Chen YN, Ren CC, Yang L, et al.MicroRNA let‑7d‑5p rescues ovarian cancer cell apoptosis and restores chemosensitivity by regulating the p53 signaling pathway via HMGA1.
Int J Oncol. 2019; 54(5):1771-1784 [PubMed
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Ovarian cancer (OC) is the gynecological malignancy type with the highest mortality rate in females. The regulatory effect of microRNAs (miRs) on their target genes serves a key role in tumor development. Therefore, in the present study, whether miR let‑7d‑5p targeting high mobility group A1 (HMGA1) regulated biological characteristics and chemosensitivity of OC cells by mediating the p53 signaling pathway was investigated. The let‑7d‑5p level was detected in OC tissues and adjacent normal tissues, followed by detection in OC cell lines SKOV3, A2780, OVCAR‑3 and CaOV3, and human normal ovarian epithelial cell line (IOSE‑80), in order to select the OC cell line for the following experiments. Subsequently, OC cells were treated with the let‑7d‑5p mimic, siHMGA1 and Tenovin‑1. The targeting association between let‑7d‑5p and HMGA1 was then examined, and the OC cell viability, migration, cycle and apoptosis were evaluated. Subsequently, the chemosensitivity of OC cells to cisplatin was verified. Finally, expression levels of let‑7d‑5p, HMGA1, p21, B‑cell lymphoma‑2 (Bcl‑2)‑associated X (Bax), p27, p53 wild‑type (p53wt), p53 mutated (p53mut), proliferating cell nuclear antigen (PCNA), cyclin‑dependent kinase 2 (CDK2), matrix metallopeptidase (MMP)2, MMP9 and Bcl‑2 were determined. As demonstrated in the results, let‑7d‑5p expression was low in OC tissues and had an increased reduction in the OVCAR‑3 cell line. HMGA1 was confirmed as a target of let‑7d‑5p, and its expression was also silenced by let‑7d‑5p. let‑7d‑5p repressed OC cell viability, migration, cell cycle progression and apoptosis, while it promoted the chemosensitivity of OC cells to cisplatin by targeting HMGA1. The expression of let‑7d‑5p, p21, Bax, p27 and p53wt was increased, while that of HMGA1, p53mut, PCNA, CDK2, MMP2, MMP9 and Bcl‑2 was reduced following cell transfection. The results in the present study provided evidence that let‑7d‑5p may suppress proliferation, and facilitate apoptosis and cisplatin chemosensitivity of OC cells by silencing HMGA1 via the p53 signaling pathway.
DNA methylation is recognized as one of several epigenetic regulators of gene expression and as potential driver of carcinogenesis through gene-silencing of tumor suppressors and activation of oncogenes. However, abnormal methylation, even of promoter regions, does not necessarily alter gene expression levels, especially if the gene is already silenced, leaving the exact mechanisms of methylation unanswered. Using a large cohort of matching DNA methylation and gene expression samples of colorectal cancer (CRC; n = 77) and normal adjacent mucosa tissues (n = 108), we investigated the regulatory role of methylation on gene expression. We show that on a subset of genes enriched in common cancer pathways, methylation is significantly associated with gene regulation through gene-specific mechanisms. We built two classification models to infer gene regulation in CRC from methylation differences of tumor and normal tissues, taking into account both gene-silencing and gene-activation effects through hyper- and hypo-methylation of CpGs. The classification models result in high prediction performances in both training and independent CRC testing cohorts (0.92
Ohe K, Miyajima S, Abe I, et al.HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells.
J Steroid Biochem Mol Biol. 2018; 182:21-26 [PubMed
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The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells.
High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating
Sgarra R, Pegoraro S, Ros G, et al.High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression.
Biochim Biophys Acta Rev Cancer. 2018; 1869(2):216-229 [PubMed
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Cancer heterogeneity is one of the factors that constitute an obstacle towards an efficient targeting of this multifaceted disease. Molecular information can help in classifying cancer subtypes and in providing clinicians with novel targeted therapeutic opportunities. In this regard, classification of breast cancer into intrinsic subtypes based on molecular profiling represents a valuable prototype. The High Mobility Group A (HMGA) chromatin architectural factors (HMGA1a, HMGA1b, and HMGA2) have a relevant and causal role in breast cancer onset and development, by influencing virtually all cancer hallmarks. The regulation of HMGA expression is under the control of major pathways involved in cell proliferation and survival, as well as in other cancer-related processes, thereby suggesting, for the HMGA members, a high degree of homology and overlapping activities. Despite of this evidence, HMGA proteins display also specific functions. In this review, we provide an overview of (i) the pathways involved in HMGA transcriptional and post-transcriptional regulation, (ii) the utilization of HMGA as molecular markers, and (iii) the biological role of HMGA in the context of breast cancer. We focus on the potential significance of HMGA in governing the onset and development of this tumour, as well as on the potential of these factors as novel specific targets for preventing and treating strategies. The emerging picture is a highly interconnected triad of proteins that could mutually influence each other, either in a competitive or cooperative manner, and that, in our opinion, should be considered as a unified and integrated protein system.
