Oncogenic HMGA2: short or small?: Figure 1.

Young, Andrew; Narita, Masashi

doi:10.1101/gad.1554707

Cited by 93 publications

(88 citation statements)

References 43 publications

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“…HMGA2 codes for a chromatin-associated protein that can modulate transcription by binding to DNA and altering the chromatin architecture [17,18]. HMGA2 is primarily expressed in undifferentiated cells during fetal development and in various tumors of mesenchymal origin, including fibroadenomas of the breast, lipomas and uterine leiomyomas [19][20][21].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐490‐3p regulates cell proliferation and apoptosis by targeting HMGA2 in osteosarcoma

Liu

et al. 2015

FEBS Letters

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Edited by Tamas Dalmay Keywords:MicroRNA-490-3p High mobility group a isoform 2 Osteosarcoma Proliferation a b s t r a c t ) has been implicated in several human malignancies; however, its potential functions and the underlying molecular mechanisms in osteosarcoma progression remain largely unclear. Here, we showed that miR-490-3p was down-regulated in osteosarcoma cell lines. Ectopic expression of miR-490-3p decreased cell proliferation, induced G1 arrest and apoptosis in vitro and inhibited tumorigenicity in a mouse xenograft model. Furthermore, miR-490-3p bound directly to HMGA2 mRNA 3 0 UTR and mediated a decrease in HMGA2 mRNA and protein expression. Re-expression of HMGA2 reversed the inhibitory effects of miR-490-3p. Further investigations showed an inverse correlation between low miR-490-3p and high HMGA2 expression in osteosarcoma tissues. Taken together, our results suggest that miR-490-3p functions as a potential tumor suppressor by down-regulating HMGA2 expression directly, and it may represent a potential therapeutic target for patients with osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

MicroRNA‐490‐3p regulates cell proliferation and apoptosis by targeting HMGA2 in osteosarcoma

Liu

et al. 2015

FEBS Letters

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“…26,36 Similar to the KRAS, HMGA1 and HMGA2 mRNAs have a long 3ЈUTR, 37 and are targeted by the let-7 microRNAs in mammalian cells. 22,24,25,38 Because constitutively active mutations of KRAS mostly occur during early development of pancreatic cancer, 28 it is of great interest as to whether let-7 can inhibit mutant KRAS or HMGA in pancreatic cancer cells. In AsPC1 and Panc1 cells, the 3ЈUTRs of HMGA2, as well as KRAS transcripts, were targeted by let-7 for down-regulation (Figures 6 and 7).…”

Section: Discussionmentioning

confidence: 99%

“…Similar to the KRAS, HMGA1 and HMGA2 have a long 3ЈUTR, 37 and are targeted by the let-7 microRNAs in mammalian cells. 22,24,25,38 Using the miRanda (http:// www.microrna.org/) and TargetScan (http://genes.mit. edu/targetscan/), as shown in Figure 6A, HMGA1, HMGA2, and KRAS commonly had let-7 family and miR-370 complementary sites in their 3ЈUTR.…”

Section: Effect Of the Let-7 Micrornas On The Phenotypes Of Pancreatimentioning

confidence: 99%

HMGA2 Maintains Oncogenic RAS-Induced Epithelial-Mesenchymal Transition in Human Pancreatic Cancer Cells

Watanabe

Ueda

Akaboshi

et al. 2009

The American Journal of Pathology

172

155

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Pancreatic cancer is a highly aggressive malignancy due to elevated mitotic activities and epithelial-mesenchymal transition (EMT). Oncogenic RAS and transforming growth factor-␤ signaling are implicated in these malignant features. The mechanisms that underlie EMT need to be addressed since it promotes tissue invasion and metastasis. The high-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor that is primarily expressed in undifferentiated tissues and tumors of mesenchymal origin. However, its role in EMT in pancreatic cancer is largely unknown. Here we report that HMGA2 is involved in EMT maintenance in human pancreatic cancer cells. Specific knockdown of HMGA2 inhibited cell proliferation, leading to an epithelial-state transition that restores cell-cell contact due to E-cadherin up-regulation. Consistently, an inverse correlation between HMGA2-positive cells and E-cadherin-positive cells was found in cancer tissues. Inhibition of the RAS/ MEK pathway also induced an epithelial transition, together with HMGA2 down-regulation. Transcriptional repressors of the E-cadherin gene, such as SNAIL, decreased after HMGA2 knockdown since HMGA2 directly activated the SNAlL gene promoter. The decrease of SNAIL after RAS/MEK inhibition was suppressed by HMGA2 overexpression. Further, let-7 microRNA-mediated HMGA2 down-regulation had no effect on the prevention of the transformed phenotype in these cells. These data shed light on the importance of HMGA2 in reversibly maintaining EMT, suggesting that HMGA2 is a potential therapeutic target for the treatment of pancreatic cancer. Pancreatic cancer has the poorest prognosis among human neoplasms due to its highly aggressive and metastasizing features.1-3 Current diagnostic tools have difficulty in detecting the early stage of this disease, and therapeutic applications often remain ineffective at advanced stages. Thus, the mechanisms leading to progression of this cancer especially need to be understood at molecular levels. The epithelial-mesenchymal transition (EMT) is a physiological process, originally found in embryonic development, in which the cells lose epithelial characteristics and gain mesenchymal properties. 4 This process is accompanied by loss of cell-to-cell contact and subsequent increased cell movement. Recent reports have implicated EMT in a malignant conversion of transformed cells, which represents invasive or metastasizing properties in a variety of cancers. 5,6 In pancreatic cancer cells, EMT is also reported to be a crucial step for tumor cell migration and invasion.7 Previous studies suggest that aberrations in pathways emerging from oncogenic RAS and transforming growth factor-␤ (TGF-␤) stimulate the malignant features, including EMT.6,8 Several transcriptional factors have been identified that control EMT by repressing E-cadherin and other epithelial genes in embryonic morphogenesis and cancer metastasis.6,9 These include the Snail-related zinc-finger factors (SNAIL and SLUG), the other zinc-finger factors (SIP1/ZEB2 and ZEB1/␦EF-1), ...

