Gene Summary

Gene:HMGA2; high mobility group AT-hook 2
Summary:This gene encodes a protein that belongs to the non-histone chromosomal high mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhancesome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with myxoid liposarcoma suggests a role in adipogenesis and mesenchymal differentiation. A gene knock out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:high mobility group protein HMGI-C
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Biological Models
  • Synovial Membrane
  • TFAP2A
  • Lung Cancer
  • Cancer Gene Expression Regulation
  • SOXB1 Transcription Factors
  • Single Nucleotide Polymorphism
  • Chromosome 12
  • Pelvic Pain
  • FISH
  • Wound Healing
  • Uterus
  • Cell Proliferation
  • Sex Factors
  • Ovarian Cancer
  • TOR Serine-Threonine Kinases
  • MicroRNAs
  • Sensitivity and Specificity
  • Cell Movement
  • Myocytes, Smooth Muscle
  • Neoplasm Invasiveness
  • RNA Interference
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Nervous System Neoplasms
  • Biomarkers, Tumor
  • Transfection
  • Odontogenic Tumors
  • Transcriptional Activation
  • Leiomyoma
  • Salivary Glands
  • siRNA
  • DNA Sequence Analysis
  • Smooth Muscle Tumor
  • Seizures
  • Ultrasonography
  • Immunohistochemistry
  • Gene Expression Profiling
  • Vulvar Cancer
  • Systems Biology
  • HMGA2
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HMGA2 (cancer-related)

Binabaj MM, Soleimani A, Rahmani F, et al.
Prognostic value of high mobility group protein A2 (HMGA2) over-expression in cancer progression.
Gene. 2019; 706:131-139 [PubMed] Related Publications
The high mobility group A2 (HMGA2; also called HMGI-C) gene is an architectural transcription factor that belonging to the high mobility group AT-hook (HMGA) gene family. HMGA2 is aberrantly regulated in several human tumors. Over-expression of HMGA2 is correlated with a higher risk of metastasis and an unfavorable prognosis in patients with cancer. We performed a meta-analysis to determine the clinic-pathological and prognostic value of HMGA2 overexpression in different human tumors. A comprehensive literature search was performed using PubMed, Embase, Cochrane Library, Scopus, MEDLINE, Google Scholar and ISI Web of Science. Hazard ratios (HRs)/odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of the association between HMGA2 expression and overall survival (OS)/progression free survival (PFS)/disease free survival (DFS). A total of 5319 patients with 19 different types of cancer from 35 articles were evaluated. Pooled data analysis indicated that increased HMGA2 expression in cancer patients predicted a poor OS (HR = 1.70; 95% CI = 1.6-1.81; P < 0.001; fixed-effect model). In subgroup analyses, high HMGA2 expression was particularly associated with poor OS in individuals with gastrointestinal (GI) cancer (HR = 1.89, 95% CI: 1.83-1.96; fixed-effect model) and HNSCC cancer (HR-1.78, 95%CI: 1.44-2.21; fixed-effect model). Over-expression of HMGA2 was associated with vascular invasion (OR = 0.16, 95% CI = 0.05-0.49; P = 0.001) and lymphatic invasion (OR = 1.89, 95% CI = 1.06-3.38; P = 0.032). Further studies should be conducted to validate the prognostic value of HMGA2 for patients with GI cancers.

Yadav P, Shankar BS
Radio resistance in breast cancer cells is mediated through TGF-β signalling, hybrid epithelial-mesenchymal phenotype and cancer stem cells.
Biomed Pharmacother. 2019; 111:119-130 [PubMed] Related Publications
AIMS: A major obstacle for effective cancer treatment by radiation therapy is the development of radio-resistance and identification of underlying mechanisms and activated pathways will lead to better combination therapies.
MAIN METHODS: Irradiated MCF-7 and MDA-MB-231 breast cancer cell lines were characterised following different recovery periods. Proliferation was assessed by MTT, BrdU and clonogenic assays and apoptosis by Annexin V/ propidium iodide staining and flow cytometry. Gene expression was monitored by real time PCR/ELISA/antibody labelling and migration using transwell inserts.
KEY FINDINGS: Breast cancer cell lines exposed to 6 Gy followed by recovery period for 7 days (D7-6 G) had increased ability for proliferation as well as apoptosis. D7-6 G from both cell lines had increased expression of transforming growth factor isoforms (TGF)-β1, β2 and β3, their receptors TGF-βR1 and TGF-βR2 which are known for such dual effects. The expression of downstream transcription factors Snail, Zeb-1 and HMGA2 also showed a differential pattern in D7-6 G cells with upregulation of at least two of these transcription factors. D7-6 G cells from both cell lines displayed hybrid epithelial-mesenchymal (E/M) phenotype with increased expression of E/M markers and migration. D7-6 G cells had increased expression of cancer stem cells markers Oct4, Sox2, and Nanog; aldehyde dehydrogenase expression and activity; proportion of CD44
SIGNIFICANCE: Blocking of TGF-β signalling may therefore be an effective strategy for overcoming radio resistance induced by radiation exposure.

Sun J, Qiao Y, Song T, Wang H
MiR‑495 suppresses cell proliferation by directly targeting HMGA2 in lung cancer.
Mol Med Rep. 2019; 19(3):1463-1470 [PubMed] Free Access to Full Article Related Publications
The present study aimed to investigate the expression of microRNA‑495 (miR‑495) in non‑small cell lung cancer (NSCLC) tissues and cells, as well as its function on the proliferation of lung cancer cells. The expression of miR‑495 in 122 pairs of NSCLC tissues and matched paracarcinoma tissues, as well as in human lung cancer cell lines (A549, H460, H1650, H520 and SK‑MES‑1) and the normal human pulmonary bronchial epithelial cell line 16HBE was determined using reverse transcription quantitative polymerase chain reaction (RT‑qPCR). As predicted by bioinformatics analysis, high mobility group A2 (HMGA2) may be a potential target gene of miR‑495. In addition, the regulatory function of miR‑495 on its target gene HMGA2 was evaluated using a dual‑luciferase reporter assay, RT‑qPCR and western blotting. Furthermore, the effect of miR‑495 on the proliferation of A549 lung cancer cells was investigated using a Cell Counting Kit‑8 (CCK‑8) assay. The results demonstrated that the expression of miR‑495 in NSCLC tissues and cells was significantly downregulated compared with the control. In addition, downregulated expression of miR‑495 was associated with tumor differentiation, lymph node metastasis and tumor, node and metastasis staging. Additionally, a dual‑luciferase reporter assay revealed that miR‑495 could directly associated with the 3'‑untranslated region of HMGA2. Upregulated expression of miR‑495 significantly downregulated the mRNA and protein expression levels of HMGA2 in A549 cells. Furthermore, the results of CCK‑8 assay revealed that upregulated expression of miR‑495 significantly suppressed the proliferation of A549 cells; HMGA2 overexpression reversed this inhibition. In summary, the findings of the present study demonstrated that miR‑495 was downregulated in NSCLC tissues and cells. In addition, miR‑495 suppressed the proliferation of lung cancer cells by directly targeting HMGA2.

