High Mobility Group A1 Protein Research Articles

The critical role of HMGA2 in regulation of EMT in epithelial ovarian carcinomas.

The high mobility group A2 (HMGA2), an oncofetal protein, was shown to play a role in tumor development and progression. However, the molecular and clinical role of HMGA2 in epithelial ovarian carcinomas (EOCs) is still unknown. In the present study, EOC cell line SKOV3 was subjected to in vitro assays. Here, our findings showed that HMGA2 was highly expressed in EOC cell line SKOV3. HMGA2 knockdown promoted cell apoptosis and the cleavage of caspase 3, and decreased the B cell lymphoma 2 (Bcl-2)/Bax ratio in SKOV3. Functionally, HMGA2 knockdown resulted in reduction of SKOV3 cell migration and invasion. Mechanically, HMGA2 knockdown affected the occurrence of EMT by increasing E-cadherin gene and protein expression and decreasing the gene and protein expression of N-cadherin, slug, and vimentin. At the same time, HMGA2 also repressed the expression of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9), which was consistent with the decreased invasion capacity. In conclusion, HMGA2 is associated with migration and invasiveness and regulates the progression of EMT in the development of EOC, and HMGA2 gene and protein may be a novel therapeutic target against EOC in the clinical practice.

High-mobility group A2 overexpression is an unfavorable prognostic biomarker for nasopharyngeal carcinoma patients.

Our previous study showed that knockdown of high-mobility group A2 (HMGA2) could suppress nasopharyngeal carcinoma (NPC) cell migration, invasion, and epithelial-mesenchymal transition (EMT) process, and HMGA2 is a direct functional target of let-7 to regulate NPC cell migration, invasion, and EMT process. However, little is known about the clinical and prognostic significance of HMGA2 protein in NPC patients. The purpose of this study is to identify the clinical and prognostic roles of HMGA2 in NPC patients. We initially analyzed the microarray data and verified mRNA and protein levels of HMGA2 in NPC tissues. Immunohistochemical staining for HMGA2 protein was performed in 116 NPC patients. The associations between HMGA2 protein expression and clinicopathologic features and its prognostic significance were analyzed. In our results, we found mRNA and protein expressions of HMGA2 were upregulated in NPC tissues and cell lines. In 116 NPC tissue samples, we observed that HMGA2 protein overexpression was associated with clinical stage, lymph node metastasis, and distant metastasis. Moreover, NPC patients with high levels of HMGA2 protein expression had shorter overall survival in comparison to patients with low levels of HMGA2 protein. In multivariate analysis, HMGA2 protein overexpression was an unfavorable prognostic factor for NPC patients. In conclusion, HMGA2 is an important biomarker to predicting NPC patient's survival time.

Dysregulated protease activated receptor 1 (PAR1) promotes metastatic phenotype in breast cancer through HMGA2.

As the majority of patients with basal-like breast carcinoma present with invasive, metastatic disease that do not respond to available therapies, it is essential to identify new therapeutic targets that impact invasion and metastasis. Protease-activated receptor 1 (PAR1), a G-protein coupled receptor has been shown to act as an oncogene, but underlying mechanisms are not well understood. Here, we show that ectopic expression of functionally active PAR1 in MCF-7 cells induced a hormone-refractory, invasive phenotype representative of advanced basal-like breast carcinoma that readily formed metastatic lesions in lungs of mice. PAR1 was found to globally upregulate mesenchymal markers, including vimentin, a direct target of PAR1, and downregulate the epithelial markers including E-cadherin, as well as estrogen receptor. In contrast, non-signaling PAR1 mutant receptor did not lead to an invasive, hormone refractory phenotype. PAR1 expression increased spheroid formation and the level of stemness markers and self-renewal capacity in human breast cancer cells. We identified HMGA2 (high mobility group A2) as an important regulator of PAR1-mediated invasion. Inhibition of PAR1 signaling suppresses HMGA2-driven invasion in breast cancer cells. HMGA2 gene and protein are highly expressed in metastatic breast cancer cells. Overall, our results show that PAR1/HMGA2 pathway may present a novel therapeutic target.