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“…Despite its function in remodeling the tumor microenvironment, ANG1 may play a minor role in transforming MECs into neoplastic cells. Untimely expression of HMGA2 is observed in many benign and malignant tumors, suggesting its potential as an oncogene (31). Thus, demonstration of a similar regulation of HMGA2 by BRCA1 will offer a plausible mechanism addressing how BRCA1 inactivation contributes to breast carcinogenesis, specifically through HMGA2 activation.…”

Section: Discussionmentioning

confidence: 99%

Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

Ahmed

Tsai

Lee

2010

Journal of Biological Chemistry

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The high mobility group AT-hook 2 (HMGA2), a DNA architectural protein, is highly regulated during development and plays an important role in tumorigenesis. Indeed, HMGA2 was overexpressed in many different kinds of tumors. However, the mechanisms regulating HMGA2 expression remain elusive. Using microarray analysis, we found that HMGA2, along with a dozen of other genes, was co-repressed by ZBRK1, BRCA1, and CtIP. BRCA1 exerts its transcriptional repression activity through interaction with the transcriptional repressor ZBRK1 in the central domain, and with CtIP in the C-terminal BRCT domain. Here, we show that ZBRK1, BRCA1, and CtIP form a repression complex that coordinately regulates HMGA2 expression via a ZBRK1 recognition site in the HMGA2 promoter. Depletion of any of the proteins in this complex via adenoviral RNA interference in MCF10A mammary epithelial cells activates HMGA2 expression, resulting in increased colony formation in soft agar. Similarly, depletion of ZBRK1, or ectopic overexpression of HMGA2, in MCF10A cells induces abnormal acinar size with increased cell number and inhibits normal acinar formation. Consistently, many BRCA1-deficient mouse breast tumors express higher levels of HMGA2 than BRCA1-proficient tumors. These results suggest that activation of HMGA2 gene expression through derepression of the ZBRK1/ BRCA1/CtIP complex is a significant step in accelerating breast tumorigenesis.The HMGA family consists of four proteins: HMGA1a, HMGA1b, HMGA1c, and HMGA2.2 HMGA1a, -b, and -c are all encoded by the same gene but vary in length due to alternative splicing (1-3), whereas HMGA2 is encoded by a distinctive gene (4). The common structural motifs in this group include an acidic C terminus and three DNA binding domains called A-T hooks, because they bind short (4 Ϯ 6 bp) AT-rich sequences in the minor groove (5-8). HMGA proteins regulate the expression of many genes through architectural remodeling of the chromatin structure and the formation of multiprotein complexes on promoter/enhancer regions. In accordance with their many roles in transcriptional regulation, aberrant expression of HMGA proteins has been observed in a large number of human cancers (reviewed by Farnet et al. (9)). The HMGA2 architectural protein is critical for a variety of cellular processes, including gene transcription, induction of neoplastic transformation, and promotion of metastatic progression (10, 11). Importantly, HMGA2 overexpression in tumors is associated with poor prognosis and metastasis in breast cancer patients (12). Although it is known that transcriptional repression of HMGA2 may prevent mammary tumorigenesis, the mechanisms governing repression remain elusive.The potential role of BRCA1 in transcriptional regulation has been revealed by discovering its ability to bind many important transcription factors, including p53, c-Myc, and STAT1 (13-15). Expression of several target proteins, including p21 WAF1 , cyclin B1, and EGR1, is activated or repressed by the presence of BRCA1. BRCA1 lacks DNA sequence...

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Oncogenic HMGA2: short or small?: Figure 1.

Cited by 93 publications

References 43 publications

MicroRNA‐490‐3p regulates cell proliferation and apoptosis by targeting HMGA2 in osteosarcoma

MicroRNA‐490‐3p regulates cell proliferation and apoptosis by targeting HMGA2 in osteosarcoma

HMGA2 Maintains Oncogenic RAS-Induced Epithelial-Mesenchymal Transition in Human Pancreatic Cancer Cells

Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

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