Asano R, Asai-Sato M, Matsukuma S, et al.
Expression of erythropoietin messenger ribonucleic acid in wild-type MED12 uterine leiomyomas under estrogenic influence: new insights into related growth disparities.
Fertil Steril. 2019; 111(1):178-185 [PubMed] Related Publications
OBJECTIVE: To determine factors that impact erythropoietin (EPO) production in leiomyomas. We have previously implicated EPO production in promoting the growth of some leiomyomas.
DESIGN: The relationship between EPO messenger RNA (mRNA) expression and MED12 gene mutations or mRNA expression levels of high-mobility group AT-hook (HMGA) 1 and HMGA2 were analyzed. Effects of 10
SETTING: Graduate school of medicine.
PATIENT(S): Patients with leiomyoma.
INTERVENTION(S): We used tissue samples and clinical data of 108 patients with leiomyomas to analyze the relation between EPO mRNA expression and MED12 mutation. Tissue samples from another 10 patients with leiomyomas were collected for in vitro experimentation using primary cultures of leiomyoma and myometrial cells.
MAIN OUTCOME MEASURE(S): Relations between EPO mRNA expression, MED12 exon 2 mutation, and HMGA1/HMGA2 mRNA expression levels in leiomyoma samplings, in addition to effects of estrogen (E) on EPO mRNA expression in cultures of leiomyoma cells.
RESULT(S): The EPO mRNA level was threefold higher in leiomyomas with wild-type (vs. mutated) MED12 genes. There was no correlation between EPO and HMGA1 or HMGA2 mRNA expression levels. In wild-type MED12 leiomyomas only, E
CONCLUSION(S): The EPO mRNA expression increased significantly after E

Wang J, Liang H, Ge H, et al.
MicroRNA‑363‑3p inhibits hepatocarcinogenesis by targeting HMGA2 and is associated with liver cancer stage.
Mol Med Rep. 2019; 19(2):935-942 [PubMed] Free Access to Full Article Related Publications
The importance of microRNAs (miRNAs) in cancer development has been widely recognized in recent decades. In the present study, the function and mechanism of miRNA‑363‑3p (miR‑363‑3p), formerly characterized as a tumor suppressor, in the hepatocarcinogenesis of liver cancer cells was investigated. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was applied to detect the expression of miR‑363‑3p in liver cancer tissues. Cell proliferation, survival and migration capacities were determined by MTT, colony formation and wound‑healing assays, respectively. The targeting of high mobility group AT‑hook 2 (HMGA2) mRNA by miR‑363‑3p was confirmed by bioinformatics analysis, and RT‑qPCR, luciferase reporter and western blot assays. The correlation between the expression levels of HMGA2 and miR‑363‑3p was analyzed. The RT‑qPCR results revealed that the levels of miR‑363‑3p were downregulated in liver cancer tissues. Cellular assays validated that miR‑363‑3p exerted tumor suppressing functions, including the inhibition of cell proliferation, survival and migration abilities in two liver cancer cell lines. Bioinformatics prediction and subsequent experiments demonstrated that HMGA2 was a direct target of miR‑363‑3p. Restoration of the expression of HMGA2 in miR‑363‑3p mimic‑transfected cells reversed the tumor suppressing effects caused by miR‑363‑3p. Finally, there was a significant negative correlation between the expression levels of HMGA2 and miR‑363‑3p in liver cancer tissues. miR‑363‑3p was identified as an important tumor suppressor in liver cancer via targeting HMGA2, which may have potential benefits in liver cancer therapy.

Zhang N, Jiang W
Long non‑coding RNA DANCR promotes HMGA2‑mediated invasion in lung adenocarcinoma cells.
Oncol Rep. 2019; 41(2):1083-1090 [PubMed] Related Publications
Long non‑coding RNAs (lncRNAs) have been reported to be key regulators in various types of cancer, including lung adenocarcinoma (LAD). The roles of the lncRNA differentiation antagonizing non‑protein coding RNA (DANCR) and high mobility group AT‑hook 2 (HMGA2) in LAD remain unclear. In the present study, it was revealed that the lncRNA DANCR was upregulated in LAD tissue and cell lines, compared with para‑tumor tissue and a normal lung cell line. Additionally, elevated DANCR expression was associated with poor prognosis in the patients with LAD. Functionally, the study revealed that knockdown of DANCR inhibited invasion and HMGA2 expression in the LAD cell lines, SPCA1 and A549. Furthermore, HMGA2 was overexpressed in LAD tissue and in SPCA1 and A549 cells, compared with para‑tumor tissue and a normal lung cell line. Inhibition of HMGA2 suppressed the invasive ability of SPCA1 and A549 cells, and DANCR promoted the invasive ability via regulation of HMGA2 in SPCA1 and A549 cells. The findings of the present study revealed that DANCR promoted the invasion of LAD cells by positively regulating HMGA2. Thus, a DANCR/HMGA2 axis may be a novel potential target in the molecular treatment of LAD.

