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Uterine fibroids and the endometrium
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Deborah E. Ikhena, Serdar E. Bulun
An incident genetic hit may be responsible for the development of a fibroid stem cell from within a population of myometrial stem cells (5). These genetic hits include hereditary chromosomal rearrangements in the high-mobility group AT-hook 2 (HMGA2) gene, as well as de novo mutations in the MED12 gene. Chromosomal rearrangements of HMGA2 on the long arm of chromosome 12 have been identified in fibroids and are thought to play a role in the induction of fibroid stem cells and thus fibroid tumorigenesis, especially in larger tumors (5,9). Additionally, some fibroid stem cells possess MED12 mutations that have not been identified in the myometrium stem cell population (10). These observations support the hypothesis that there is likely an important genetic component in the initiation of fibroid growth in some cases (5).
MicroRNAs in Human Cancers
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Global miRNA profiling has revealed that miRNA functions in the regulation of cell development and the maintenance of pluripotency. In 2003, stem cell-specific miRNA signature was first described in mouse embryonic stem cells [92]. Involvement of miRNAs during cancer stem cell (CSC) formation and maintenance was also reported. For example, let-7 expression was found to be reduced in breast cancer stem cells and its downregulation released the overexpression of H-RAS and HMGA2 [93]. The upregulation of H-RAS and HMGA2 increased stem cell-like self-renewal and reduced differentiation properties. Another miRNA, miR-200b, was also found to be a cancer-specific signature in breast cancers and epigenetically lost during CSC formation [94]. Mechanistically, the loss of miR-200 upregulates its direct target gene expression, SUZ12, which epigenetically mediates polycomb-mediated repression of the E-cadherin gene [94]. Since CSCs have been thought to initiate tumor formation and induce cancer recurrences, CSC-related miRNA signatures can serve as diagnostic/prognostic markers and therapeutic targets.
Genetics of Uterine Leiomyomata
Published in John C. Petrozza, Uterine Fibroids, 2020
C. Scott Gallagher, Cynthia C. Morton
The t(12;14)(q14-q15;q23-q24) is observed in nearly 20% of all cytogenetically abnormal UL and is associated with larger-sized neoplasms than karyotypically normal tumors [2,14,18,19,22–30]. Breakpoints on chromosome 12 span a large genomic region 5′ and 3′ of HMGA2 (high mobility group AT-hook 2) [31,32], which encodes a DNA architectural factor that regulates transcription [33,34]. Generally, balanced translocations result in dysregulated expression of the transcript (a gain or loss of function) or fusion genes (production of chimeric protein with novel function), as illustrated in Figure 5.1 [35–37]. Expression of HMGA2 is elevated in UL with t(12;14) compared to karyotypically normal UL and myometrium, suggesting the rearrangement has a gain-of-function effect on HMGA2 [38,39]. Truncation of HMGA2 with deletion of the 3′-UTR removes a site of transcription inhibition mediated by the microRNA let-7 [40,41]. Overexpression in both cases suggests HMGA2 harbors potential for dysregulated growth in UL, which is also supported by the observation of trisomy 12 in UL [9,13,18]. Interestingly, in a male with a pericentric inversion of chromosome 12 that results in constitutional truncation of HMGA2, extreme somatic overgrowth and multiple lipomas (another common mesenchymal tumor with documented frequent chromosomal rearrangements in HMGA2 [40,41]) were reported [31,42,43]. A number of additional “UL genes” have been implicated through chromosomal studies: HMGA1 at 6p21.3 [2,13,18,26,44,45], CUX1 at 7q22.1 [7,46], KAT6B at 10q22 [47], RAD51L1 at 14q23-q24 [18,37,48] and both COL4A5 and COL4A6 at Xq22.3 [7].