Childhood neuroblastoma is one of the most common types of extra-cranial cancer affecting children with a clinical spectrum ranging from spontaneous regression to malignant and fatal progression. In order to improve the clinical outcomes of children with high-risk neuroblastoma, it is crucial to understand the tumorigenic mechanisms that govern its malignant behaviors. MYCN proto-oncogene, bHLH transcription factor (MYCN) amplification has been implicated in the malignant, treatment-evasive nature of aggressive, high-risk neuroblastoma. In this study, we used a SILAC approach to compare the proteomic signatures of MYCN-amplified IMR-32 and non-MYCN-amplified SK-N-SH human neuroblastoma cells. Tumorigenic proteins, including fatty-acid binding protein 5 (FABP5), L1-cell adhesion molecule (L1-CAM), baculoviral IAP repeat containing 5 [BIRC5 (survivin)] and high mobility group protein A1 (HMGA1) were found to be significantly upregulated in the IMR-32 compared to the SK-N-SH cells and mapped to highly tumorigenic pathways including, MYC, MYCN, microtubule associated protein Tau (MAPT), E2F transcription factor 1 (E2F1), sterol regulatory element binding transcription factor 1 or 2 (SREBF1/2), hypoxia-inducible factor 1α (HIF-1α), Sp1 transcription factor (SP1) and amyloid precursor protein (APP). The transcriptional knockdown (KD) of MYCN, HMGA1, FABP5 and L1-CAM significantly abrogated the proliferation of the IMR-32 cells at 48 h post transfection. The early apoptotic rates were significantly higher in the IMR-32 cells in which FABP5 and MYCN were knocked down, whereas cellular migration was significantly abrogated with FABP5 and HMGA1 KD compared to the controls. Of note, L1-CAM, HMGA1 and FABP5 KD concomitantly downregulated MYCN protein expression and MYCN KD concomitantly downregulated L1-CAM, HMGA1 and FABP5 protein expression, while survivin protein expression was significantly downregulated by MYCN, HMGA1 and FABP5 KD. In addition, combined L1-CAM and FABP5 KD led to the concomitant downregulation of HMGA1 protein expression. On the whole, our data indicate that this inter-play between MYCN and the highly tumorigenic proteins which are upregulated in the malignant IMR-32 cells may be fueling their aggressive behavior, thereby signifying the importance of combination, multi-modality targeted therapy to eradicate this deadly childhood cancer.
Palumbo A, De Martino M, Esposito F, et al.HMGA2, but not HMGA1, is overexpressed in human larynx carcinomas.
Histopathology. 2018; 72(7):1102-1114 [PubMed
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AIMS: Malignant tumours from the upper aerodigestive tract are grouped collectively in the class of head and neck squamous cell carcinoma (HNSCC). The head and neck tumours were responsible for more than 500 000 cancer cases in 2012, accounting for the sixth highest incidence rate and mortality worldwide among all tumour types. Laryngeal squamous cell carcinoma (LSCC) possesses the second highest incidence rate among all HNSCC. Despite significant advances in surgery and radiotherapy during the last few decades, no treatment has been shown to achieve a satisfactory therapeutic outcome and the mortality rate of LSCC is still high, with a 5-year survival rate of 64%. Therefore, further investigations are required to identify the pathogenesis of LSCC.
METHODS AND RESULTS: In order to search for new LSCC biomarkers, we have analysed the expression of the HMGA family members, HMGA1 and HMGA2, by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. HMGA proteins are usually absent in the healthy adult tissues. In contrast, their constitutive expression is a feature of several neoplasias, being associated with a highly malignant phenotype and reduced survival. Here, we report HMGA2 overexpression in larynx carcinomas. Conversely, HMGA1 does not show any differences in its expression between normal and carcinoma tissues. Interestingly, HMGA2 overexpression appears associated with that of two HMGA1-pseudogenes, HMGA1P6 and HMGA1P7, acting as a sponge for HMGA1- and HMGA2-targeting microRNAs and involved in several human cancers.
CONCLUSIONS: Therefore, HMGA2 overexpression appears to be a strong feature of larynx carcinoma, supporting its detection as a valid tool for the diagnosis of these malignancies.