Xing F, Song Z, He Y
MiR-219-5p inhibits growth and metastasis of ovarian cancer cells by targeting HMGA2.
Biol Res. 2018; 51(1):50 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating studies have demonstrated that high-mobility group A2 (HMGA2), an oncofetal protein, plays a role in tumor development and progression. However, the molecular role of HMGA2 in ovarian carcinoma is yet to be established. MicroRNAs (miRNAs), a group of small noncoding RNAs, negatively regulate gene expression and their dysregulation has been implicated in tumorigenesis. The aim of this study was to investigate the potential involvement of a specific miRNA, miR-219-5p, in HMGA2-induced ovarian cancer.
METHODS: The ovarian cancer cell line, SKOV3, was employed, and miR-219-5p and HMGA2 overexpression vectors constructed. The CCK-8 kit was used to determine cell proliferation and the Transwell
RESULTS: Expression of miR-219-5p led to suppression of proliferation, invasion and migration of the ovarian cancer cell line, SKOV3, by targeting HMGA2. The inhibitory effects of miR-219-5p were reversed upon overexpression of HMGA2. Data from the luciferase reporter assay showed that miR-219-5p downregulates HMGA2 via direct integration with its 3'-UTR. Consistent with in vitro findings, expression of miR-219-5p led to significant inhibition of tumor growth in vivo.
CONCLUSION: Our results collectively suggest that miR-219-5p inhibits tumor growth and metastasis by targeting HMGA2.

Kleemann M, Schneider H, Unger K, et al.
Induction of apoptosis in ovarian cancer cells by miR-493-3p directly targeting AKT2, STK38L, HMGA2, ETS1 and E2F5.
Cell Mol Life Sci. 2019; 76(3):539-559 [PubMed] Related Publications
Apoptosis is a form of directed programmed cell death with a tightly regulated signalling cascade for the destruction of single cells. MicroRNAs (miRNAs) play an important role as fine tuners in the regulation of apoptotic processes. MiR-493-3p mimic transfection leads to the induction of apoptosis causing the breakdown of mitochondrial membrane potential and the activation of Caspases resulting in the fragmentation of DNA in several ovarian carcinoma cell lines. Ovarian cancer shows with its pronounced heterogeneity a very high death-to-incidence ratio. A target gene analysis for miR-493-3p was performed for the investigation of underlying molecular mechanisms involved in apoptosis signalling pathways. Elevated miR-493-3p levels downregulated the mRNA and protein expression levels of Serine/Threonine Kinase 38 Like (STK38L), High Mobility Group AT-Hook 2 (HMGA2) and AKT Serine/Threonine Kinase 2 (AKT2) by direct binding as demonstrated by luciferase reporter assays. Notably, the protein expression of RAF1 Proto-Oncogene, Serine/Threonine Kinase (RAF1) was almost completely downregulated by miR-493-3p. This interaction, however, was indirect and regulated by STK38L phosphorylation. In addition, RAF1 transcription was diminished as a result of reduced transcription of ETS proto-oncogene 1 (ETS1), another direct target of miR-493-3p. Taken together, our observations have uncovered the apoptosis inducing potential of miR-493-3p through its regulation of multiple target genes participating in the extrinsic and intrinsic apoptosis pathway.

Mello JBH, Barros-Filho MC, Abreu FB, et al.
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma.
Mol Hum Reprod. 2018; 24(11):556-563 [PubMed] Related Publications
STUDY QUESTION: Can the mediator complex subunit 12 (MED12) mutation and high mobility group AT-hook 2 (HMGA2) overexpression co-occurrence be explained by the alternative mechanism of HMGA2 dysregulation in uterine leiomyomas (UL)?
SUMMARY ANSWER: The co-occurrence of MED12 mutation and HMGA2 overexpression, and a negative correlation of five validated or predicted microRNAs that target HMGA2 were reported.
WHAT IS KNOWN ALREADY: The recent stratification of UL, according to recurrent and mutually exclusive genomic alterations affecting HMGA2, MED12, fumarate hydratase (FH) and collagen type IV alpha 5-alpha 6 (COL4A5-COL4A6) pointed out the involvement of distinct molecular pathways. However, the mechanisms of regulation involving these drivers are poorly explored.
STUDY DESIGN, SIZE, DURATION: A total of 78 UL and 34 adjacent normal myometrium (NM) tissues was collected from 56 patients who underwent hysterectomies at a single institution. The patients were treated at the Department of Gynecology and Obstetrics, School of Medicine, Sao Paulo State University, Botucatu, SP, Brazil, from October 1995 to February 2004.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Gene expression profiling was evaluated from fresh frozen tissues and compared with MED12 mutations at exon 2. In addition, RT-qPCR was applied to evaluate the expression levels of HMGA2 and their predictive miRNA regulators: hsa-let-7a, miR-26a, miR-26b, mir-93 and mir-106b.
MAIN RESULTS AND THE ROLE OF CHANCE: An unsupervised hierarchical clustering analysis revealed two main clusters with one of them (26 of 42 UL) showing an enrichment of MED12 mutated cases (18 of 26 UL). Increased expression levels of HMGA2 were observed in both clusters, including cases with MED12 mutation (cluster 1:18 UL). A significant HMGA2 overexpression (P < 0.001) in UL in comparison with NM was found. Five miRNAs predicted to regulate HMGA2 were significantly downregulated (P < 0.001) and negatively correlated to HMGA2 expression levels (P < 0.05) in UL.
LIMITATIONS REASONS FOR CAUTION: An in vivo functional study was not performed to validate the microRNAs and HMGA2 interaction due to technical limitations.
WIDER IMPLICATIONS OF THE FINDINGS: HMGA2 overexpression was detected in a significant number of MED12 mutated ULs, suggesting that these alterations coexist. Furthermore, five miRNAs were described as potential regulators of HMGA2 expression in UL.
LARGE-SCALE DATA: Data available in the Gene Expression Omnibus GSE42939.
STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (# 2008/58835-2) and Conselho Nacional de Pesquisa (# 485032/2007-4), Brazil. The authors declared having no conflicts of interest.

