Antiproliferative Effects by <i>Let-7</i> Repression of High-Mobility Group A2 in Uterine Leiomyoma

Peng, Yi; Laser, Jordan; Shi, Guizhi; Mittal, Khush; Melamed, Jonathan; Lee, Peng; Wei, Jian Jun

doi:10.1158/1541-7786.mcr-07-0370

Cited by 125 publications

(117 citation statements)

References 46 publications

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“…27 HMGA2 overexpression is associated with tumor growth, 28 differentiation, 9,16,28 metastasis, 29 unfavorable outcome and resistance to treatment. 25,30 The function of HMGA2 in behaviors of aggressive tumor growth in ovarian high-grade papillary serous carcinomas deserves further investigation.…”

Section: Discussionmentioning

confidence: 99%

HMGA2: A biomarker significantly overexpressed in high-grade ovarian serous carcinoma

et al. 2010

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Ovarian carcinoma consists of a group of histologically heterogeneous diseases involving distinct tumorigenic pathways. High-grade papillary serous carcinoma of the ovary is commonly associated with p53 mutations. HMGA2, an oncofetal protein, is found to be overexpressed in ovarian cancer. To study the function of HMGA2 in ovarian cancer, it is important to know which subtypes of ovarian cancer are associated with HMGA2 overexpression. In this study, we collected six different types of ovarian cancer and examined HMGA2 expression by immunohistochemistry, along with HMGA1, p53 and Ki-67. We found that HMGA2 overexpression was significantly higher in high-grade papillary serous carcinoma (64%) and carcinosarcoma (60%) than in other types of ovarian cancers (7-23%). HMGA2 overexpression was moderately associated with dominant p53 mutations (R ¼ 0.51). In addition, the microRNA in situ analysis revealed that let-7b, the HMGA2-negative regulators, were significantly lost in high-grade serous carcinoma. Our findings suggest that HMGA2 is an important molecular change significantly related to high-grade papillary serous carcinoma and is less common in other histological types of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

HMGA2: A biomarker significantly overexpressed in high-grade ovarian serous carcinoma

et al. 2010

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“…Similar finding also has been discussed in small leiomyomas. 44 But HMGA2 expression has been detected in about half of adenomas with normal or a little high expression of let-7. These findings implied that more let-7 may be needed in tumor than in normal tissue for effectively regulating target genes.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas

et al. 2009

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High-mobility group A2 is highly expressed during embryogenesis and in various benign and malignant tumors. Recent studies report that high-mobility group A2 is negatively regulated by the let-7 microRNAs (miRNAs) family in vitro. The development of pituitary adenomas in high-mobility group A2 transgenic mice showed that high-mobility group A2 may be involved in pituitary tumorigenesis. However, no studies have investigated the clinical significance of high-mobility group A2 and its relationship to the let-7 miRNA family in human pituitary adenomas. Using immunohistochemistry, we analyzed high-mobility group A2 expression with respect to various clinicopathologic factors in 98 pituitary adenomas. Overexpression of high-mobility group A2 was observed in 39% (38/98) of pituitary adenomas compared with normal adenohypophysial tissue and was frequently found in adenomas including prolactin (PRL), adrenocorticotrophic hormone, or follicle-stimulating hormone/luteinizing hormone and in null cell adenomas, but relatively rare in growth hormone (GH) and mixed GH/PRL adenomas. High-mobility group A2 expression was significantly associated with tumor invasion (Po0.05) and was significantly higher in grade IV than in grades I, II, and III adenomas (Po0.05). High levels of high-mobility group A2 expression were more frequently observed in macroadenomas than in microadenomas (Po0.05). High levels of high-mobility group A2 expression also significantly correlated with the proliferation marker Ki-67 (Po0.0001). Real-time quantitative RT-PCR analysis was carried out to evaluate the expression of let-7 in 55 pituitary adenomas. Subsequently, decreased expression of let-7 was confirmed in 23 of 55 (42%) adenomas and was correlated with high-grade tumors (Po0.05). An inverse correlation between let-7 and highmobility group A2 expression was evident (R ¼ À0.33, Po0.05). These findings support a causal link between let-7 and high-mobility group A2 whereby loss of let-7 expression induces high-mobility group A2 upregulation that represents an important mechanism in pituitary tumorigenesis and progression.

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“…These data are significantly correlated with immunohistochemical expression of HMGA2 in our series and in several other studies. [42][43][44] Among vulvovaginal lesions, aggressive angiomyxomas also have rearrangements of 12q13-15 region with translocations involving chromosomes 1, 7, 8 and 21. [45][46][47][48] But HMGA2 was identified as the only regulated gene, and RT-PCR techniques have reported breakpoints in HMGA2 at different levels: preferentially in the 5 0 part of gene and also described in intron 3.…”

Section: Hmga2 In Mesenchymal Tumorsmentioning

confidence: 99%

Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases

et al. 2010

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The high mobility group A (HMGA2) gene encodes a protein that alters chromatin structure and regulates the transcription of many genes; it is implicated in both benign and malignant neoplasias, but its rearrangements are a feature of development of several mesenchymal tumors. Given its implication in these tumors and particularly adipocytic tumors, and the availability of antibodies usable on paraffin-embedded tissues, we evaluated the immunohistochemical expression of this gene in a series of 1052 mesenchymal tumors. The objective was to define the value and limitations of HMGA2 immunohistochemical expression for histotyping, and compare with molecular data reported in the literature. We thus analyzed 880 cases on tissue microarray and 182 cases on whole sections (211 adipocytic tumors, 628 sarcomas, 213 benign mesenchymal tumors, and 10 normal adipose tissues). A nuclear immunostaining was detected in 86% of conventional and intramuscular lipomas, in 86% of well-differentiated liposarcomas and in 67% of dedifferentiated liposarcomas, as opposed to 16% of other benign adipose tumors and to 15% of non-well-differentiated liposarcoma/dedifferentiated liposarcoma sarcomas. Among benign mesenchymal tumors and lesions, it was detected in 90% of nodular fasciitis and in 88% of benign fibrous histiocytomas with respective specificities of 85 and 100%, and in 90% of aggressive angiomyxoma, contrary to other vulvovaginal tumor types, which expressed HMGA2 only rarely. The normal adipose tissue was always negative for HMGA2. Although not specific, immunohistochemical detection of the HMGA2 protein is helpful for the distinction of normal adipose tissue from well-differentiated lesions, particularly on biopsy or on re-excision. It is less sensitive than MDM2/CDK4 for dedifferentiated liposarcomas diagnosis, but it appears more specific to distinguish dedifferentiated liposarcomas from other poorly differentiated sarcomas. Finally, and may be more importantly, HMGA2 is useful for the diagnosis of benign fibrous histiocytoma, nodular fasciitis and vulvovaginal benign mesenchymal tumors.

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Antiproliferative Effects by Let-7 Repression of High-Mobility Group A2 in Uterine Leiomyoma

Cited by 125 publications

References 46 publications

HMGA2: A biomarker significantly overexpressed in high-grade ovarian serous carcinoma

HMGA2: A biomarker significantly overexpressed in high-grade ovarian serous carcinoma

Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas

Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases

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