Hepatocellular carcinoma (HCC) is one of the major causes of cancer‑related mortality, and the prognosis of HCC patients is unsatisfactory. It is known that the occurrence and development of HCC involves numerous genes, as well as various steps and stages in the pathological process. High mobility group AT‑hook 1 (HMGA1) and integrin‑linked kinase (ILK) may be overexpressed in HCC and may serve important roles in the development of cancer; however, the relationship between HMGA1 and ILK in HCC has not been examined. The present study demonstrated that inhibition of HMGA1 expression significantly decreased the levels of expression of ILK and the downstream elements phosphorylated (p)‑Akt, p‑glycogen synthase kinase 3β (GSK3β), matrix metalloproteinase (MMP)2, MMP9, CyclinD1 and c‑Myc. Transfection with an ILK expression vector was able to recover the decreased expression of these downstream genes, and affected cell proliferation and apoptosis. In addition, results from Transwell and wound‑healing experiments indicated that HMGA1 participates cell invasion and migration through the ILK/Akt/GSK3β pathway. The present study aimed to improve our understanding about the regulatory pathway involved in HCC and provides the basis for exploring HMGA1 inhibition as a therapy for patients with HCC and a new treatment strategy to prevent the development of HCC.
DNA replication control is vital for maintaining genome stability and the cell cycle, perhaps most notably during cell division. Malignancies often exhibit defective minichromosome maintenance protein 2 (MCM2), a cancer proliferation biomarker that serves as a licensing factor in the initiation of DNA replication. MCM2 is also known to be one of the ATPase active sites that facilitates conformational changes and drives DNA unwinding at the origin of DNA replication. However, the biological networks of MCM2 in lung cancer cells via protein phosphorylation remain unmapped. The RNA-seq datasets from The Cancer Genome Atlas (TCGA) revealed that MCM2 overexpression is correlated with poor survival rate in lung cancer patients. To uncover MCM2-regulated functional networks in lung cancer, we performed multi-dimensional proteomic approach by integrating analysis of the phosphoproteome and proteome, and identified a total of 2361 phosphorylation sites on 753 phosphoproteins, and 4672 proteins. We found that the deregulation of MCM2 is involved in lung cancer cell proliferation, the cell cycle, and migration. Furthermore, HMGA1
Chandrasekaran KS, Sathyanarayanan A, Karunagaran DmiR-214 activates TP53 but suppresses the expression of RELA, CTNNB1, and STAT3 in human cervical and colorectal cancer cells.
Cell Biochem Funct. 2017; 35(7):464-471 [PubMed
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High Mobility Group AT-hook 1 (HMGA1) was identified as a target of miR-214 in human cervical and colorectal cancers (CaCx and CRC) in a previous study. While the expression of miR-214 remains suppressed, HMGA1 behaves as a potent oncogene and plays crucial roles in several aberrant signalling pathways by interacting with intermediates like RELA, CTNNB1, STAT3, and TP53 in CaCx and CRC. Hypothetically, miR-214 should be able to regulate the stabilization of some of these intermediates through the regulation of HMGA1. This was assessed by ectopically expressing miR-214 or complementarily, by inhibiting the expression of HMGA1. In promoter luciferase assays, miR-214 inhibited NF-κB and Wnt activities but elevated TP53 activity in cancer cells. Further, miR-214 suppressed the expression of HMGA1, RELA, CTNNB1, and STAT3 while elevating TP53 levels, similar to when small interfering RNA (siRNA) against HMGA1 was used, as revealed by Western blotting. It is suggested that poor expression of miR-214, commonly reported in CaCx and CRC tissues, may not only result in the sustained expression of HMGA1 but also that of RELA, CTNNB1, and STAT3, and a congruent suppression of TP53 during cancer initiation/progression. These several states are, however, reversed when miR-214 is reintroduced and could explain the tumour suppressive functions observed in earlier studies. Further studies are, however, required to reveal how microRNA-mediated regulation of HMGA1 expression may affect individual signalling pathways in CaCx and CRC. Current results reveal that miR-214 is not only able to regulate the expression of its direct target, HMGA1, but also that of a few signalling intermediates like TP53, RELA, CTNNB1, and STAT3, with which HMGA1 interacts. These intermediates play crucial roles in signalling pathways commonly deregulated in human CaCx and CRC. Hence, it is proposed that miR-214 might act as a tumour suppressor by regulating several aberrant signalling pathways through HMGA1. This knowledge has the potential to help design novel therapeutic strategies in CaCx and CRC.
Cancer cells secrete proteins that modify the extracellular environment acting as autocrine and paracrine stimulatory factors and have a relevant role in cancer progression. The HMGA1 oncofetal protein has a prominent role in controlling the expression of an articulated set of genes involved in various aspect of cancer cell transformation. However, little is known about its role in influencing the secretome of cancer cells. Performing an iTRAQ LC-MS/MS screening for the identification of secreted proteins, in an inducible model of HMGA1 silencing in breast cancer cells, we found that HMGA1 has a profound impact on cancer cell secretome. We demonstrated that the pool of HMGA1-linked secreted proteins has pro-migratory and pro-invasive stimulatory roles. From an inspection of the HMGA1-dependent secreted factors it turned out that HMGA1 influences the presence in the extra cellular milieu of key components of the Plasminogen activation system (PLAU, SERPINE1, and PLAUR) that has a prominent role in promoting metastasis, and that HMGA1 has a direct role in regulating the transcription of two of them, i.e. PLAU and SERPINE1. The ability of HMGA1 to regulate the plasminogen activator system may constitute an important mechanism by which HMGA1 promotes cancer progression.