Asahina M, Saito T, Hayashi T, et al.
Clinicopathological effect of PLAG1 fusion genes in pleomorphic adenoma and carcinoma ex pleomorphic adenoma with special emphasis on histological features.
Histopathology. 2019; 74(3):514-525 [PubMed] Related Publications
AIMS: Pleomorphic adenoma gene 1 (PLAG1) rearrangement is well known in pleomorphic adenoma (PA), which is histologically characterised by admixed epithelial and mesenchymal components. Multiple fusion variants of PLAG1 and HMGA2 have been reported; currently, however, little is known regarding the clinicopathological impacts of these fusion types METHODS AND RESULTS: We examined the PLAG1- and HMGA2-related fusion status in 105 PAs and 11 cases of carcinoma ex PAs (CXPA) arising from salivary glands and lacrimal glands to elucidate their correlation to the clinicopathological factors. Forty cases harboured PLAG1 fusion genes: CTNNB1-PLAG1 in 22 cases, CHCHD7-PLAG1 in 14 cases and LIFR-PLAG1 in four cases. Only two cases possessed HMGA2 fusion genes. The mean age of LIFR-PLAG1-positive cases was significantly higher than that of CTNNB1-PLAG1- and CHCHD7-PLAG1-positive cases (P = 0.0358). PAs located in the submandibular gland demonstrated CTNNB1-PLAG1 fusion at a significantly higher rate than other fusions (P = 0.0109). Histologically, PLAG1 fusion-positive cases exhibited chondroid formation and plasmacytoid features more commonly (P = 0.043, P = 0.015, respectively) and myxoid abundant feature less frequently (P = 0.031) than PLAG1 fusion-negative cases. For CXPAs, four CTNNB1-PLAG1 fusions were detected in two salivary duct carcinomas and two myoepithelial carcinomas. Ductal formation was observed frequently (90.9%) in residual PA.
CONCLUSIONS: The presence of PLAG1 fusion was associated with specific histological features in PA. Detecting the PLAG1 fusion gene and searching residual ductal formation in salivary gland malignant tumours with extensive hyalinisation could be useful for diagnosis.

Mok Y, Agaimy A, Wang S, et al.
High-grade myoepithelial carcinoma can show histologically undifferentiated/anaplastic features.
Ann Diagn Pathol. 2018; 37:20-24 [PubMed] Related Publications
High grade malignant tumors with a poorly-/un-differentiated morphology pose significant diagnostic challenges. Increasingly, the use of adjunct immunohistochemical and molecular tests to characterize and delineate the histopathologic phenotype of these tumors has become necessary, particularly in head and neck tumors. Recently, several entities with a poorly-/un-differentiated light microscopic morphology have been defined based on specific immunohistochemical and genetic characteristics. We herein describe two cases of high-grade myoepithelial carcinoma, one occurring in the submandibular gland and the other occurring in the left nasal cavity, both showing undifferentiated histological and anaplastic cytomorphological features. This led to very broad differential diagnostic considerations and the diagnosis was only established after extensive immunohistochemical studies. Molecular testing for HPV was negative in both cases. Gene fusion analysis using a targeted sequencing assay (Archer® FusionPlex® system) did not identify fusions involving PLAG1, HMGA2, EWSR1 or ALK genes in either case. The submandibular tumor showed an aggressive clinical course, with diffuse pulmonary metastases at presentation, whilst the nasal cavity tumor showed only localized disease. Awareness of a subcategory of high-grade myoepithelial carcinomas with undifferentiated light microscopical features is of significant importance in antibody selection for immunohistochemical investigation of poorly-/undifferentiated malignant tumors in the head and neck region. This histological variant of myoepithelial carcinoma adds to the growing list of differential diagnoses in this diagnostically complex and multifaceted field.

Vitkeviciene A, Baksiene S, Borutinskaite V, Navakauskiene R
Epigallocatechin-3-gallate and BIX-01294 have different impact on epigenetics and senescence modulation in acute and chronic myeloid leukemia cells.
Eur J Pharmacol. 2018; 838:32-40 [PubMed] Related Publications
Myeloid leukemia treatment is quite successful nowadays; nevertheless the development of new therapies is still necessary. In the present study, we investigated the potential of epigenetic modulators EGCG (epigallocatechin-3-gallate) and BIX-01294 (N-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine) to alter epigenetic state and cause cellular senescence in acute and chronic myeloid leukemia NB4 and K562 cells. We have shown that after leukemia cell treatment with EGCG and BIX-01294 the proliferation and survival were inhibited of both cell lines; however, only NB4 cells underwent apoptosis. Both epigenetic modulators caused cell cycle arrest in G0/G1 phase as assessed by RT-qPCR (p53, p21, Rb) and flow cytometry analysis. Increased levels of ATM, HMGA2, phosphorylated ATM, and SA-β-galactosidase staining indicated that EGCG caused cellular senescence, whereas BIX-01294 did not. Immunoblot analysis of epigenetic players DNMT1, HP1α, H3K9me3, EZH2, and SUZ12 demonstrated beneficial epigenetic modulation by both agents with exception of mainly no epigenetic changes caused in K562 cells by EGCG. Therefore, we suggest EGCG as a promising epigenetic modulator for acute promyelocytic leukemia therapy and as a potential cellular senescence inducer in both acute and chronic myeloid leukemia treatment, whereas BIX-01294 could be beneficial as an epigenetic modifier for both myeloid leukemias treatment.

Hawsawi O, Henderson V, Burton LJ, et al.
High mobility group A2 (HMGA2) promotes EMT via MAPK pathway in prostate cancer.
Biochem Biophys Res Commun. 2018; 504(1):196-202 [PubMed] Article available free on PMC after 26/09/2019 Related Publications
Studies have shown that High mobility group A2 (HMGA2), a non-histone protein, can promote epithelial-mesenchymal transition (EMT), which plays a critical role in prostate cancer progression and metastasis. Interestingly, full-length or wild-type HMGA2 and truncated (lacking the 3'UTR) HMGA2 isoforms are overexpressed in several cancers. However, there are no studies investigating the expression and differential roles of WT vs truncated HMGA2 isoforms in prostate cancer. Immunohistochemical staining of prostate tissue microarray revealed low membrane expression in normal epithelial prostate cells, and that expression increased with tumor grade as well as a switch from predominantly cytoplasmic HMGA2 in lower tumor grades, to mostly nuclear in high grade and bone metastatic tissue. LNCaP cells stably overexpressing wild-type HMGA2 displayed nuclear localization of HMGA2 and induction of EMT associated with increased Snail, Twist and vimentin expression compared to LNCaP Neo control cells, as shown by immunofluorescence and western blot analyses. This was associated with increased cell migration on collagen shown using boyden chamber assay. Conversely, LNCaP cells overexpressing truncated HMGA2 showed cytoplasmic HMGA2 expression that did not induce EMT yet displayed increased cell proliferation and migration compared to LNCaP Neo. Both wild-type and truncated HMGA2 increased levels of phospho-ERK, and interestingly, treatment with U0126, MAPK inhibitor, antagonized wild-type HMGA2-mediated EMT and cell migration, but did not affect truncated HMGA2-mediated cell proliferation or migration. Therefore, although both wild-type and truncated HMGA2 may promote prostate tumor progression, wild-type HMGA2 acts by inducing EMT via MAPK pathway.