P34. Role of high-mobility group A1 protein in trophoblast invasion

Objectives Early in pregnancy, abundant neovascularization at the implantation site is important for normal placentation. For placental development and reduction of uterine vascular resistance, cytotrophoblasts must migrate to the decidua and the uterine myometrium, with subsequent invasion of the spiral arteries resulting in the spiral artery remodeling. Especially, extravillous trophoblasts (EVT) invade into the uterine decidual spiral arterioles and regulate the remodeling of these vessels for fetal blood supply. While, disturbed arterial remodeling can lead to the serious complications such as preeclampsia and fetal growth restriction. High-mobility group A1 protein (HMGA1) is known to play an important role in the proliferation of trophoblast; however, no specific function of HMGA1 has been reported for trophoblast invasion. The aim of this study was to evaluate the effect of HMGA1 on trophoblast invasion. Methods We investigated HMGA1 expressions in cytotrophoblast derived from preeclampsia model mouse, CD40-L mouse, using immunofluorescence analysis. Wound healing cell migration and matrigel invasion test was also performed using HTR-8/SVneo cells transfected with HMGA1 plasmid. Results HMGA1 was expressed in nucleus of trophoblasts derived from control mouse; in contrast, cytoplasmic expression was observed in CD40-L mouse. HMGA1 plasmid stimulated cell migration and invasion in HTR/SVneo cells; however, extranuclear translocation of HMGA1 suppressed cell migration and invasion. Conclusions Cellular localization disorder of HMGA1 resulted in a lowering of its invasions and migration. Transfer of HMGA1 in cytotrophoblast is crucial for the trophoblast invasion into decidua in preeclampsia.

Deregulation of HMGA1 expression induces chromosome instability through regulation of spindle assembly checkpoint genes.

The mitotic spindle assembly checkpoint (SAC) is an essential control system of the cell cycle that contributes to mantain the genomic stability of eukaryotic cells. SAC genes expression is often deregulated in cancer cells, leading to checkpoint impairment and chromosome instability. The mechanisms responsible for the transcriptional regulation and deregulation of these genes are still largely unknown. Herein we identify the nonhistone architectural nuclear proteins High Mobility Group A1 (HMGA1), whose overexpression is a feature of several human malignancies and has a key role in cancer progression, as transcriptional regulators of SAC genes expression. In particular, we show that HMGA1 proteins are able to increase the expression of the SAC genes Ttk, Mad2l1, Bub1 and Bub1b, binding to their promoter regions. Consistently, HMGA1-depletion induces SAC genes downregulation associated to several mitotic defects. In particular, we observed a high number of unaligned chromosomes in metaphase, a reduction of prometaphase time, a delay of anaphase, a higher cytokinesis time and a higher percentage of cytokinesis failure by using live-cell microscopy. Finally, a significant direct correlation between HMGA1 and SAC genes expression was detected in human colon carcinomas indicating a novel mechanism by which HMGA1 contributes to cancer progression.

RNA-Mediated Regulation of HMGA1 Function.

The high mobility group protein A1 (HMGA1) is a master regulator of chromatin structure mediating its major gene regulatory activity by direct interactions with A/T-rich DNA sequences located in the promoter and enhancer regions of a large variety of genes. HMGA1 DNA-binding through three AT-hook motifs results in an open chromatin structure and subsequently leads to changes in gene expression. Apart from its significant expression during development, HMGA1 is over-expressed in virtually every cancer, where HMGA1 expression levels correlate with tumor malignancy. The exogenous overexpression of HMGA1 can lead to malignant cell transformation, assigning the protein a key role during cancerogenesis. Recent studies have unveiled highly specific competitive interactions of HMGA1 with cellular and viral RNAs also through an AT-hook domain of the protein, significantly impacting the HMGA1-dependent gene expression. In this review, we discuss the structure and function of HMGA1-RNA complexes during transcription and epigenomic regulation and their implications in HMGA1-related diseases.

Molecular Evaluation of Transformation‐Induced Methylation of the High Mobility Group A1 (HMGA1) Chromatin Binding Proteins

Aberrant expression of high mobility group A1 (hmga1), resulting from inactivating defects in upstream tumor suppressor genes or upregulation of oncogenic transactivators, induces the initiation of cancer progression pathways. The protein products of hmga1, HMGA1a and HMGA1b, are characterized by the presence of three DNA-binding motifs that possess a central RGR sequence and preferentially bind to the minor-groove of AT-rich stretches of target DNA. Importantly, R25 of the RGR sequence within the first DNA-binding motif bears covalent modifications that may recruit or repel specific transcriptional regulators in cancer cells. Despite the implication of hmga1 and arginine methylation in oncogenic function, the role of epigenetic regulation of hmga1 by arginine methylation has not been evaluated. Here, we investigate the impact of R25 substitutions on HMGA1b binding DNA targets using fluorescence spectroscopy and functional cellular assays. R25 substitutions disrupt DNA binding to various targets and suppress HMGA1-dependent oncogenic transformation. Together, our data reveals new potential anti-cancer strategies by targeting HMGA1 protein methylation and downstream targets.