High Mobility Group A1 (HMGA1) is an architectural chromatin protein whose overexpression is a feature of malignant neoplasias with a causal role in cancer initiation and progression. HMGA1 promotes tumor growth by several mechanisms, including increase of cell proliferation and survival, impairment of DNA repair and induction of chromosome instability. Autophagy is a self-degradative process that, by providing energy sources and removing damaged organelles and misfolded proteins, allows cell survival under stress conditions. On the other hand, hyper-activated autophagy can lead to non-apoptotic programmed cell death. Autophagy deregulation is a common feature of cancer cells in which has a complex role, showing either an oncogenic or tumor suppressor activity, depending on cellular context and tumor stage. Here, we report that depletion of HMGA1 perturbs autophagy by different mechanisms. HMGA1-knockdown increases autophagosome formation by constraining the activity of the mTOR pathway, a major regulator of autophagy, and transcriptionally upregulating the autophagy-initiating kinase Unc-51-like kinase 1 (ULK1). Consistently, functional experiments demonstrate that HMGA1 binds ULK1 promoter region and negatively regulates its transcription. On the other hand, the increase in autophagosomes is not associated to a proportionate increase in their maturation. Overall, the effects of HMGA1 depletion on autophagy are associated to a decrease in cell proliferation and ultimately impact on cancer cells viability. Importantly, silencing of ULK1 prevents the effects of HMGA1-knockdown on cellular proliferation, viability and autophagic activity, highlighting how these effects are, at least in part, mediated by ULK1. Interestingly, this phenomenon is not restricted to skin cancer cells, as similar results have been observed also in HeLa cells silenced for HMGA1. Taken together, these results clearly indicate HMGA1 as a key regulator of the autophagic pathway in cancer cells, thus suggesting a novel mechanism through which HMGA1 can contribute to cancer progression.
Maurus K, Hufnagel A, Geiger F, et al.The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation.
Oncogene. 2017; 36(36):5110-5121 [PubMed
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The MAPK pathway is activated in the majority of melanomas and is the target of therapeutic approaches. Under normal conditions, it initiates the so-called immediate early response, which encompasses the transient transcription of several genes belonging to the AP-1 transcription factor family. Under pathological conditions, such as continuous MAPK pathway overactivation due to oncogenic alterations occurring in melanoma, these genes are constitutively expressed. The consequences of a permanent expression of these genes are largely unknown. Here, we show that FOSL1 is the main immediate early AP-1 member induced by melanoma oncogenes. We first examined its role in established melanoma cells. We found that FOSL1 is involved in melanoma cell migration as well as cell proliferation and anoikis-independent growth, which is mediated by the gene product of its target gene HMGA1, encoding a multipotent chromatin modifier. As FOSL1 expression is increased in patient melanoma samples compared to nevi, we investigated the effect of enhanced FOSL1 expression on melanocytes. Intriguingly, we found that FOSL1 acts oncogenic and transforms melanocytes, enabling subcutaneous tumor growth in vivo. During the process of transformation, FOSL1 reprogrammed the melanocytes and downregulated MITF in a HMGA1-dependent manner. At the same time, AXL was upregulated, leading to a shift in the MITF/AXL balance. Furthermore, FOSL1 re-enforced pro-tumorigenic transcription factors MYC, E2F3 and AP-1. Together, this led to the enhancement of several growth-promoting processes, such as ribosome biogenesis, cellular detachment and pyrimidine metabolism. Overall, we demonstrate that FOSL1 is a novel reprogramming factor for melanocytes with potent tumor transformation potential.
Santuario-Facio SK, Cardona-Huerta S, Perez-Paramo YX, et al.A New Gene Expression Signature for Triple Negative Breast Cancer Using Frozen Fresh Tissue before Neoadjuvant Chemotherapy.
Mol Med. 2017; 23:101-111 [PubMed
] Free Access to Full Article Related Publications
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer tumors. Comparisons between TNBC and non-triple negative breast cancer (nTNBC) may help to differentiate key components involved in TNBC neoplasms. The purpose of the study was to analyze the expression profile of TNBC versus nTNBC tumors in a homogeneous population from northeastern Mexico. A prospective study of 50 patients was conducted (25 TNBC and 25 nTNBC). Clinic parameters were equally distributed for TNBC and nTNBC: age at diagnosis (51 vs 47 years, p=0.1), glucose levels (107 mg/dl vs 104 mg/dl, p=0.64), and body mass index (28 vs 29, p=0.14), respectively. Core biopsies were collected for histopathological diagnosis and gene expression analyses. Total RNA was isolated and expression profiling was performed. 40 genes showed differential expression pattern in TNBC tumors. Among these, 9 over-expressed genes (
Quintavalle C, Burmeister K, Piscuoglio S, et al.High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy.