Zhang X, Wu M, Chong QY, et al.
Amplification of hsa-miR-191/425 locus promotes breast cancer proliferation and metastasis by targeting DICER1.
Carcinogenesis. 2018; 39(12):1506-1516 [PubMed] Related Publications
The dysregulation of micro RNAs (miRNAs) is a crucial characteristic of human cancers. Herein, we observed frequent amplification of the MIR191/425 locus in breast cancer, which is correlated with poor survival outcome. We demonstrated that the miR-191/425 cluster binds the 3' untranslated region of the DICER1 transcript and posttranscriptionally represses DICER1 expression, thereby impairing global miRNAs biogenesis. Functionally, the forced expression of miR-191 or miR-425 stimulated the proliferation, survival, migration and invasion of breast cancer cells, whereas the inhibition of miR-191 or miR-425 suppressed these oncogenic behaviors of breast cancer cells, in a manner dependent on miR-191/425-mediated downregulation of DICER1. Furthermore, the miR-191/425 cluster promoted breast tumor growth, invasion and metastasis in vivo. The let-7 family of miRNAs was downregulated upon forced expression of miR-191 or miR-425, with a corresponding increase in the levels of let-7 target, high-mobility group AT-hook 2 (HMGA2). The forced expression of let-7 partially abrogated the miR-191/425-mediated oncogenic effects in breast cancer cells, suggestive of let-7 as a downstream effector of the miR-191/425-DICER1 axis. Collectively, we proposed that the inhibition of global miRNA processing, through miR-191/425-mediated downregulation of DICER1, promotes breast cancer progression.

Wang MJ, Zhang H, Li J, Zhao HD
microRNA-98 inhibits the proliferation, invasion, migration and promotes apoptosis of breast cancer cells by binding to HMGA2.
Biosci Rep. 2018; 38(5) [PubMed] Article available free on PMC after 26/09/2019 Related Publications
Breast cancer is a major contributor leading to cancer death in females worldwide. The aim of the present study was to investigate the effects of microRNA-98 (miR-98) on the processes of cell proliferation, invasion, migration and apoptosis by binding to high-mobility group AT-hook 2 (HMGA2) in breast cancer. Breast cancer tissues and adjacent normal tissues were collected from 112 patients suffering from breast cancer. The target relationship between miR-98 and HMGA2 was verified by in connection with the bioinformatics website as well as a dual-luciferase reporter assay, both of which provided evidence indicating that HMGA2 was a target gene of miR-98. Human breast cancer MDA-MB-231 cells were treated with miR-98 mimics, miR-98 inhibitors, siRNA-HMGA2 or miR-98 inhibitors + siRNA-HMGA2. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry methods were performed to determine cell proliferation, cell cycle and apoptosis, respectively, while a Transwell assay was employed to detect cell migration and invasion. Breast cancer tissues exhibited decreased miR-98 expression, while increased expression levels of HMGA2 were recorded. The mRNA and protein expressions of HMGA2, cell proliferation, cells at the S phase, cell migration, invasion, expressions of matrix metalloproteinase (MMP)2 as well as MMP9 were all reduced in response to miR-98 mimics or siRNA-HMGA2, while a contradictory trend was observed in the miR-98 inhibitors group. In conclusion, the results of the study demonstrate that miR-98 inhibits cell proliferation, migration and invasion, while acting to promote apoptosis by negatively regulating HMGA2 in breast cancer.

Galindo LJ, Hernández-Beeftink T, Salas A, et al.
HMGA2 and MED12 alterations frequently co-occur in uterine leiomyomas.
Gynecol Oncol. 2018; 150(3):562-568 [PubMed] Related Publications
OBJECTIVE: Around 70% of uterine leiomyomas show MED12 mutations while overexpression of HMGA2 mRNA is also highly frequent in fibroids. However, previous studies suggested that alterations in both genes are mutually exclusive. In the present study, we searched for mutation in MED12 and analyzed the expression of HMGA2 in 20 uterine leiomyomas and their matched myometrium.
METHODS: Normal and tumor tissue obtained from premenopausal women who underwent hysterectomy were collected after surgery and DNA, RNA and proteins were isolated and analyzed for MED12 mutations using Sanger sequencing, HMGA2 mRNA expression by quantitative PCR and HMGA2 protein detection by western blot and immunohistochemistry.
RESULTS: 75% of the tumors displayed MED12 mutation while 65% of them showed overexpression of HMGA2 mRNA in leiomyomata compared to myometrial tissues (p = 0,0008). Interestingly, 50% of the tumors showed mutations in MED12 and overexpression of HMGA2 mRNA simultaneously, suggesting that alterations in both genes are relatively frequent in uterine leiomyomas.
CONCLUSIONS: Contrary to the present findings, former studies showed that mutations in MED12 and overexpression of HMGA2 are mutually exclusive. Here, we observed that overexpression of HMGA2 mRNA in tumors measured by quantitative PCR and compared to myometrium is a common phenomenon in fibroids and is frequently associated with MED12 mutations. In addition, the common clonal origin of tumors overexpressing HMGA2 mRNA and its expression in few myometrial tissue points to HMGA2 up-regulation as an early event in leiomyoma tumorigenesis.

