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Roles of HMGA proteins in cancer

Key Points

  • The high mobility group A (HMGA) family is composed of four proteins, HMGA1a, HMGA1b, HMGA1c and HMGA2, encoded by two distinct genes. HMGA1 proteins are products of the same gene, generated through alternative splicing. They are non-histone nuclear proteins known as 'architectural transcriptional factors'.

  • HMGA gene rearrangements, due to chromosomal translocations, are a feature of human benign tumours of mesenchymal origin. In most of the cases the breakpoint occurs in the third intron of the HMGA2 gene, resulting in deregulation of its expression, truncation or, more frequently, in the generation of fusion genes encoding chimeric transcripts containing the first three exons of HMGA2 and ectopic sequences from other genes.

  • HMGA protein overexpression is a constant feature of human malignant neoplasias. It represents a poor prognostic index as their overexpression often correlates with the presence of metastasis and with a reduced survival.

  • HMGA proteins have a crucial role in cell transformation. They show oncogenic activities in vitro and in vivo, and blockage of their synthesis suppresses the malignant phenotype.

  • The appearance of a neoplastic phenotype in Hmga1−/− and Hmga1+/− mice revealed that HMGA proteins also have a tumour suppressor function.

  • HMGA proteins exert their oncogenic activity through several mechanisms: induction of E2F1 and AP1 activity, induction of cyclin A expression, inactivation of p53-induced apoptosis, impairment of DNA repair, enhancement of the expression of proteins involved in inflammation, and modulation of the expression of microRNAs and genes involved in epithelial–mesenchymal transition.

  • Blocking HMGA function could be an excellent tool for cancer treatment because of the specificity, low toxicity and wide range of applications of such therapy.

Abstract

The high mobility group A (HMGA) non-histone chromatin proteins alter chromatin structure and thereby regulate the transcription of several genes by either enhancing or suppressing transcription factors. This protein family is implicated, through different mechanisms, in both benign and malignant neoplasias. Rearrangements of HMGA genes are a feature of most benign human mesenchymal tumours. Conversely, unrearranged HMGA overexpression is a feature of malignant tumours and is also causally related to neoplastic cell transformation. Here, we focus on the role of the HMGA proteins in human neoplastic diseases, the mechanisms by which they contribute to carcinogenesis, and therapeutic strategies based on targeting HMGA proteins.

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Figure 1: Loss of microRNA-mediated repression of HMGA2 in mesenchymal tumours.
Figure 2: Some of the best characterized mechanisms of action of HMGA proteins in cancer (I).
Figure 3: Some of the best characterized mechanisms of action of HMGA proteins in cancer (II).

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Acknowledgements

The studies by M.F. and A.F. on the HMGA proteins were supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC). We thank V. Giancotti (who started the studies on the HMGA proteins) for his enthusiastic collaboration during the past 20 years. The authors are grateful to M. T. Berlingieri, G. M. Pierantoni and G. Chiappetta for their important contribution to the HMGA work carried out by their group. A.F. thanks C. M. Croce and G. Della Porta for their continuous support.

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Glossary

LIM domain

A cysteine-rich, zinc-binding sequence that is present in various proteins that are involved in cell-fate regulation, differentiation, cytoskeletal organization and tumour formation. They dimerize with other nuclear proteins, many of which are transcription factors.

Retropseudogene

A locus, within DNA, which is an intronless retrotransposed copy of mature mRNA from functional antecedent genes. They are layered throughout genomes as a molecular fossil record of genome evolution.

Megakaryocyte

A bone-marrow cell that is responsible for the production of blood platelets necessary for normal blood clotting.

Erythrocytes

Also known as red blood cells, erythocytes are the most common type of blood cell and the vertebrate body's principal means of delivering oxygen from the lungs or gills to body tissues through the blood.

Monocyte

A type of leukocyte: part of the human body's immune system that protects against blood-borne pathogens and moves quickly (in 8–12 hours) to sites of infection in the tissues. They are usually identified in stained smears by their large bilobate nucleus.

Richter transformation

The transformation of chronic lymphocytic lymphoma to diffuse large-cell lymphoma.

Haploinsufficient

A phenotypic state that results from the loss of one functional allele of any given gene in diploid cells.

Micronuclei

Small nuclei, left over from programmed cell death (apoptosis).

Lagging chromosome

A chromosome that is unattached to the mitotic spindle during anaphase.

Anaphase bridge

A chromatin bridge between separating chromosome masses during anaphase, which may result in gene amplification or loss when breaking

Cellular atypia

Clinical term for abnormality in a cell. It may or may not be a precancerous indication associated with later malignancy, but the appropriate level of concern is highly dependent on the context in which it is diagnosed.

Dukes' classification

Widespread system of staging colorectal carcinoma.

Holliday junction

A mobile junction between four strands of DNA. It accounts for a particular type of exchange of genetic information known as homologous recombination and is important in maintaining genomic integrity.

Polycomb gene

Genes coding for a family of proteins that can remodel chromatin such that transcription factors cannot bind to promoter sequences in DNA. Mutations in polycomb genes have been associated with several types of cancers, and abnormal levels of several polycomb proteins correlate with the severity and invasiveness of certain types of cancer.

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Fusco, A., Fedele, M. Roles of HMGA proteins in cancer. Nat Rev Cancer 7, 899–910 (2007). https://doi.org/10.1038/nrc2271

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