Mol Carcinog. 2017; 56(9):2146-2157 [PubMed
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High mobility group A1 (HMGA1) protein has been described to play an important role in numerous types of human carcinoma. By the modulation of several target genes HMGA1 promotes proliferation and epithelial-mesenchymal transition of tumor cells. However, its role in cholangiocarcinoma (CCA) has not been addressed yet. Therefore, we determined HMGA1 mRNA expression in CCA samples in a transcriptome array (n = 104) and a smaller cohort (n = 13) by qRT-PCR. Protein expression was evaluated by immunohistochemistry in a tissue microarray (n = 67). In addition, we analyzed changes in cell proliferation, colony formation, response to gemcitabine treatment, and target gene expression after modulation of HMGA1 expression in CCA cell lines. mRNA levels of HMGA1 were found to be upregulated in 15-62% depending on the cohort analyzed. Immunohistochemistry showed HMGA1 overexpression in 51% of CCA specimens. Integration with clinico-pathological data revealed that high HMGA1 expression was associated with reduced time to recurrence and a positive lymph node status in extrahepatic cholangiocellular carcinoma. In vitro experiments showed that overexpression of HMGA1 in CCA cell lines promoted cell proliferation, whereas its suppression reduced growth rate. HMGA1 further promoted colony formation in an anchorage independent growth and conferred resistance to gemcitabine treatment. Finally, HMGA1 modulated the expression of two genes involved in CCA carcinogenesis, iNOS and ERBB2. In conclusion, our findings indicate that HMGA1 expression is increased in a substantial number of CCA specimens. HMGA1 further promotes CCA tumorigenicity and confers resistance to chemotherapy.
Wang J, Zhao X, Guo Z, et al.Regulation of NEAT1/miR-214-3p on the growth, migration and invasion of endometrial carcinoma cells.
Arch Gynecol Obstet. 2017; 295(6):1469-1475 [PubMed
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OBJECTIVE: To investigate the function and mechanism of lnc NEAT1 in regulating the growth, migration and invasion of endometrial carcinoma (EC) cells.
MATERIALS AND METHODS: NEAT1 and miR-214-3p levels were measured by qRT-PCR. The protein levels of HMGA1, β-catenin, c-myc and MMP9 were evaluated by Western blot. The effects of NEAT1, HMGA1, miR-214-3p on the viability, migration and invasion of HEC-1A cells were accessed by WST-1 assay and transwell migration/invasion assay. The effect of miR-214-3p on Wnt signaling activity was tested by luciferase reporter assay.
RESULTS: NEAT1, HMGA1 and β-catenin were significantly upregulated in EC tissues, and miR-214-3p was significantly downregulated. NEAT1 promoted the growth, migration and invasion of HEC-1A cells, and mRNA level of Wnt/β-catenin downstream genes c-myc and MMP9. In addition, HMGA1 upregualted the protein and mRNA levels of Wnt/β-catenin downstream genes c-myc and MMP9, and could improve cell viability, and increase numbers of migration and invasion of HEC-1A cells. miR-214-3p overexpression inhibited the proliferation, migration and invasion of HEC-1A cells, while NEAT1 overexpression reversed these effects. miR-214-3p overexpression inhibited the activity of Wnt/β-catenin pathway, while NEAT1 overexpression reversed this effect. Then, si-HMGA1 reduced the activity of Wnt/β-catenin pathway. Moreover, we found NEAT1 and HMGA1 bound to miR-214-3p by luciferase reporter assay, and NEAT1 and HMGA1 expression were negatively correlated with miR-214-3p.
CONCLUSION: NEAT1 regulates HMGA1 via miR-214-3p to regulate Wnt/β-catenin pathway, thus promotes the growth, migration and invasion of HEC-1A cells.
The role of transforming growth factor-β1 (TGF-β1) is complicated and plays a different role in the development of cancer. High mobility group A (HMGA1) participates in multiple cellular biology processes, and exerts important roles in the epithelial-mesenchymal transition (EMT). However, the correlation of TGF-β1 and HMGA1 in cancer cells is not yet fully understood. In this study, we determined the effects of TGF-β1 on HMGA1 expression in thyroid cancer cells and examined the role of HMGA1 in thyroid cancer progression. With real-time PCR and immunofluorescence staining, our study demonstrated that TGF-β1 induced the expression of HMGA1 through phosphoinositide 3-kinase (PI3K) and the extracellular signal-related kinase (ERK) signaling in thyroid cancer cells. With luciferase reported assay, the HMGA1 promoter activity was activated by TGF-β1 in the SW579 cells. Furthermore, lentivirus-mediated HMGA1 knockdown inhibits cellular oncogenic properties of thyroid cancer cells. Clinically, tissue microarray revealed that HMGA1 was expressed in thyroid carcinoma more than that in normal thyroid tissues (P<0.001); expression of HMGA1 and MMP-2 was identified to be positively correlated (P=0.017). The present study established the first link between HMGA1 and TGF-β1 in the regulation of thyroid cancer proliferation and invasion, and provided evidence for the pivotal role of HMGA1 in the progression of thyroid cancer, indicating HMGA1 to be potential biological marker for the diagnosis of thyroid cancer.