Xu X, Bao Z, Liu Y, et al.
PBX3/MEK/ERK1/2/LIN28/let-7b positive feedback loop enhances mesenchymal phenotype to promote glioblastoma migration and invasion.
J Exp Clin Cancer Res. 2018; 37(1):158 [PubMed] Article available free on PMC after 26/09/2019 Related Publications
BACKGROUND: Brain invasion by glioblastoma (GBM) determines recurrence and prognosis in patients, which is, in part, attributed to increased mesenchymal transition. Here, we report evidence favoring such a role for the Pre-B-cell leukemia homebox (PBX) family member PBX3.
METHODS: Western blot, immunohistochemistry, qRT-PCR and datasets mining were used to determined proteins or genes expression levels. Wound-healing and transwell assays were used to examine the invasive abilities of GBM cells. Dual-luciferase reporter assays were used to determine how let-7b regulates PBX3. Chromatin-immunoprecipitation (ChIP) and rescue experiments were performed to investigate the involved molecular mechanisms. Orthotopic mouse models were used to assess the role of PBX3 in vivo.
RESULTS: We found that PBX3 expression levels positively correlated with glioma mesenchymal markers. Ectopic expression of PBX3 promoted invasive phenotypes and triggered the expression of mesenchymal markers, whereas depletion of PBX3 reduced GBM cell invasive abilities and decreased the expression of mesenchymal markers. In addition, inhibition of PBX3 attenuated transforming growth factor-β (TGFβ)-induced GBM mesenchymal transition. Mechanistic studies revealed that PBX3 mediated GBM mesenchymal transition through activation of MEK/ERK1/2, leading to increased expression of LIN28 by c-myc. Increased LIN28 inhibited let-7b biogenesis, which then promoted the pro-invasive genes, such as HMGA2 and IL-6. Furthermore, let-7b suppressed PBX3 by directly targeting 3'-UTR of PBX3. Thus, repressed let-7b by PBX3 amplifies PBX3 signaling and forms a positive feedback loop to promote GBM mesenchymal transition.
CONCLUSIONS: These data highlight the importance of PBX3 as a key driver of mesenchymal transition and potential therapeutic target.

Li W, Wang H, Yang Y, et al.
Integrative Analysis of Proteome and Ubiquitylome Reveals Unique Features of Lysosomal and Endocytic Pathways in Gefitinib-Resistant Non-Small Cell Lung Cancer Cells.
Proteomics. 2018; 18(15):e1700388 [PubMed] Article available free on PMC after 26/09/2019 Related Publications
Non-small cell lung cancer (NSCLC) patients carrying EGFR activating mutations treated with gefitinib, a tyrosine kinase inhibitor, will develop drug resistance. Ubiquitylation is one of major posttranslational modifications of proteins affecting the stability or function of proteins. However, the role of protein ubiquitylation in gefitinib resistance is poorly understood. To systematically identify the global change in protein expression and ubiquitylation during gefitinib resistance, a quantitative global proteome and ubiquitylome study in a pair of gefitinib-resistant and sensitive NSCLC cells is carried out. Altogether, changes in expression of 3773 proteins are quantified, and changes in ubiquitylation of 2893 lysine sites in 1415 proteins are measured in both cells. Interestingly, lysosomal and endocytic pathways, which are involved in autophagy regulation, are enriched with upregulated proteins or ubiquitylated proteins in gefitinib-resistant cells. In addition, HMGA2 overexpression or ALOX5 knockdown suppresses gefitinib resistance in NSCLC cells by inhibiting autophagy. Overall, these results reveal the previously unknown global ubiquitylome and proteomic features associated with gefitinib resistance, uncover the opposing roles of HMGA2 or ALOX5 in regulating gefitinib resistance and autophagy, and will help to identify new therapeutic targets in overcoming gefitinib resistance.

Xie J, Ubango J, Ban Y, et al.
Comparative analysis of AKT and the related biomarkers in uterine leiomyomas with MED12, HMGA2, and FH mutations.
Genes Chromosomes Cancer. 2018; 57(10):485-494 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Uterine leiomyomas (ULM) are histologically and molecularly heterogeneous and clinically they grow at vastly different rates. Several driver gene mutations have been identified in ULM, including MED12 mutations, HMGA2 overexpression, and biallelic FH inactivation. ULM with different driver mutant genes may use different molecular pathways, but currently no clear correlation between gene mutations and growth related pathways has been established. To better define this relationship, we collected ULM with MED12 (n = 25), HMGA2 (n = 15), and FH (n = 27) mutations and examined the sex steroid hormone, cell cycle, and AKT pathway genes by immunohistochemistry. While ER and PR were highly expressed in all types of ULM, FH ULM showed lower ER expression and higher PR expression. HMGA2 tumors had significantly higher levels of AKT signaling and mitogenic activity than other ULM types. HMGA2 activated AKT signaling through upregulation of IGF2BP2. Silencing HMGA2 in ULM cells resulted in downregulation of AKT and upregulation of p16 and p21, which eventually led to cell senescence. HMGA2 overexpression in ULM is not only related to tumor development but also plays a role in controlling cellular proliferation through the AKT pathway.

Qiu Z, Zhou J, Zhang C, et al.
Antiproliferative effect of urolithin A, the ellagic acid-derived colonic metabolite, on hepatocellular carcinoma HepG2.2.15 cells by targeting Lin28a/let-7a axis.
Braz J Med Biol Res. 2018; 51(7):e7220 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
An abnormality in the Lin28/let-7a axis is relevant to the progression of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), which could be a novel therapeutic target for this malignant tumor. The present study aimed to investigate the antiproliferative and anti-invasive effects of urolithin A in a stable full-length HBV gene integrated cell line HepG2.2.15 using CCK-8 and transwell assays. The RNA and protein expressions of targets were assessed by quantitative PCR and western blot, respectively. Results revealed that urolithin A induced cytotoxicity in HepG2.2.15 cells, which was accompanied by the cleavage of caspase-3 protein and down-regulation of Bcl-2/Bax ratio. Moreover, urolithin A suppressed the protein expressions of Sp-1, Lin28a, and Zcchc11, and elevated the expression of microRNA let-7a. Importantly, urolithin A also regulated the Lin28a/let-7a axis in transient HBx-transfected HCC HepG2 cells. Furthermore, urolithin A decelerated the HepG2.2.15 cell invasion, which was involved in suppressing the let-7a downstream factors HMGA2 and K-ras. These findings indicated that urolithin A exerted the antiproliferative effect by regulating the Lin28a/let-7a axis and may be a potential supplement for HBV-infected HCC therapy.

