Human IGF2 Gene Epigenetic and Transcriptional Regulation: At the Core of Developmental Growth and Tumorigenic Behavior

Abstract

Regulation of the human IGF2 gene displays multiple layers of control, which secures a genetically and epigenetically predetermined gene expression pattern throughout embryonal growth and postnatal life. These predominantly nuclear regulatory mechanisms converge on the function of the IGF2-H19 gene cluster on Chromosome 11 and ultimately affect IGF2 gene expression. Deregulation of such control checkpoints leads to the enhancement of IGF2 gene transcription and/or transcript stabilization, ultimately leading to IGF-II peptide overproduction. This type of anomaly is responsible for the effects observed in terms of both abnormal fetal growth and increased cell proliferation, typically observed in pediatric overgrowth syndromes and cancer. We performed a review of relevant experimental work on the mechanisms affecting the human IGF2 gene at the epigenetic, transcriptional and transcript regulatory levels. The result of our work, indeed, provides a wider and diversified scenario for IGF2 gene activation than previously envisioned by shedding new light on its extended regulation. Overall, we focused on the functional integration between the epigenetic and genetic machinery driving its overexpression in overgrowth syndromes and malignancy, independently of the underlying presence of loss of imprinting (LOI). The molecular landscape provided at last strengthens the role of IGF2 in cancer initiation, progression and malignant phenotype maintenance. Finally, this review suggests potential actionable targets for IGF2 gene- and regulatory protein target-degradation therapies.

Dysfunction in IGF2R Pathway and Associated Perturbations in Autophagy and WNT Processes in Beckwith–Wiedemann Syndrome Cell Lines

“…Scalia et al recently reviewed the diverse pathomechanisms behind loss of imprinting which lead to IGF2 dysregulation in BWS and consequent bi-allelic IGF2 expression [60]. Contrastingly, Silver-Russell syndrome (SRS), a disease associated with the opposite genetic defect, is characterized by reduced growth and lower expression of IGF2 [61].…”

Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy

“…While IGF2 expression in somatic cells is regulated via parental imprinting, its regulation in cancer cells is determined by a combination of both imprinting and transcriptional regulation mechanisms reviewed elsewhere [ [28], ibidem]. Ultimately, independently of the underlying genetic, translational, and post-translational mechanisms involved, the phenotypic and functional effects of such increased expression is reflected in the secretion of high molecular IGF-II pro-hormone variants [9] and its autocrine signal, which has been associated with both paraneoplastic hypoglycemia and malignancy (summarized in Figure 2 and Table 1).…”

“…As for those advanced cancers (more than 50%) with loss of function of TP53, this condition has been shown to further trigger IGF2 transcription [18] and further consolidate the ability of a cancer cell to maintain its malignant features. Although the genetic and epigenetic mechanisms underlying IGF2 expression in cancer have been reviewed elsewhere [ [28], ibidem] and are not the subject of the present perspective, we included this mechanism as an example of the role of TP53 in the regulation of IGFBP-3, which is directly involved in the high-affinity binding of mature IGF-I and IGF-II but not of cancer-secreted big-IGF-II.…”

“…In particular, the latter two methods (in circulating tumor cells) provide ex vivo testable parameters attainable as part of a liquid biopsy. These approaches can be several magnitudes more sensitive compared to the cancer patient IGF-I/IGF-II high blood ratio currently reported as the discriminating metabolic hallmark for paraneoplastic hypoglycemia-associated cancers [28]. In this context, the proposed parameters for inclusion of a solid tumor under the proposed IGF-IIsT extended group include previously described tumors with the following features:…”