Yang Q, Wang X, Tang C, et al.H19 promotes the migration and invasion of colon cancer by sponging miR-138 to upregulate the expression of HMGA1.
Int J Oncol. 2017; 50(5):1801-1809 [PubMed
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Colon cancer is the most common digestive system malignancy, along with high mortality rate, familial transmissibility and hepatic metastasis. Our study investigated the role of long non-coding RNA H19 in colon cancer. We found that H19 was overexpressed in colon cancer tissues and cell lines, the interference of H19 by short hairpin RNA (shRNA) effectively decreased the migration and invasion of colon cancer cells (HT-29 and RKO). Besides, miR-138 was predicted a target of H19, and low expression of miR-138 was found in colon cancer tissues and cells. The silence of H19 strongly increased the expression of miR-138. The decreased level of miR-138 was elevated adding miR-138 mimic in RKO cells transfected with lncRNA-H19. Similarly, the upregulated level of miR-138 was downregulated adding miR-138 inhibitor in RKO cells transfected with H19 shRNA. The luciferase reporter confirmed the targeting reaction between H19 and miR-138. Moreover, the high-mobility group A (HMGA1) protein was predicted as a target of miR-138. HMGA1 was suppressed by H19 shRNA and could be up-regulated by miR-138 inhibitor. The migration and invasion ability of colon cancer was restrained by H19 shRNA and promoted by miR-138 inhibitor. Finally, the in vivo experiment revealed that H19 shRNA strongly reduced the tumor growth and tumor volume. H19 shRNA also inhibited metastasis via suppressing hepatic metastases and the expression of metastasis-related proteins. Taken together, our research indicated an H19-miR138-HMGA1 pathway in regulating the migration and invasion of colon cancer, providing new insight for treatment of colon cancer.
Paez AV, Pallavicini C, Schuster F, et al.Heme oxygenase-1 in the forefront of a multi-molecular network that governs cell-cell contacts and filopodia-induced zippering in prostate cancer.
Cell Death Dis. 2016; 7(12):e2570 [PubMed
] Free Access to Full Article Related Publications
Prostate cancer (PCa) cells display abnormal expression of cytoskeletal proteins resulting in an augmented capacity to resist chemotherapy and colonize distant organs. We have previously shown that heme oxygenase 1 (HO-1) is implicated in cell morphology regulation in PCa. Here, through a multi 'omics' approach we define the HO-1 interactome in PCa, identifying HO-1 molecular partners associated with the integrity of the cellular cytoskeleton. The bioinformatics screening for these cytoskeletal-related partners reveal that they are highly misregulated in prostate adenocarcinoma compared with normal prostate tissue. Under HO-1 induction, PCa cells present reduced frequency in migration events, trajectory and cell velocity and, a significant higher proportion of filopodia-like protrusions favoring zippering among neighboring cells. Moreover forced expression of HO-1 was also capable of altering cell protrusions in transwell co-culture systems of PCa cells with MC3T3 cells (pre-osteoblastic cell line). Accordingly, these effects were reversed under siHO. Transcriptomics profiling evidenced significant modulation of key markers related to cell adhesion and cell-cell communication under HO-1 induction. The integration from our omics-based research provides a four molecular pathway foundation (ANXA2/HMGA1/POU3F1; NFRSF13/GSN; TMOD3/RAI14/VWF; and PLAT/PLAU) behind HO-1 regulation of tumor cytoskeletal cell compartments. The complementary proteomics and transcriptomics approaches presented here promise to move us closer to unravel the molecular framework underpinning HO-1 involvement in the modulation of cytoskeleton pathways, pushing toward a less aggressive phenotype in PCa.
Sekimoto N, Suzuki A, Suzuki Y, Sugano SExpression of miR‑26a exhibits a negative correlation with HMGA1 and regulates cancer progression by targeting HMGA1 in lung adenocarcinoma cells.