Let-7a inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2 in nasopharyngeal carcinoma.

BackgroundLet-7a has been shown to play important roles in nasopharyngeal carcinoma (NPC) cell proliferation and apoptosis, but little is known about the function and mechanism of let-7a in nasopharyngeal carcinoma metastasis. We aimed to investigate the function and mechanism of let-7a in nasopharyngeal carcinoma metastasis and clarified the regulation of high mobility group A2 (HMGA2) by let-7a.MethodsThe expression levels of let-7a and HMGA2 were examined in NPC clinical specimens using quantitative reverse transcription-PCR (RT-qPCR). HMGA2 was confirmed as a target of let-7a through luciferase reporter assays, RT-qPCR, and Western blotting. Furthermore, the roles of let-7a and HMGA2 in regulating NPC cells biological properties including proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process were analyzed with let-7a mimics and si-HMGA2 transfected cells.ResultsOur study demonstrated that let-7a was downregulated and inversely associated with the clinical stage, T classification and N classification, and HMGA2 was upregulated and directly associated with the clinical stage and N classification in patients with NPC. Moreover, there was an inverse correlation between let-7a expression and HMGA2 expression in NPC patient. In addition, HMGA2 was negatively regulated at the posttranscriptional level by let-7a via a binding site of HMGA2-3′UTR. In addition, synthetic let-7a mimics suppressed NPC cells migration, invasion and EMT process and knockdown of HMGA2 was consistent with the effects of let-7a in NPC cells.ConclusionLet-7a directly downregulates HMGA2 protein expression, which suppress NPC cell migration, invasion and EMT process. Let-7a could serve as a potential diagnostic marker and therapeutic target for NPC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0462-8) contains supplementary material, which is available to authorized users.

Overexpression of HMGA1 correlates with the malignant status and prognosis of breast cancer

High mobility group A1 (HMGA1), as a major member of HMGA family, plays an important part in promotion of cell proliferation and motility, induction of epithelial-mesenchymal transition, and maintenance of stemness, but little is known about the pathological role of HMGA1 in breast cancer patients. The aim of this study was to identify the pathological roles of HMGA1 in breast cancer. In our results, we found that mRNA and protein expression levels of HMGA1 were markedly higher in breast cancer tissues than in normal breast tissues. Using immunohistochemistry, high levels of HMGA1 protein were positively correlated with the status of histological grade (I-II vs. III-IV; P = 0.023), clinical stage (I-II vs. III-IV; P = 0.008), tumor size (T1-T2 vs. T3-T4; P = 0.015), lymph node metastasis (N0-N1 vs. N2-N3; P = 0.002), distant metastasis (M0 vs. M1; P < 0.001), and triple-negative breast cancer (No vs. Yes; P = 0.014) of breast cancer patients. Patients with higher HMGA1 expression had a significantly shorter overall survival time than did patients with low HMGA1 expression. Multivariate analysis indicated that the level of HMGA1 expression was an independent prognostic indicator (P < 0.001) for the survival of patients with breast cancer. In conclusion, HMGA1 plays an important role on breast cancer aggressiveness and prognosis and may act as a promising target for prognostic prediction.

HMGA1 drives metabolic reprogramming of intestinal epithelium during hyperproliferation, polyposis, and colorectal carcinogenesis.