Xia C, Liang S, He Z, et al.
Metformin, a first-line drug for type 2 diabetes mellitus, disrupts the MALAT1/miR-142-3p sponge to decrease invasion and migration in cervical cancer cells.
Eur J Pharmacol. 2018; 830:59-67 [PubMed] Related Publications
The molecular mechanisms underlying the anti-neoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. To explore the novel anti-neoplastic mechanisms of metformin, the transwell chamber and wound-healing assays were used to evaluate its effects on the migration and invasion of human cervical cancer cells. Real-time PCR and Western blotting were used to measure the gene and protein expression, respectively, of microRNA (miRNA) miR-142-3p, long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript-1 (MALAT1), and high-mobility group AT-hook 2 (HMGA2). The dual-luciferase reporter assay system was used to examine the direct interaction between miR-142-3p and lncRNA MALAT1 and HMGA2. Immunofluorescence was used to detect the protein expression of HMGA2. In addition, tumor xenografts in a nude mouse model were developed to evaluate the anti-tumor efficacy of metformin. We found that metformin could suppress cervical cancer migration and invasion. During the process of tumor metastasis, miR-142-3p was significantly upregulated, whereas lncRNA MATAL1 and HMGA2 were suppressed by metformin. The binding site that allow the direct interaction between miR-142-3p and MALAT1 were located in the 3' untranslated region (3' UTR) of lncRNA MATAL1 and HMGA2 at base pairs (bp) 4452-5255, while that between miR-142-3p and HMGA2 was located at bp 1562-2521 of HMGA2. Metformin markedly inhibited the growth and angiogenesis of SiHa xenografts in nude mice. In conclusion, this study provides evidence that metformin can prevent the MALAT1/miR-142-3p sponge from developing anti-neoplastic properties in human cervical cancer cells and cervical cancer cell xenografts in nude mice. Thus, our findings demonstrate the novel anti-tumor effects of metformin in cervical cancer.

Panagopoulos I, Gorunova L, Lund-Iversen M, et al.
Cytogenetics of Spindle Cell/Pleomorphic Lipomas: Karyotyping and FISH Analysis of 31 Tumors.
Cancer Genomics Proteomics. 2018 May-Jun; 15(3):193-200 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Spindle cell/pleomorphic lipomas are benign tumors. Here, we present our cytogenetic data on 31 such tumors.
MATERIALS AND METHODS: G-banding chromosome analysis and (in selected cases) fluorescence in situ hybridization (FISH) using probes for FOXO1, RB1, and HMGA2 were performed.
RESULTS: Rearrangements of chromosome 13 were found in 58% of tumors. Chromosomes 6, 1, 12, and 11 were also involved in 42%, 26%, 26%, and 23% of tumors, respectively. FISH analysis showed heterozygous deletion of RB1 in seven samples with chromosome 13 aberrations. In four of them, FOXO1 was also deleted. In two tumors with 12q15 rearrangements, FISH confirmed that HMGA2 was targeted.
CONCLUSION: Structural rearrangements of 13q or losses of an entire chromosome 13 are the most common cytogenetic aberrations in spindle cell/pleomorphic lipomas. However, cytogenetic variation exists similarly to what is found in other lipomas, suggesting that various pathways may be responsible for tumorigenesis.

Yang Y, Jiang H, Xiao L, Yang X
MicroRNA-33b-5p is overexpressed and inhibits GLUT4 by targeting HMGA2 in polycystic ovarian syndrome: An in vivo and in vitro study.
Oncol Rep. 2018; 39(6):3073-3085 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disease, but its pathogenesis remains largely unknown. The present study explored the role of microRNA‑33b‑5p (miR‑33b‑5p) in PCOS pathogenesis, with a particular focus on its role in regulating glucose transporter 4 (GLUT4). A rat model of PCOS was developed by injecting female SD rats with insulin and HCG. miR‑33b‑5p, GLUT4, sterol regulatory element‑binding protein 1 (SREBF1), and high mobility group A2 (HMGA2) expression in rat ovarian tissues was examined by qRT‑PCR and immunohistochemistry. The effect of a high dose of either glucose or insulin on miR‑33b‑5p, GLUT4, SREBF1 and HMGA2 expression was also examined in cultured adipocytes by qRT‑PCR and western blotting. Additionally, the luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to explore the role of miR‑33b‑5p in regulating HMGA2, SREBF‑1 and/or GLUT4. Elevated levels of miR‑33b‑5p expression were detected in the ovarian tissues of insulin resistant PCOS rats, and those levels were negatively correlated with those of GLUT4, HMGA2 and SREBF1 expression (P<0.05). Immunohistochemistry studies revealed that GLUT4, SREBF1, and HMGA2 expression levels in the ovarian tissues of insulin resistant PCOS rats were significantly lower than those in other groups of rats. In cultured adipocytes, excess extracellular glucose or insulin increased miR‑33b‑5p expression but reduced GLUT4, SREBF1 and HMGA2 expression, whereas the levels of GLUT4, SREBF1 and HMGA2 were elevated by inhibition of miR‑33b‑5. HMGA2 could directly bind to the 5'‑promoter region of GLUT4 and promote its expression, and could also promote SREBF1 expression. Moreover, SREBF1 could also directly bind to the 5'‑promoter region of GLUT4 and promote its expression. Our findings revealed that miR‑33b‑5p was overexpressed in the ovarian tissues of insulin resistant PCOS rats, and thus may play an important role in the development of insulin resistance in PCOS patients. miR‑33b‑5p can inhibit GLUT4 production by targeting HMGA2, and in addition, HMGA2 and SREBF1 are important molecules involved in modulating GLUT4 expression.