Mol Med Rep. 2017; 15(2):534-542 [PubMed
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Lung cancer is the most common cause of cancer‑associated mortality worldwide, and the number of cases is increasing annually. Several studies have shown that microRNAs (miRNAs) control proliferation, differentiation, and apoptosis in various cell types, and increasing evidence indicates the presence of aberrant miRNA expression profiles and unique miRNA signaling pathways in several types of cancer. The present study aimed to identify miRNAs, which correlated specifically with the progression of lung cancer through the analysis of 57,100 transcripts and 1,341 small RNA expression profiles in 26 lung adenocarcinoma cell lines using next‑generation sequencing. The most marked negative correlation was found between the expression of hsa‑miR‑26a‑1 and messenger RNA (mRNA), and a list of mRNAs, which exhibited negative correlation with hsa‑miR‑26a‑1 were investigated. The most marked negative correlation was observed between the expression levels of hsa‑miR‑26a‑1 and high mobility group A1 (HMGA1). Using a lung adenocarcinoma cell line, the present study analyzed the effect of the overexpression of miR‑26a on the expression of HMGA1 and found that miR‑26a repressed the expression of HMGA1 by reducing the mRNA levels of HMGA1. Furthermore, it was demonstrated that the overexpression of miR‑26a in a lung adenocarcinoma cell line repressed cell migration, invasion and growth by targeting HMGA1. Taken together, the present study showed a significant negative correlation between the expression of miR‑26a and HMGA1 in 26 lung adenocarcinoma cell lines, and provided evidence that the suppression of miR‑26a supports the progression of cancer by stimulating the expression of HMGA1.
Toyozumi T, Hoshino I, Takahashi M, et al.Fra-1 Regulates the Expression of HMGA1, Which is Associated with a Poor Prognosis in Human Esophageal Squamous Cell Carcinoma.
Ann Surg Oncol. 2017; 24(11):3446-3455 [PubMed
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BACKGROUND: The expression of Fos-related antigen 1 (Fra-1) affects tumor progression, migration, and invasion. In this study, we identified the genes regulated by Fra-1 in esophageal squamous cell carcinoma (ESCC).
METHODS: We constructed Fra-1 knockdown models via the transfection of small interfering RNA (siRNA) into ESCC cell lines (TE10, TE11). The expression levels of the genes in the knockdown models were analyzed using a microarray and a Biobase Upstream Analysis, while the expression levels of the candidate genes in the primary tumors of surgical specimens obtained from ESCC patients were determined using real-time polymerase chain reaction (PCR) and immunohistochemical staining. The clinicopathological features were then analyzed.
RESULTS: The Biobase Upstream Analysis showed the high-mobility-group protein-1 (HMGA1) to be a significant gene regulated by Fra-1. Actual binding of Fra-1 to the promotor region of HMGA1 was revealed in subsequent chromatin immunoprecipitation PCR experiments. Patients with a positive HMGA1 expression had a poor prognosis, and a multivariate analysis demonstrated a positive HMGA1 expression to be a significant independent prognostic factor.
CONCLUSION: HMGA1 is regulated by Fra-1 in ESCC, and the HMGA1 expression is significantly associated with a poor prognosis in ESCC patients. Downregulation of the HMGA1 expression may become a practical treatment strategy against ESCC in the future.
Recent studies have revealed that pseudogene transcripts can function as competing endogenous RNAs, and thereby can also contribute to cancer when dysregulated. We have recently identified two pseudogenes, HMGA1P6 and HMGA1P7 for the HMGA1 gene whose overexpression has a critical role in cancer progression. These pseudogenes work as competitive endogenous RNA decoys for HMGA1 and other cancer related genes suggesting their role in carcinogenesis. Looking for new HMGA1 pseudogene ceRNAs, we performed RNA sequencing technology on mouse embryonic fibroblasts deriving from transgenic mice overexpressing HMGA1P7. Here, we report that HMGA1P7 mRNA sustains the H19 and Igf2 overexpression by acting as miRNA decoy. Lastly, the expression of HMGA1P7 was significantly correlated with H19 and IGF2 levels in human breast cancer thereby suggesting a role for HMGA1P7 deregulation in this neoplasia.
Andreozzi M, Quintavalle C, Benz D, et al.HMGA1 Expression in Human Hepatocellular Carcinoma Correlates with Poor Prognosis and Promotes Tumor Growth and Migration in in vitro Models.
Neoplasia. 2016; 18(12):724-731 [PubMed
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BACKGROUND: HMGA1 is a non-histone nuclear protein that regulates cellular proliferation, invasion and apoptosis and is overexpressed in many carcinomas. In this study we sought to explore the expression of HMGA1 in HCCs and cirrhotic tissues, and its effect in in vitro models.
METHODS: We evaluated HMGA1 expression using gene expression microarrays (59 HCCs, of which 37 were matched with their corresponding cirrhotic tissue and 5 normal liver donors) and tissue microarray (192 HCCs, 108 cirrhotic tissues and 79 normal liver samples). HMGA1 expression was correlated with clinicopathologic features and patient outcome. Four liver cancer cell lines with stable induced or knockdown expression of HMGA1 were characterized using in vitro assays, including proliferation, migration and anchorage-independent growth.
RESULTS: HMGA1 expression increased monotonically from normal liver tissues to cirrhotic tissue to HCC (P<.01) and was associated with Edmondson grade (P<.01). Overall, 51% and 42% of HCCs and cirrhotic tissues expressed HMGA1, respectively. Patients with HMGA1-positive HCCs had earlier disease progression and worse overall survival. Forced expression of HMGA1 in liver cancer models resulted in increased cell growth and migration, and vice versa. Soft agar assay showed that forced expression of HMGA1 led to increased foci formation, suggesting an oncogenic role of HMGA1 in hepatocarcinogenesis.