Although significant progress has been made in the diagnosis and treatment of colorectal cancer (CRC), it remains a leading cause of cancer death worldwide. Early identification and removal of polyps that may progress to overt CRC is the cornerstone of CRC prevention. Expression of the High Mobility Group A1 (HMGA1) gene is significantly elevated in CRCs as compared with adjacent, nonmalignant tissues. We investigated metabolic aberrations induced by HMGA1 overexpression in small intestinal and colonic epithelium using traveling wave ion mobility mass spectrometry (TWIMMS) in a transgenic model in which murine Hmga1 was misexpressed in colonic epithelium. To determine if these Hmga1-induced metabolic alterations in mice were relevant to human colorectal carcinogenesis, we also investigated tumors from patients with CRC and matched, adjacent, nonmalignant tissues. Multivariate statistical methods and manual comparisons were used to identify metabolites specific to Hmga1 and CRC. Statistical modeling of data revealed distinct metabolic patterns in Hmga1 transgenics and human CRC samples as compared with the control tissues. We discovered that 13 metabolites were specific for Hmga1 in murine intestinal epithelium and also found in human CRC. Several of these metabolites function in fatty acid metabolism and membrane composition. Although further validation is needed, our results suggest that high levels of HMGA1 protein drive metabolic alterations that contribute to CRC pathogenesis through fatty acid synthesis. These metabolites could serve as potential biomarkers or therapeutic targets.

The high mobility group A2 protein epigenetically silences the Cdh1 gene during epithelial-to-mesenchymal transition.

The loss of the tumour suppressor E-cadherin (Cdh1) is a key event during tumourigenesis and epithelial–mesenchymal transition (EMT). Transforming growth factor-β (TGFβ) triggers EMT by inducing the expression of non-histone chromatin protein High Mobility Group A2 (HMGA2). We have previously shown that HMGA2, together with Smads, regulate a network of EMT-transcription factors (EMT-TFs) like Snail1, Snail2, ZEB1, ZEB2 and Twist1, most of which are well-known repressors of the Cdh1 gene. In this study, we show that the Cdh1 promoter is hypermethylated and epigenetically silenced in our constitutive EMT cell model, whereby HMGA2 is ectopically expressed in mammary epithelial NMuMG cells and these cells are highly motile and invasive. Furthermore, HMGA2 remodels the chromatin to favour binding of de novo DNA methyltransferase 3A (DNMT3A) to the Cdh1 promoter. E-cadherin expression could be restored after treatment with the DNA de-methylating agent 5-aza-2′-deoxycytidine. Here, we describe a new epigenetic role for HMGA2, which follows the actions that HMGA2 initiates via the EMT-TFs, thus achieving sustained silencing of E-cadherin expression and promoting tumour cell invasion.

High Mobility Group A1 (HMGA1) Chromatin Remodeling Protein Mediates Crosstalk Between Acute Myeloid Leukemia Blasts & the Tumor Microenvironment

Introduction: Acute myeloid leukemias (AMLs) are highly lethal hematologic malignancies that arise from diverse genetic abnormalities in hematopoietic progenitor cells. Unfortunately, most patients with AML will die of their disease due to failure of currently available cytotoxic chemotherapies. Accordingly, there is an urgent need to better understand the biologic interactions between AML blasts and signals from bone marrow stromal cells (BMSCs) within the niche that support their survival and protect them from exposure to chemotherapy. The high mobility group A1 (HMGA1) chromatin remodeling proteins are present at high levels during development and enriched in AML blasts, leukemic stem cells, diverse solid tumors, embryonic stem cells, and adult stem cells, such as hematopoietic stem cells (HSCs). HMGA1 proteins regulate gene expression by modulating chromatin structure and recruiting NF-κB and other transcription factor complexes to DNA. We discovered that HMGA1 acts as a potent oncogene in transgenic mouse and cultured cell models (Xu et. al, Cancer Research, 2004) by inducing stem cell transcriptional networks (Schuldenfrei et. al, BMC Genomics, 2011, Shah et. al, PLoS ONE, 2013). Here, we describe a novel role for HMGA1 in mediating crosstalk between AML blasts and BMSCs within the bone marrow microenvironment.Methods & Results: To investigate HMGA1 in regulating AML-niche signaling, we used potent lentiviruses to deliver short hairpin RNA and silence HMGA1 in AML blasts or BMSCs. We found that silencing HMGA1 rapidly halts proliferation and induces apoptotic cell death in 3 different AML cell lines. To determine how HMGA1 mediates survival in AML blasts, we assessed expression of pro-survival genes in AML cell lines and primary AML blasts, including those encoding NF-E2-related factor 2 (NRF2), cMYC, and the C-X-C chemokine receptor type 4 (CXCR4). CXCR4 is the receptor for stromal cell-derived factor 1 (SDF-1 or CXCL12), a growth factor secreted by BMSCs that also serves as a chemo-attractant for AML blasts or HSCs within the bone marrow microenvironment. We found that silencing HMGA1 represses expression of NRF2, cMYC, and CXCR4. This led us to hypothesize that HMGA1 regulates crosstalk between AML blasts and the leukemic cell niche via CXCR4 and SDF-1. To test this, we silenced HMGA1 in cultured AML cells and assessed migration in the presence of SDF-1. Strikingly, migration was significantly impaired in the AML cells with HMGA1 knock-down. Next, we silenced HMGA1 in primary, patient-derived BMSCs, which were co-cultured with primary AML blasts from the same patients to mimic the bone marrow microenvironment. We found that knock-down of HMGA1 in BMSCs also results in apoptosis in primary AML blasts.Conclusions: Together, our results demonstrate for the first time that HMGA1 mediates AML survival through cell-autonomous pathways in AML blasts and through non-cell-autonomous crosstalk from BMSCs within the bone marrow microenvironment. Studies are underway to determine if HMGA1 directly regulates expression of SDF-1 or other factors secreted by BMSCs within the hematopoietic niche. This knowledge should inform biologically rational strategies to enhance existing treatments and facilitate the design of novel therapies. DisclosuresNo relevant conflicts of interest to declare.

