Correlated Expression of HMGA2 and PLAG1 in Thyroid Tumors, Uterine Leiomyomas and Experimental Models

Abstract

In pleomorphic adenomas of the salivary glands (PASG) recurrent chromosomal rearrangements affecting either 8q12 or 12q14∼15 lead to an overexpression of the genes of the genuine transcription factor PLAG1 or the architectural transcription factor HMGA2, respectively. Both genes are also affected by recurrent chromosomal rearrangements in benign adipocytic tumors as e. g. lipomas and lipoblastomas. Herein, we observed a strong correlation between the expression of HMGA2 and PLAG1 in 14 benign and 23 malignant thyroid tumors. To address the question if PLAG1 can be activated by HMGA2, the expression of both genes was quantified in 32 uterine leiomyomas 17 of which exhibited an overexpression of HMGA2. All leiomyomas with HMGA2 overexpression also revealed an activation of PLAG1 in the absence of detectable chromosome 8 abnormalities affecting the PLAG1 locus. To further investigate if the overexpression of PLAG1 is inducible by HMGA2 alone, HMGA2 was transiently overexpressed in MCF-7 cells. An increased PLAG1 expression was observed 24 and 48 h after transfection. Likewise, stimulation of HMGA2 by FGF1 in adipose tissue-derived stem cells led to a simultaneous increase of PLAG1 mRNA. Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. Accordingly, this may explain the formation of tumors as similar as lipomas and lipoblastomas resulting from an activation of either of both genes by chromosomal rearrangements.

Plag1 regulates neuronal gene expression and neuronal differentiation of neocortical neural progenitor cells

“…This finding is consistent with previous studies suggestive of a relation between Hmga2 and Plag1, especially in the context of cancer cells (Klemke et al, 2014;Ren et al, 2017). Hmga2 appears to regulate the expression of Plag1 directly, as it binds to the TSS region of the gene.…”

HMGA2 is a specific immunohistochemical marker for pleomorphic adenoma and carcinoma ex‐pleomorphic adenoma

“…This staining tended to be weak and limited to the myoepithelial component of the PA (Figure F) as compared with PLAG1‐positive, HMGA2‐negative PAs (Figure C). Studies in other tumour types, including various thyroid neoplasms, uterine leiomyomas, and cell culture models of breast cancer, suggest that PLAG1 may be a downstream target of HMGA2 . Our immunohistochemical data support the hypothesis that, even in HMGA2 ‐rearranged PA, PLAG1 may represent a common downstream target that drives tumorigenesis.…”

“…Studies in other tumour types, including various thyroid neoplasms, uterine leiomyomas, and cell culture models of breast cancer, suggest that PLAG1 may be a downstream target of HMGA2. 20,21 Our immunohistochemical data support the hypothesis that, even in HMGA2rearranged PA, PLAG1 may represent a common downstream target that drives tumorigenesis. This hypothesis would also explain why studies examining PLAG1 immunohistochemical expression were not always able to identify PLAG1 rearrangement despite immunohistochemical PLAG1 detection.…”

PLAG1 and NCAPG‐LCORL in livestock

“…Since HMGA2 stimulates PLAG1 gene expression (Klemke et al . 2014), PLAG1 might be another locus for birth weight and length in humans that was not detected in the GWAS.…”