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View Article and Find Full Text PDFHigh-mobility group A1 (Hmga1) chromatin remodelling proteins are enriched in intestinal stem cells (ISCs), although their function in this setting was unknown. Prior studies showed that Hmga1 drives hyperproliferation, aberrant crypt formation and polyposis in transgenic mice. Here we demonstrate that Hmga1 amplifies Wnt/β-catenin signalling to enhance self-renewal and expand the ISC compartment.
View Article and Find Full Text PDFAlthough significant progress has been made in the diagnosis and treatment of colorectal cancer (CRC), it remains a leading cause of cancer death worldwide. Early identification and removal of polyps that may progress to overt CRC is the cornerstone of CRC prevention. Expression of the High Mobility Group A1 (HMGA1) gene is significantly elevated in CRCs as compared with adjacent, nonmalignant tissues.
View Article and Find Full Text PDFEmerging evidence suggests that tumor cells metastasize by co-opting stem cell transcriptional networks, although the molecular underpinnings of this process are poorly understood. Here, we show for the first time that the high mobility group A1 (HMGA1) gene drives metastatic progression in triple negative breast cancer cells (MDA-MB-231, Hs578T) by reprogramming cancer cells to a stem-like state. Silencing HMGA1 expression in invasive, aggressive breast cancer cells dramatically halts cell growth and results in striking morphologic changes from mesenchymal-like, spindle-shaped cells to cuboidal, epithelial-like cells.
View Article and Find Full Text PDFBackground: Although recent studies have identified genes expressed in human embryonic stem cells (hESCs) that induce pluripotency, the molecular underpinnings of normal stem cell function remain poorly understood. The high mobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly differentiated, stem-like cancers; however, its role in these settings has been unclear.
Methods/principal Findings: We show that HMGA1 is highly expressed in fully reprogrammed iPSCs and hESCs, with intermediate levels in ECCs and low levels in fibroblasts.
Context: Although pancreatic cancer is a common, highly lethal malignancy, the molecular events that enable precursor lesions to become invasive carcinoma remain unclear. We previously reported that the high-mobility group A1 (HMGA1) protein is overexpressed in >90% of primary pancreatic cancers, with absent or low levels in early precursor lesions.
Methods: Here, we investigate the role of HMGA1 in reprogramming pancreatic epithelium into invasive cancer cells.
Background: Although metastatic colon cancer is a leading cause of cancer death worldwide, the molecular mechanisms that enable colon cancer cells to metastasize remain unclear. Emerging evidence suggests that metastatic cells develop by usurping transcriptional networks from embryonic stem (ES) cells to facilitate an epithelial-mesenchymal transition (EMT), invasion, and metastatic progression. Previous studies identified HMGA1 as a key transcription factor enriched in ES cells, colon cancer, and other aggressive tumors, although its role in these settings is poorly understood.
View Article and Find Full Text PDFBackground: Although the high mobility group A1 (HMGA1) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. HMGA1 functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, HMGA1 is thought to drive malignant transformation by modulating expression of specific genes.
View Article and Find Full Text PDFDefinitive evidence on the impact of MnSOD/SOD2-deficiency and the consequent effects of high flux of mitochondrial reactive oxygen species (ROS) on pre-natal/pre-adult development has yet to be reported for either Drosophila or mice. Here we report that oocytes lacking maternal SOD2 protein develop into adults just like normal SOD2-containing oocytes suggesting that maternal SOD2-mediated protection against mitochondrial ROS is not essential for oocyte viability. However, the capacity of SOD2-null larvae to undergo successful metamorphosis into adults is negatively influenced in the absence of SOD2.
View Article and Find Full Text PDFAlthough lung cancer is the leading cause of cancer death worldwide, the precise molecular mechanisms that give rise to lung cancer are incompletely understood. Here, we show that HMGA1 is an important oncogene that drives transformation in undifferentiated, large-cell carcinoma. First, we show that the HMGA1 gene is overexpressed in lung cancer cell lines and primary human lung tumors.
View Article and Find Full Text PDFAlthough pancreatic ductal adenocarcinoma is a common and almost uniformly fatal cancer, little is known about the molecular events that lead to tumor progression. The high-mobility group A1 (HMGA1) protein is an architectural transcription factor that has been implicated in the pathogenesis and progression of diverse human cancers, including pancreatic ductal adenocarcinoma. In this study, we investigated HMGA1 expression in pancreatic ductal adenocarcinoma cell lines and surgically resected tumors to determine whether it could be a marker for more advanced disease.
View Article and Find Full Text PDFAlthough HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis.
View Article and Find Full Text PDFManganese superoxide dismutase (MnSOD or SOD2) is a key mitochondrial enzymatic antioxidant. Arguably the most striking phenotype associated with complete loss of SOD2 in flies and mice is shortened life span. To further explore the role of SOD2 in protecting animals from aging and age-associated pathology, we generated a unique collection of Drosophila mutants that progressively reduce SOD2 expression and function.
View Article and Find Full Text PDFTwo deletions, Df(2R)Sod2-11 and Df(2R)Sod2-332, are recovered that encompass the manganese superoxide dismutase (MnSOD) gene or a null mutant referred to as SOD2n283 in Drosophila. Molecular analysis has revealed that the Df(2R)Sod2-332 deletion completely uncovered both MnSOD and its adjacent gene, Arp53D, whereas Df(2R)Sod2-11 was missing the promoter region of MnSOD gene. As a consequence of reduced MnSOD expression, these deletion heterozygotes are now sensitive to oxidative stress.
View Article and Find Full Text PDFA null mutation for the Sod2 gene, Sod2n283, was obtained in Drosophila melanogaster. Homozygous Sod2 null (Sodn283/Sodn283) adult flies survive up to 24 hr following eclosion, a phenotype reminiscent of mice, where Sod2-/- progeny suffer neonatal lethality. Sodn283/+ heterozygotes are sensitive to oxidative stress induced by paraquat treatment.
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