Abstract
Background: Recent studies have underlined HMGA protein’s key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted that the HMGA1 transcript is strictly regulated by a set of inhibitory microRNAs. Thus, the aim of this study is to test whether HMGA1 overexpression in human seminomas may be induced by the deregulation of miR-26a and Let-7a—two HMGA1-targeting microRNAs. Methods: HMGA1 mRNA and Let-7a and miR-26a levels were measured in a seminoma dataset available in the Cancer Genome Atlas database and confirmed in a subset of seminomas by qRT-PCR and western blot. A TCam-2 seminoma cell line was then transfected with Let-7a and miR-26a and tested for proliferation and motility abilities. Results: an inverse correlation was found between the expression of miR-26a and Let-7a and HMGA1 expression levels in seminomas samples, suggesting a critical role of these microRNAs in HMGA1 levels regulation. Accordingly, functional studies showed that miR-26a and Let-7a inhibited the proliferation, migration and invasion capabilities of the human seminoma derived cell line TCam-2. Conclusions: these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is—at least in part—due to the downregulation of HMGA1-targeting microRNAs.
Highlights
Testicular germ cell tumors (TGCTs) afflict a wide age range of patients from children to young adults, and represent the most frequent cause of death due to cancer in this lifetime
We demonstrated that high mobility group A (HMGA) expression is dependent on the state of differentiation of TGCTs: HMGA1 is overexpressed in seminomas, HMGA1 and HMGA2 are overexpressed in pluripotential embryonal carcinoma cells, and just HMGA2 is upregulated in yolk sac tumor (YST), the expression of both proteins is lost in mature adult tissue of teratoma areas [4,18]
We evaluated the correlation between HMGA1 mRNA, Let-7a and miR-26a expression levels (Figure 1A,B) in a seminoma dataset available in the Cancer Genome Atlas (TCGA)
Summary
Testicular germ cell tumors (TGCTs) afflict a wide age range of patients from children to young adults, and represent the most frequent cause of death due to cancer in this lifetime. TGCTs have their origin in a blocked maturation of a primordial germ cells (PGCs) [1], and more and more evidence reinforce the idea that the alteration of the epigenetic status is able to initiate human malignant germ cell tumors instead of somatic mutations. Seminomas represent about 50% of all TGCTs, diagnosed in patients with a median age of 35 years, whereas NSGCTs arise prematurely at a median age of 25 years [2] These latter can show several histological tumor elements, that is, the stem cell component embryonal carcinoma, teratoma (somatic differentiation), choriocarcinoma (extra-embryonic differentiation) and YST. Conclusions: these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is—at least in part—due to the downregulation of HMGA1-targeting microRNAs
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