR. HMGA2 potential target genes were classified in KEGG database and Gene Ontology (GO) analyses. To our knowledge, this is the first report on the genome-wide analysis of HMGA2 downstream direct targets, and these findings will be valuable in understanding the roles of HMGA2 in EMT.

Knockdown of HMGA1 expression by short/small hairpin RNA inhibits growth of ovarian carcinoma cells

The aim of the current study was to investigate the influence of downregulating high-mobility group protein A1 (HMGA1) on the tumor gene and the mechanisms underlying the antitumor of HMGA1. The efficient short/small hairpin RNAs (shRNAs) of HMGA1 were constructed and transfected into human ovarian carcinoma OVCAR cells. The changes were identified by reverse transcription PCR (RT-PCR), Western blotting, methyl thiazolyl tetrazolium, and invasion assay. The knockdown of HMGA1 expression in OVCAR cells could obviously change cell morphology, decrease cell proliferation, and reduce invasion in vitro. BALB/C nude mice injected with OVCAR cells transfected HMGA1 shRNA showed a significantly lower tumor weight and volume than those in the control group. Taken together, HMGA1 knockdown could reduce the growth and metastasis potentials of OVCAR cells.

Molecular mechanisms of MYCN-dependent apoptosis and the MDM2–p53 pathway: an Achille’s heel to be exploited for the therapy of MYCN-amplified neuroblastoma

The p53 oncosuppressor is very seldom mutated in neuroblastoma, but several mechanisms cooperate to its functional inactivation in this tumor. Increased MDM2 levels, due to genetic amplification or constitutive inhibition of p14 ARF, significantly contribute to this event highlighting p53 reactivation as an attractive perspective for neuroblastoma treatment. In addition to its role in tumorigenesis, MYCN sensitizes untransformed and cancer cells to apoptosis. This is associated to a fine modulation of the MDM2–p53 pathway. Indeed MYCN induces p53 and MDM2 transcription, and, by evoking a DNA damage response (DDR), it stabilizes p53 and its proapoptotic kinase Homeodomain Interacting Protein Kinase 2 (HIPK2). Through the regulation of the HIPK2-p53 inhibitor High Mobility Group protein A1 (HMGA1) and the homeobox proteins BMI-1 and TWIST-1, MYCN establishes a delicate balance between pro- and antiapoptotic molecules that might be easily perturbed by a variety of insults, leading to cell death. MDM2–p53 antagonists, such as Nutlin-3, are strikingly prone to inducing death in MYCN-amplified neuroblastoma, by further pushing on HIPK2 accumulation. Here we discuss implications and caveats of exploiting this pathway and its connections to MYCN-induced DDR for a tailored therapy of MYCN-amplified neuroblastoma.

Functional relationship between high mobility group A1 (HMGA1) protein and insulin-like growth factor-binding protein 3 (IGFBP-3) in human chondrocytes

IntroductionInsulin-like growth factor I (IGF-I) regulates articular cartilage homeostasis. During osteoarthritis (OA), the anabolic responses of chondrocytes to IGF-I are likely to be prevented by the enhanced production of IGF-binding proteins (IGFBPs), especially IGFBP-3. The aim of this study is to evaluate whether the architectural transcription factor high mobility group A1 (HMGA1) influences IGFBP-3 overexpression in vitro, in cultured chondrocytic cell lines, and ex vivo, in human osteoarthritic cartilage compared to healthy human cartilage controls.MethodsQuantitative real-time reverse transcription-PCR (qRT-PCR) was performed to assess the relative transcript levels of HMGA1 and IGFBP-3 in vitro, in the human chondrocytic cell lines T/C-28a4 and C-28/I2. An electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and transient transfection assays were performed to investigate the HMGA1-IGFBP-3 gene interaction. Samples of articular cartilage were harvested from osteoarthritic patients and controls and analyzed by qRT-PCR for HMGA1 and IGFBP-3 mRNA levels.ResultsA parallelism between HMGA1 protein levels and IGFBP-3 gene expression has been observed in T/C-28a4 and C-28/I2 cells. The interaction of HMGA1 with the IGFBP-3 gene promoter has been demonstrated by EMSA and ChIP. In transient transfections, IGFBP-3 promoter activity increased in cells overexpressing HMGA1 and decreased in cells pretreated with siRNA detected against HMGA1. IGFBP-3 mRNA expression was higher in cartilage from patients with OA, where the increased expression of IGFBP-3 closely paralleled the increased expression of HMGA1 mRNA.ConclusionsOur observations indicate that increased HMGA1 expression in human chondrocytes is associated with increased expression of IGFBP-3. It is tempting to speculate that, through the regulation of IGFBP3 expression, HMGA1 may act as a pathogenetic factor for OA.

