Abstract
Colorectal cancer (CRC) is one of the most common cancers in men and women worldwide as well as is the leading cause of death in the western world. Almost a third of the patients has or will develop liver metastases. While genetic as well as epigenetic mechanisms are important in CRC pathogenesis, the basis of the most cases of cancer is unknown. High spatial and inter-patient variability of the molecular alterations qualifies this cancer in the group of highly heterogeneous tumors, which makes it harder to elucidate the mechanisms underlying CRC progression. Determination of highly sensitive and specific early diagnosis markers and understanding the cellular and molecular mechanism(s) of cancer progression are still a challenge of the current era in oncology of solid tumors. One of the accepted risk factors for CRC development is overexpression of insulin-like growth factor 2 (IGF2), a 7.5-kDa peptide produced by liver and many other tissues. IGF2 is the first gene discovered to be parentally imprinted. Loss of imprinting (LOI) or aberrant imprinting of IGF2 could lead to IGF2 overexpression, increased cell proliferation, and CRC development. IGF2 as a mitogen is associated with increased risk of developing colorectal neoplasia. Higher serum IGF2 concentration as well as its tissue overexpression in CRC compared to control are associated with metastasis. IGF2 protein was one of the three candidates for a selective marker of CRC progression and staging. Recent research indicates dysregulation of different micro- and long non-coding RNAs (miRNAs and lncRNAs, respectively) embedded within the IGF2 gene in CRC carcinogenesis, with some of them indicated as potential diagnostic and prognostic CRC biomarkers. This review systematises the knowledge on the role of genetic and epigenetic instabilities of IGF2 gene, free (active form of IGF2) and IGF-binding protein (IGFBP) bound (inactive form), paracrine/autocrine secretion of IGF2, as well as mechanisms of inducing dysplasia in vitro and tumorigenicity in vivo. We have tried to answer which molecular changes of the IGF2 gene and its regulatory mechanisms have the most significance in initiation, progression (including liver metastasis), prognosis, and potential anti-IGF2 therapy in CRC patients.
Highlights
Colorectal cancer (CRC) is one of the most common and severe malignant tumors in humans
While some studies did not show quantitative differences in insulin-like growth factor 2 (IGF2) expression in CRC patients with T2DM, compared to those not affected by diabetes [75], newer research report that upregulation of DOK5, IGF2, and IRS2 in colorectal cancer and T2DM patients is associated with significantly decreased overall survival (OS) [73]
We have tried to answer which molecular changes of the IGF2 gene have the most significance in initiation, progression, prognosis, and anti-IGF2 therapy in CRC patients
Summary
Colorectal cancer (CRC) is one of the most common and severe malignant tumors in humans. The Cancer Genome Atlas (TCGA) contains an examination of CRC tumors [6,7,13,14,15] In this way (2013), three molecular types of CRC were identified: hypermutated (13%), ultra-mutated (3%), and with chromosomal instability (CIN) (84%). While some studies did not show quantitative differences in IGF2 expression in CRC patients with T2DM, compared to those not affected by diabetes [75], newer research report that upregulation of DOK5, IGF2, and IRS2 in colorectal cancer and T2DM patients is associated with significantly decreased overall survival (OS) [73]. The role of IGF2 in CRC etiology and pathogenesis is indicated by epidemiological data and studies on tissue IGF2 expression in colorectal tumors. We have tried to answer which molecular changes of the IGF2 gene have the most significance in initiation, progression (including liver metastasis), prognosis, and anti-IGF2 therapy in CRC patients
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