Background & Objectives
Chromatin structure is the single most important feature that
distinguishes a cancer cell from a normal cell histologically. Chromatin
remodeling proteins regulate chromatin structure and high mobility group A
(HMGA1) proteins are among the most abundant, nonhistone chromatin
remodeling proteins found in cancer cells. These proteins include
HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The
HMGA1 gene is overexpressed in cancer and high levels
portend a poor prognosis in diverse tumors. HMGA1 is also
highly expressed during embryogenesis and postnatally in adult stem cells.
Overexpression of HMGA1 drives neoplastic transformation in
cultured cells, while inhibiting HMGA1 blocks oncogenic and
cancer stem cell properties. Hmga1 transgenic mice succumb
to aggressive tumors, demonstrating that dysregulated expression of
HMGA1 causes cancer in vivo. HMGA1 is
also required for reprogramming somatic cells into induced pluripotent stem
cells. HMGA1 proteins function as ancillary transcription factors that bend
chromatin and recruit other transcription factors to DNA. They induce
oncogenic transformation by activating or repressing specific genes involved
in this process and an HMGA1 “transcriptome” is emerging.
Although prior studies reveal potent oncogenic properties of
HMGA1, we are only beginning to understand the
molecular mechanisms through which HMGA1 functions. In this
review, we summarize the list of putative downstream transcriptional targets
regulated by HMGA1. We also briefly discuss studies linking
HMGA1 to Alzheimer’s disease and type-2
diabetes.
Conclusion
Further elucidation of HMGA1 function should lead to
novel therapeutic strategies for cancer and possibly for other diseases
associated with aberrant HMGA1 expression.
Objectives
Although uterine cancer is the fourth most common cause for cancer death in
women worldwide, the molecular underpinnings of tumor progression remain poorly
understood. The High Mobility Group A1 (HMGA1) gene is overexpressed in
aggressive cancers and high levels portend adverse outcomes in diverse tumors. We
previously reported that Hmga1 transgenic mice develop uterine tumors
with complete penetrance. Because HMGA1 drives tumor progression by inducing
matrix metalloproteinase (MMP) and other genes
involved in invasion, we explored the HMGA1-MMP-2 pathway in uterine
cancer.
Methods
To investigate MMP-2 in uterine tumors driven by HMGA1, we used a genetic
approach with mouse models. Next, we assessed HMGA1 and
MMP-2 expression in primary human uterine tumors, including low-grade
carcinomas (endometrial endometrioid) and more aggressive tumors (endometrial serous
carcinomas, uterine carcinosarcomas/malignant mesodermal mixed tumors).
Results
Here, we report for the first time that uterine tumor growth is impaired in
Hmga1a transgenic mice crossed on to an Mmp-2
deficient background. In human tumors, we discovered that HMGA1 is
highest in aggressive carcinosarcomas and serous carcinomas, with lower levels in the
more indolent endometrioid carcinomas. Moreover, HMGA1 and
MMP-2 were positively correlated, but only in a subset of
carcinosarcomas. HMGA1 also occupies the MMP-2 promoter in human
carcinosarcoma cells.
Conclusions
Together, our studies define a novel HMGA1-MMP-2 pathway involved in a subset
of human carcinosarcomas and tumor progression in murine models. Our work also suggests
that targeting HMGA1 could be effective adjuvant therapy for more aggressive uterine
cancers and provides compelling data for further preclinical studies.
Abstract:Software assurance tools are a fundamental resource for providing an assurance argument for today's software applications throughout the software development lifecycle. Some tools analyze software requirements, design models, source code, or executable code to help determine if an application is secure. This document specifies the behavior of one class of software assurance tool: the source code security analyzer. Because many software security weaknesses today are introduced at the implementation phase, using a source code security analyzer should help assure that software doesn't have many security vulnerabilities. This specification defines a minimum capability to help software professionals understand how a tool will meet their software security assurance needs.
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