HMGA1 expression in human gliomas and its correlation with tumor proliferation, invasion and angiogenesis

High-mobility group A1 (HMGA1) protein is an architectural transcription factor widely expressed during embryonic development and tumor progression. The purpose of this research was to investigate the expression of HMGA1 in malignant gliomas with different WHO classification and to study the correlation of HMGA1 expression with tumor proliferation, invasion, and angiogenesis. Expression of HMGA1, Ki-67, MMP-9, VEGF-A, and MVD in malignant gliomas and their correlation were studied in 60 samples of different WHO classification by use of immunohistochemistry, and in 27 randomly selected samples by use of real-time quantitative PCR. Immunohistochemistry results showed that nuclear immunostaining of HMGA1 protein was not observed in normal brain tissues but was observed in 96.7% (58 of 60) of malignant gliomas including high (+++) in 15 (25.0%), moderate (++) in 28 (46.7%), and negligible to low (0-+) in 17 (28.3%) samples. Expression of HMGA1 protein was significantly higher in glioblastoma multiforme than in WHO grade II (P = 0.002) and WHO grade III gliomas (P = 0.024). HMGA1 protein expression correlated significantly with expression of Ki-67 (r = 0.530, P = 0.000), MMP-9 (r = 0.508, P = 0.000), VEGF-A (r = 0.316, P = 0.014), and MVD (r = 0.321, P = 0.012), but not with sex (r = 0.087, P = 0.510) and age (r = -0.121, P = 0.358). Real-time quantitative PCR results, also, were indicative of HMGA1 overexpression in glioblastoma multiforme compared with WHO grade II (P = 0.043) and WHO grade III (P = 0.031) gliomas. HMGA1 gene expression correlated significantly with gene expression of Ki-67 (r = 0.429, P = 0.025), MMP-9 (r = 0.443, P = 0.024), and VEGF-A (r = 0.409, P = 0.034). These results indicated that expression of HMGA1 correlates significantly with malignancy, proliferation, invasion, and angiogenesis of gliomas. We conclude that HMGA1 may be a potential biomarker and rational therapeutic target for human tumors.

Function and mechanism of high mobility group protein A1 in tumor

High mobility group protein A1 ( HMGA1 ) are members of a superfamily of non-histone chromatin proteins,which exist widely in eukaryotic nuclei and are mainly involved in transcriptional regulation of gene expression.Recent researches show that almost all human malignant tumors have abnormal expression of HMGA1,which may have an important role in the development of cancer,but the exact mechanism is not clear yet.In cancer research,transfection system which constructed on the basis of HMGA1 will have potential value,and also could shed some light on the treatment of cancer. Key words: Neoplasms; High mobility group proteins; Oncogenes

High-mobility group A1 proteins enhance the expression of the oncogenic miR-222 in lung cancer cells

High-mobility group A1 (HMGA1) is a non-histone chromatin protein that has the ability to regulate the transcriptional activity of many genes. Overexpression of HMGA1 is associated with malignant cellular behavior in a range of human cancers but the underlying mechanism is largely unknown. Here we showed that in a cohort of non-small cell lung cancer (NSCLC) tumors, HMGA1 overexpression was immediately associated with enhanced expression of an oncogenic miRNA, namely, miR-222. Chromatin immunoprecipitation (CHIP) assay revealed that HMGA1 directly binds to the proximal promoter of miR-222 in NSCLC cells. We further showed that HMGA1 silencing reduced miR-222 transcriptional activity, whereas forced HMGA1 expression increased it, indicating that miR-222 is directly regulated by HMGA1. Based on in silico prediction, one of the putative targets of miR-222 is phosphatase 2A subunit B (PPP2R2A) which inhibits Akt phosphorylation (p-Akt). We demonstrated that miR-222 inhibited protein expression of PPP2R2A in NSCLC cells by directly interacting with its 3'-UTR region, leading to an obvious increase of p-Akt. HMGA1 silencing augmented PPP2R2A protein expression and inhibited Akt signaling, resulting in significantly retarded cell growth response to IGF-I. These results suggested that HMGA1 is a positive regulator of miR-222, and HMGA1 overexpression might contribute to dysregulation of Akt signaling in NSCLC.