High mobility group A1 protein expression reduces the sensitivity of colon and thyroid cancer cells to antineoplastic drugs.

BackgroundDevelopment of resistance to conventional drugs and novel biological agents often impair long-term chemotherapy. HMGA gene overexpression is often associated with antineoplastic drug resistance and reduced survival. Inhibition of HMGA expression in thyroid cancer cells reduces levels of ATM protein, the main cellular sensor of DNA damage, and enhances cellular sensitivity to DNA-damaging agents. HMGA1 overexpression promotes chemoresistance to gemcitabine in pancreatic adenocarcinoma cells through an Akt-dependent mechanism.MethodsTo elucidate the role of HMGA1 proteins in chemoresistance we analyzed resistance to conventional drugs and targeted therapies of human colon carcinoma cells (GEO) that are sensitive to the epidermal growth factor receptor inhibitor cetuximab, and express minimal levels of HMGA1 and cetuximab-resistant (GEO CR) cells expressing high HMGA1 protein levels.ResultsGEO CR cells were less sensitive than GEO cells to cetuximab and 5-fluorouracil. GEO CR cells silenced for HMGA1 expression were more susceptible than empty vector-transfected cells to the drugs’ cytotoxicity. Similar results were obtained with anaplastic thyroid carcinoma cells expressing or not HMGA1 proteins, treated with doxorubicin or the HDAC inhibitor LBH589. Finally, HMGA1 overexpression promoted the DNA-damage response and stimulated Akt phosphorylation and prosurvival signaling.ConclusionsOur findings suggest that the blockage of HMGA1 expression is a promising approach to enhance cancer cell chemosensitivity, since it could increase the sensitivity of cancer cells to antineoplastic drugs by inhibiting the survival signal and DNA damage repair pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-851) contains supplementary material, which is available to authorized users.

Elevated expression of HMGA1 correlates with the malignant status and prognosis of non-small cell lung cancer.

High-mobility group A1 (HMGA1) has been suggested to play a significant role in tumor progression, but little is known about the accurate significance of HMGA1 in non-small cell lung cancer (NSCLC) patients. The aim of this study was to identify the role of HMGA1 in NSCLC. The expression status of HMGA1 was observed initially in NSCLC by Gene Expression Omnibus (GEO). The expression of HMGA1 messenger RNA (mRNA) and protein was examined in NSCLC and adjacent normal lung tissues through real-time PCR and immunohistochemistry. Meanwhile, the relationship of HMGA1 expression levels with clinical features and prognosis of NSCLC patients was analyzed. In our results, HMGA1 was overexpressed in NSCLC tissues compared with adjacent normal lung tissues in microarray data (GSE19804). HMGA1 mRNA and protein expressions were markedly higher in NSCLC tissues than in normal lung tissues (P < 0.001 and P = 0.010, respectively). Using immunohistochemistry, high levels of HMGA1 protein were positively correlated with the status of clinical stage (I-II vs. III-IV, P < 0.001), T classification (T1-T vs. T3-T4, P = 0.003), N classification (N0N1 vs. N2-N3, P < 0.001), M classification (M0 vs. M1, P = 0.002), and differentiated degree (high or middle vs. low or undifferentiated, P = 0.003) in NSCLC. Patients with higher HMGA1 expression had a significantly shorter overall survival time than did patients with low HMGA1 expression. Multivariate analysis indicated that the level of HMGA1 expression was an independent prognostic factor (P < 0.001) for the survival of patients with NSCLC. In conclusion, HMGA1 plays an important role on NSCLC progression and prognosis and may act as a convictive biomarker for prognostic prediction.

