High Mobility Group AT-Hook 2 (HMGA2) Oncogenicity in Mesenchymal and Epithelial Neoplasia

Abstract

High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding of HMGA2 pathogenicity by exploring the mechanisms by which HMGA2 misexpression and ectopic expression induces mesenchymal and epithelial tumorigenesis respectively and distinguish the pathogenesis of benign from malignant mesenchymal tumors. Importantly, we highlight the regulatory role of let-7 microRNA family of tumor suppressors in determining HMGA2 misexpression events leading to tumor pathogenesis and focused on possible mechanisms by which HMGA2 could propagate lymphangioleiomyomatosis (LAM), benign mesenchymal tumors of the lungs. Lastly, we discuss potential therapeutic strategies for epithelial and mesenchymal tumorigenesis based on targeting the HMGA2 signaling pathway.

Targeting of histone methyltransferase DOT1L plays a dual role in chemosensitization of retinoblastoma cells and enhances the efficacy of chemotherapy

“…In this regard, HMGA2 was considered as the top candidate gene for a further investigation since inhibition of HMGA2 expression has been shown to reduce RB cell proliferation [ 21 , 28 ]. Moreover, HMGA2 is known to be involved in the DNA damage response and modulation of chemosensitivity in cancer cells in addition to its role in transcriptional regulation as a chromatin-associated protein [ 22 – 25 ]. When we monitored the expression changes of HMGA2 by EPZ5676 treatment, there was a gradual decrease at both transcript and protein levels over time (Fig.…”

“…However, the role of HMGA2 in RB cell proliferation was noted nearly two decades ago, along with the observation that HMGA2 expression is high in murine embryonic retina and human RB tumors but is not detectable in terminally differentiated retina [ 21 ]. HMGA2 is a chromatin-associated protein which can modulate transcription by altering the chromatin structure and affinity of transcription factors, and ectopic expression of HMGA2 is known to induce neoplastic transformation and tumorigenesis [ 22 ]. Notably, HMGA2 is also involved in the modulation of DNA damage response by altering the expression or phosphorylation of DNA damage checkpoint proteins including ATM and ATR/CHK1 axis, leading to the increased sensitivity to diverse genotoxic insults upon HMGA2 downmodulation in cancer cells [ 23 – 25 ].…”

Long noncoding RNA LINC01410 promotes tumorigenesis of osteosarcoma cells via miR‐497‐5p/HMGA2 axis

“…HMGA2 belongs to the high mobility group protein A (HMGA) family, which can promote epithelial–mesenchymal transformation, maintain the differentiation potential and self‐renewal ability of stem cells, and participate in the regulation of multiple biological events. [ 35–37 ] Numerous recent articles verify the upregulation of HMGA2 in diverse cancer cells, which exerts a vital part in cancer genesis and progression. [ 38–40 ] Here, we showed that HMGA2 functions as a tumor promoter gene in OS, which downregulating HMGA2 remarkably suppressed cell growth, migration, and invasion.…”

MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

“…MiR-125b-5p also inhibited cell proliferation, migration, and invasion of esophageal squamous cell carcinoma partially by downregulating HMGA2 [205]. HMGA2 3′-UTR also contains repressive regulatory binding sites for let-7 miRNAs, which are responsible for HMGA2 mRNA decapping and degradation, allowing the correct tissue-type differentiation of the normal mesenchymal tissues [206]. The TRIM71 protein, which regulates early development and differentiation, can act as a tumor suppressor by post-transcriptionally repressing LIN28B and modulating the let-7/Hmga2 axis [207].…”

“…The reduction in let-7 miRNAs represents one of the main mechanisms responsible for HMGA2 overexpression in atypical teratoid/rhabdoid tumors; therefore, the reconstitution of let-7 miRNA levels or HMGA2 knockdown may represent good therapeutic strategies for cancer treatment [208]. In different mesenchymal tumors, chromosomal rearrangements and breakpoints can generate truncated HMGA2 mRNA transcripts, which are devoid of the 3′-UTR regions, thus altering miRNA-mediated regulation of HMGA2 expression [206,209,210].…”