Chiu HS, Martínez MR, Komissarova EV, et al.
The number of titrated microRNA species dictates ceRNA regulation.
Nucleic Acids Res. 2018; 46(9):4354-4369 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
microRNAs (miRNAs) play key roles in cancer, but their propensity to couple their targets as competing endogenous RNAs (ceRNAs) has only recently emerged. Multiple models have studied ceRNA regulation, but these models did not account for the effects of co-regulation by miRNAs with many targets. We modeled ceRNA and simulated its effects using established parameters for miRNA/mRNA interaction kinetics while accounting for co-regulation by multiple miRNAs with many targets. Our simulations suggested that co-regulation by many miRNA species is more likely to produce physiologically relevant context-independent couplings. To test this, we studied the overlap of inferred ceRNA networks from four tumor contexts-our proposed pan-cancer ceRNA interactome (PCI). PCI was composed of interactions between genes that were co-regulated by nearly three-times as many miRNAs as other inferred ceRNA interactions. Evidence from expression-profiling datasets suggested that PCI interactions are predictive of gene expression in 12 independent tumor- and non-tumor contexts. Biochemical assays confirmed ceRNA couplings for two PCI subnetworks, including oncogenes CCND1, HIF1A and HMGA2, and tumor suppressors PTEN, RB1 and TP53. Our results suggest that PCI is enriched for context-independent interactions that are coupled by many miRNA species and are more likely to be context independent.

Liu X, Yidayitula Y, Zhao H, et al.
LncRNA LINC00152 promoted glioblastoma progression through targeting the miR-107 expression.
Environ Sci Pollut Res Int. 2018; 25(18):17674-17681 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) LINC00152 plays important roles in the progression of some tumors. However, the role of LINC00152 in human l glioblastoma is still unknown. In this study, we indicated that LINC00152 expression level was upregulated in glioblastoma tissues and cell lines. Overexpression of LINC00152 promoted the U87 and LN229 cell proliferation and invasion. Moreover, overexpression of LINC00152 suppressed the E-cadherin expression, where ectopic expression of LINC00152 promoted the N-cadherin, Vimentin, and Snail expression. These results suggested that LINC00152 enhanced epithelial-to-mesenchymal transition (EMT) program in the glioblastoma cell. Overexpression of LINC00152 suppressed the miR-107 expression in the U87 cell and enhanced the HMGA2 expression, which is a direct target gene of miR-107. In addition, we showed that the miR-107 expression was downregulated in the glioblastoma tissues and cell lines. Interesting, the expression of LINC00152 was negatively related with miR-107 expression in the glioblastoma tissues. Furthermore, LINC00152 promoted the glioblastoma cell proliferation and invasion through inhibiting miR-107 expression. These data suggested that LINC00152 acted as oncogene roles in the glioblastoma cell partly through targeting the miR-107 expression.

Beird HC, Wu CC, Ingram DR, et al.
Genomic profiling of dedifferentiated liposarcoma compared to matched well-differentiated liposarcoma reveals higher genomic complexity and a common origin.
Cold Spring Harb Mol Case Stud. 2018; 4(2) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes (

Xi T, Zhang G
Integrated analysis of tumor differentiation genes in pancreatic adenocarcinoma.
PLoS One. 2018; 13(3):e0193427 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Tumor differentiation is an important process in the development of cancer. It is valuable to identify key differentiation related genes in the prognosis and therapy of pancreatic adenocarcinoma.
METHODS: The mRNA expression data were downloaded from the Cancer Genome Atlas database. Then, differentially expressed tumor differentiation related genes were identified. Additionally, Gene Ontology functional categories and Kyoto Encyclopedia of Genes and Genomes biochemical pathway was used to explore the function. In addition, receiver operating characteristic and survival analysis were carried out to assess the diagnosis and prognosis value. Finally, the electronic validation of selected tumor differentiation related genes was performed.
RESULTS: A total of 932 genes were identified. Among which, 8 genes including JUB, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, TCTA and SSTR1 were differentially expressed in all different tumor differentiation grades. Functional analysis revealed those genes between highly differentiated and other differentiation were remarkably enriched in pancreatic adenocarcinoma and cell cycle pathway. Finally, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, BCL2L1, E2F1 and RAC1 were associated with the survival time of pancreatic adenocarcinoma patient. Among these genes, JUB, ERLIN1, FAM110B, MCM2 and BCL2L1 also had a diagnosis value for pancreatic adenocarcinoma. Additionally, the expression trend of JUB, HMGA2 and MCM2 was increased along with the tumor differentiation grades. And the expression trend of FAM110B was decreased along with the tumor differentiation grades. The electronic validation result was consistent with the bioinformatics analysis.
CONCLUSIONS: 12 tumor differentiation related genes including JUB, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, TCTA, SSTR1, BCL2L1, E2F1, RAC1 and STAT1 played crucial roles in the differentiation of pancreatic adenocarcinoma.

Zhao H, Zhao H, Xia X, Liu X
MicroRNA-599 targets high-mobility group AT-hook 2 to inhibit cell proliferation and invasion in clear cell renal carcinoma.
Mol Med Rep. 2018; 17(5):7451-7459 [PubMed] Related Publications
Dysregulation of microRNAs (miRNAs) is associated with the occurrence and development of clear cell renal cell carcinoma (ccRCC) through their participation in a number of critical biological processes. Therefore, an in‑depth investigation into miRNAs and their biological roles within ccRCC may provide useful insights and lead to the identification of novel therapeutic methods for patients with ccRCC. miRNA‑599 (miR‑599) serves critical roles in different types of human cancer. However, the expression pattern, biological function and molecular mechanism of miR‑599 in ccRCC remain unknown. The present study aimed to detect the expression level of miR‑599 in ccRCC, examine its effect on ccRCC progression and further explore the possible underlying mechanisms. It was observed that miR‑599 was significantly underexpressed in ccRCC tissues and cell lines compared with the control. Functional assays revealed that restored expression of miR‑599 restricted the proliferation and invasion of ccRCC cells. Bioinformatics analysis, luciferase reporter assay, reverse transcription‑quantitative polymerase chain reaction and western blot analysis demonstrated that high‑mobility group AT‑hook 2 (HMGA2) was a direct target of miR‑599 in ccRCC. HMGA2 knockdown simulated the suppressive effects caused by miR‑599 overexpression in ccRCC. Recovered HMGA2 expression partially rescued the miR‑599‑mediated inhibition of ccRCC proliferation and invasion. These results suggest that miR‑599 may serve tumour suppressive roles in ccRCC by directly targeting HMGA2, indicating that miR‑599 may have potential as a treatment for patients with ccRCC.

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] Related Publications
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.

Hofving T, Arvidsson Y, Almobarak B, et al.
The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines.
Endocr Relat Cancer. 2018; 25(3):367-380 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the

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