Coexpression of HMGA2 and Oct4 predicts an unfavorable prognosis in human gastric cancer.

High mobility group protein A2 (HMGA2) and octamer-binding transcription factor 4 (Oct4) are transcription factors that play major roles in the acquisition of cancer stemness phenotypes and tumorigenicity of malignant neoplasms. The aim of this study was to analyze the association between HMGA2 and Oct4 expression and various clinicopathologic features in gastric cancer patients including invasion, metastasis, and clinical prognosis, in addition to overall survival. Immunohistochemistry was performed to explore the expression of HMGA2 and Oct4 in 158 gastric cancer and surrounding non-tumor tissues. Moreover, HMGA2 and Oct4 mRNA and protein levels were also detected by qRT-PCR and Western blotting, respectively, in 86 clinical tissue specimens and various gastric epithelial cell lines (GES-1, SGC7901, MKN45, and MKN27). Finally, associations between HMGA2 and Oct4 expression and clinicopathological features were analyzed by Pearson correlation coefficient. Survival analysis was performed by univariate and multivariate analyses. Taken together, we found that HMGA2 and Oct4 expression was significantly higher in gastric cancer tissues compared with non-cancerous tissues (P < 0.01), and HMGA2 and Oct4 protein levels were significantly higher in poorly differentiated gastric cancer cell lines (MKN45), moderately differentiated cell lines (SGC7901), and well-differentiated cell lines (MKN28) compared with human immortalized gastric epithelial cell lines (GES-1) (P < 0.01). Elevated HMGA2 and Oct4 levels were significantly associated with poor clinical prognosis (P < 0.05). Further conclusion showed that coexpression of HMGA2 and Oct4 in gastric cancer correlated with tumor invasion, metastasis, and clinical prognosis and predicted an unfavorable clinical outcome. These transcription factors may represent useful biomarkers to identify patients at high risk of postoperative recurrence.

HMGA2 is down-regulated by microRNA let-7 and associated with epithelial-mesenchymal transition in oesophageal squamous cell carcinomas of Kazakhs

To investigate the expression of let-7 and its regulation of high-mobility group A2 protein (HMGA2), and to verify the relationship between let-7, HMGA2 and the process of epithelial-mesenchymal transition (EMT), in oesophageal squamous cell carcinomas (OSCC) of Kazakh patients. Expression of let-7 was significantly lower in Eca109 cells than in normal oesophageal squamous epithelium (P = 2.4 × 10(-7) ). Increased accumulation of let-7 after transfection of Eca109 cells with synthetic let-7 inhibited cell proliferation. Let-7 could repress expression of HMGA2 after co-transfection with let-7 and HMGA2 (P = 0.002). Moreover, let-7 expression was observed less frequently (P = 2.0 × 10(-8) ), and HMGA2 expression more frequently (P = 1.0 × 10(-10) ), in OSCC than in normal adjacent tissues; and let-7 expression was observed less frequently in OSCC from Kazakh patients than in those from Han and Uygur patients (P = 0.041). There was a reverse correlation between expression of let-7 and HMGA2 (P = 0.018). Expression of Snail was statistically higher in Kazakhs' OSCC (P = 0.029), and was correlated with depth of invasion (P = 0.021) and HMGA2 expression (P = 0.026). Expression of let-7 can suppress cell proliferation by acting directly on regulation of HMGA2 in OSCC. High expression of Snail and its correlation with HMGA2 expression and tumour invasion suggest that HMGA2 may be involved in EMT in the OSCC of Kazakh patients.

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

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

HMGA1 silencing restores normal stem cell characteristics in colon cancer stem cells by increasing p53 levels.