CONCLUSIONS: HMGA1 is frequently expressed in cirrhotic tissues and HCCs and its expression is associated with high Edmondson grade and worse prognosis in HCC. Our results suggest that HMGA1 may act as oncogenic driver of progression, implicating it in tumor growth and migration potential in liver carcinogenesis.
Yang MR, Zhang Y, Wu XX, Chen WCritical genes of hepatocellular carcinoma revealed by network and module analysis of RNA-seq data.
Eur Rev Med Pharmacol Sci. 2016; 20(20):4248-4256 [PubMed
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OBJECTIVE: RNA-seq data of hepatocellular carcinoma (HCC) was analyzed to identify critical genes related to the pathogenesis and prognosis.
MATERIALS AND METHODS: Three RNA-seq datasets of HCC (GSE69164, GSE63863 and GSE55758) were downloaded from Gene Expression Omnibus (GEO), while another dataset including 54 HCC cases with survival time was obtained from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) were identified by significant analysis of microarrays (SAM) method using package samr of R. As followed, we constructed a protein-protein interaction (PPI) network based on the information in Human Protein Reference Database (HPRD). Modules in the PPI network were identified with MCODE method using plugin clusterViz of CytoScape. Gene Ontology (GO) enrichment analysis and pathway enrichment analysis were performed with DAVID. The difference in survival curves was analyzed with Kaplan-Meier (K-M) method using package survival.
RESULTS: A total of 2572 DEGs were identified in the 3 datasets from GEO (GSE69164, GSE63863 and GSE55758). The PPI network was constructed including 660 nodes and 1008 edges, and 4 modules were disclosed in the network. Module A (containing 244 DEGs) was found to related to HCC closely, which genes were involved in transcription factor binding, protein metabolism as well as regulation of apoptosis. Nine hub genes were identified in the module A, including PRKCA, YWHAZ, KRT18, NDRG1, HSPA1A, HSP90AA1, HSF1, IKGKB and UBE21. The network provides the protein-protein interaction of these critical genes, which were implicated in the pathogenesis of HCC. Survival analysis showed that there is a significant difference between two groups classified by the genes in module A. Further Univariate Cox regression analysis showed that 72 genes were associated with survival time significantly, such as NPM1, PRKDC, SPARC, HMGA1, COL1A1 and COL1A2.
CONCLUSIONS: Nine critical genes related to the pathogenesis and 72 potential prognostic markers were revealed in HCC by the network and module analysis of RNA-seq data. These findings could improve the understanding of the pathogenesis and provide valuable information to further investigate the prognostic markers of HCC.
Kooi IE, van Mil SE, MacPherson D, et al.Genomic landscape of retinoblastoma in Rb
Genes Chromosomes Cancer. 2017; 56(3):231-242 [PubMed
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Several murine retinoblastoma models have been generated by deleting the genes encoding for retinoblastoma susceptibility protein pRb and one of its family members p107 or p130. In Rb
PURPOSE: The HMGI-C (high mobility group protein isoform I-C) protein is a member of the high-mobility group AT-hook (HMGA) family of small non-histone chromosomal proteins that can modulate transcription of an ample number of genes. Genome-wide studies reveal upregulation of the HMGI-C gene in many human cancers, which suggests that HMGI-C might play a critical role in the progression of various tumors. However, the exact role of HMGI-C in breast adenocarcinoma has not been made clear.
METHODS: HMGI-C mRNA expression in breast cancer samples and marginal normal tissues was characterized using qRT-PCR. The cytotoxic effects of HMGI-C siRNA on breast adenocarcinoma cells were determined using MTT assay. Relative HMGI-C mRNA and protein levels were measured by quantitative real-time PCR and western blotting, respectively. Apoptosis detection was done using TUNEL and Annexin-V/PI assays, P53, caspase 3, 9, 8 and Bcl2 proteins evaluated by protein gel blot and miR34a, Let-7a genes investigates by QRT-PCR assay. Cell cycle was analyzed by flow cytometry assay using propidium iodide DNA staining.
RESULTS: An overexpression of HMGA2 was revealed with highly statistically significant differences between breast cancer samples and marginal normal tissues (P < 0.0001). HMGI-C siRNA significantly reduced both mRNA and protein expression levels in a 48-hour period after transfection and in a dose-dependent manner. We observed that the knockdown of HMGI-C led to the significant induction of apoptosis via mitochondrial pathway by inducing miR34a and cell cycle arrest in MDA-MB-468 cells in vitro.
CONCLUSIONS: These results propose that HMGI-C might play a critical role in the progression of breast adenocarcinoma. Here we introduced HMGI-C as a potential therapeutic target for trigger apoptosis and cell cycle arrest in human breast adenocarcinoma. Therefore HMGI-C siRNA may be an effective adjuvant in human breast adenocarcinoma.