MicroRNA-23a-3p overexpression represses proliferation and accelerates apoptosis of granular cells in polycystic ovarian syndrome by targeting HMGA2
Published in Gynecological Endocrinology, 2023
Junzi Wei, Ping Cheng, Mei Kong, Ling Zhang, Shuang Liu, Bingxue Ning, Xinlin Huang
It has been widely recognized that miRs modulate gene expression by targeting genes [29]. For instance, former research elucidated that miR-23a lowered HMGA2 expression during cellular senescence [14]. Similarly, we discovered via Starbase prediction and dual-luciferase reporter gene assay that HMGA2 was inversely targeted by miR-23a-3p. In addition, RT-qPCR and western blotting results displayed the high expression of HMGA2 in GCs of patients with PCOS. Concordant with our findings, an early study unraveled that HMGA2 was highly expressed in GCs of PCOS women [16]. Moreover, it was found that HMGA2 overexpression augmented GC cell viability and diminished their apoptosis in the presence of miR-23a-3p mimic. Li et al. observed in their study that the overexpression of HMGA2 enhanced the proliferation of ovarian GCs [16], which was concurrent with our results. In addition, several studies demonstrated that HMGA2 played a crucial role in promoting the proliferation of ovary cancer cells [30,31], which synchronously implicated the exploration feasibility of the function of HMGA2 in ovarian diseases.
Overexpression of HMGA2 in breast cancer promotes cell proliferation, migration, invasion and stemness
Published in Expert Opinion on Therapeutic Targets, 2020
Behzad Mansoori, Pascal H.G. Duijf, Ali Mohammadi, Souzan Najafi, Elmira Roshani, Dariush Shanehbandi, Khalil Hajiasgharzadeh, Solmaz Shirjang, Henrik J. Ditzel, Tohid Kazemi, Ahad Mokhtarzadeh, Morten F. Gjerstorff, Behzad Baradaran
High-mobility group AT-hook-2 (HMGA2) is a member of the family of nuclear non-histone phosphoproteins called high mobility group A (HMGA), with critical functions in various biological events such as mitosis, cell-cycle control and cell division [12–14]. HMGA2 acts as a chromatin-remodeling factor and alters chromatin architecture to either promote or inhibit the action of transcriptional enhancers [15]. It is highly expressed in embryonic cells but shows low expression in normal cells [16]. Additionally, HMGA2 overexpression is frequently observed in numerous cancers, including oral squamous cell carcinoma [17], pancreatic cancer [18], non-small-cell lung cancer [14,19], gastrointestinal cancer [20] and breast cancer [12,21]. Moreover, HMGA2 promotes tumor invasion and metastasis in breast cancer [22]. HMGA2 has also been demonstrated to confer stem-like features to embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and CSCs [15]. Therefore, due to the importance of HMGA2 in breast cancer progression and CSC biology, we aimed to investigate HMGA2 overexpression in breast cancer carcinogenesis and stemness..
Non-coding RNAs – A primer for the laboratory scientist
Published in British Journal of Biomedical Science, 2019
The list of miRNAs with likely roles in cancer grows exponentially, and in this disease many (such as those of the let-7 family) act to inhibit tumour suppressors (such as p53, MYC, and Rb, often regulators of the cell cycle), whilst others (such as the miR-17-92 cluster and miR-155) may also act as oncogenes in their own right, and some (such as miR-165 and miR-166) have epigenetic effects [5,8,26,27]. Investigation of these molecules has enriched our knowledge of the molecular genetics of carcinogenesis [26–28]. For example, the product of HMGA2 at 12q14.3 (previously HMGI-C) is a transcription factor named high-mobility AT-hook 2 (HMGA2) with physiological roles in embryological growth [29]. However, upstream chromosomal disturbances, such as at 12q13-15, can influence the open reading frames of HMGA2 and may result in its overexpression and so neoplastic transformation. The miRNA let-7 can destabilize the HMGA2 message, and so interrupt this transformation, therefore acting as a classic tumour suppressor [30]. Low expression of let-7 can be found in many cases of lung cancer [27], a presumed mechanism being that loss of the miRNA permits the oncogenic mRNA to develop the malignancy.