High-mobility group A1 (HMGA1) proteins are architectural chromatinic proteins, abundantly expressed during embryogenesis and in most cancer tissues, but expressed at low levels or absent in normal adult tissues. Several studies have demonstrated that HMGA1 proteins play a causal role in neoplastic cell transformation. The aim of this study was to investigate the role of these proteins in the control of cancer stem cells (CSCs), which have emerged as a preferred target in cancer therapy, because of their role in cancer recurrence. We observed that HMGA1 is overexpressed in colon tumour stem cell (CTSC) lines compared to normal and colon cancer tissues. We demonstrated that HMGA1 silencing in CTSCs increases stem cell quiescence and reduces self-renewal and sphere-forming efficiency (SFE). The latter, together with the upregulation and asymmetric distribution of NUMB, is indicative of the recovery of an asymmetric division pattern, typical of normal stem cells. We further found that HMGA1 transcriptionally regulates p53, which is known to control the balance between symmetric and asymmetric divisions in CSCs. Therefore, our data indicate a critical role for HMGA1 in regulating both self-renewal and the symmetric/asymmetric division ratio in CSCs, suggesting that blocking HMGA1 function may be an effective anti-cancer therapy.

HMGA1 Interacts with β-Catenin to Positively Regulate Wnt/β-Catenin Signaling in Colorectal Cancer Cells

The high mobility group A1 (HMGA1) protein plays an important role in numerous biological processes, such as embryogenesis, cell proliferation, differentiation, apoptosis and carcinogenesis. Wnt/β-catenin signaling pathway plays a key role in development and cancer. Although previous reports have shown HMGA1 protein level can be induced by Wnt/β-catenin signaling pathway, however, the specific mechanism of HMGA1 on regulating Wnt/β-catenin signaling remains unclear. Here, we reported that HMGA1 interacted with β-catenin by using coimmunoprecipitation approach with exogenous and endogenous protein samples. HMGA1 positively regulated Wnt/β-catenin signaling, as determined by that HMGA1 increased the TOP-FLASH activity in a dose-dependent manner and β-catenin downstream target gene expression. Moreover, HMGA1 induced proliferation of colorectal cancer cells. Mechanistically, HMGA1 increased the β-catenin-TCF4 complex formation. Importantly, there was a correlation between HMGA1 and β-catenin expression in human colorectal cancer tissues. In summary, HMGA1 positively regulates Wnt/β-catenin signaling through interacting with β-catenin, which leads to increase the β-catenin-TCF4 complex formation. This suggests that targeting HMGA1 may be a useful therapeutic option in clinical application.

Correlation between the expression of high mobility group protein A2 and epithelial-mesenchymal transition in esophageal squamous cell carcinoma of Kazakh ethnic

Objective To investigate the expression of high mobility group protein A2 (HMGA2) in esophageal squamous cell carcinoma (ESCC) of Kazakh ethnic and its regulation role in epithelial-mesenchymal transition (EMT).Methods The expression of HMGA2 and EMT related protein Snail and E-cadherin in carcinoma tissues and adjacent tissues of 72 Kazakh with ESCC was detected by immunohistochemistry (IHC) SP method,and the correlation among these proteins and invasion as well as metastasis of ESCC was analyzed.McNemar's test and Chi square test were performed for the rate comparison.Spearman method was used for correlation analysis.Results The positive rate of HMGA2 and Snail expression in carcinoma tissues of patients with ESCC was 83.3％ (60/72) and 45.8％ (33/72),which were higher than those of adjacent tissues (52.8 ％,38/72,McNemar's test,P＜0.01 ; 29.2 ％,21/72,McNemar's test,P＜ 0.05).The expression of HMGA2 was positively correlated with the expression of Snail in adjacent tissues (r=0.262,P＜0.05).The positive expression rate of E-cadherin in carcinoma tissues was 40.3 ％ (29/72),which was significantly lower than the expression in carcinoma adjacent tissues (72.2％,52/72,McNemar's test,P＜0.01).The expression of Snail was correlated with depth of tumor invasion.The expression quantity of Snail in patients with tumor invasion to the outer membrane of the esophagus and surrounding tissues was significantly higher than that in patients with tumor invasion to mucous layer and muscular layer (x2 =5.308,P＜0.05).The expression of E-cadherin was correlated with the age of patients and the degree of tumor differentiation.The expression of E-cadherin was higher in patients less than 58 years old (x2 =3.952,P＜0.05) and with high degree of differentiation (x2 =8.080,P＜0.05).Conclusion The low expressions of E-cadherin and the high expressions of HMGA2 and Snail in carcinoma tissues of Kazakh's patients with ESCC indicates that EMT may participate in the genesis and development of ESCC. Key words: Esophageal neoplasms; Kazakh; HMGA2 protein; Immunohistochemistry; Epithelial mesenchymal transition