Methylation in MIRLET7A3 Gene Induces the Expression of IGF-II and Its mRNA Binding Proteins IGF2BP-2 and 3 in Hepatocellular Carcinoma

Abstract

miR-let-7a is a tumor suppressor miRNA with reduced expression in most cancers. Methylation of MIRLET7A3 gene was reported to be the cause of this suppression in several cancers; however, it was not explicitly investigated in hepatocellular carcinoma (HCC). We aimed at investigating miR-let-7a expression and molecular mode in HCC, identifying drug-targetable networks, which might be affected by its abundance. Our results illustrated a significant repression of miR-let-7a, which correlated with hypermethylation of its gene of origin MIRLRT7A3. This was further supported by the induction of miR-let-7a expression upon treatment of HCC cells with a DNA-methyltransferase inhibitor. Using a computational approach, insulin-like growth factor (IGF)-II and IGF-2 mRNA binding proteins (IGF2BP)-2/-3 were identified as potential targets for miR-let-7a that was further confirmed experimentally. Indeed, miR-let-7a mimics diminished IGF-II as well as IGF2BP-2/-3 expression. Direct binding of miR-let-7a to each respective transcript was confirmed using a luciferase reporter assay. In conclusion, this study suggests that DNA hypermethylation leads to epigenetic repression of miR-let-7a in HCC cells, which induces the oncogenic IGF-signaling pathway.

The Curious Case of the HepG2 Cell Line: 40 Years of Expertise

“…A similar pattern was found in the case of insulin-like growth factor 2 (IGF2) [ 106 , 107 , 108 , 109 ], which is associated with the development of various diseases in children—for example, Beckwith–Wiedemann syndrome [ 110 , 111 , 112 , 113 ]. Moreover, increased IGF2 expression is associated with a poor prognosis of the course of cancer because it supports both the proliferation and migration of tumor cells [ 114 , 115 , 116 ].…”

The role of IGF2BP2, an m6A reader gene, in human metabolic diseases and cancers

“…Hepatitis B virus suppresses p53-mediated activation of miR-216b and promotes the expression of IGF2BP2. Furthermore, the expression of miR-let-7a which positively correlates with hypermethylation of MIRLRT7A3, modulates the expression of IGF2BP2 [ 18 ]. In lung cancer, the over-expressed miR-485-5p inhibits growth and invasion of cancer cells, arrests the G0/G1 cycle and disrupts the TGF-β-induced EMT by directly targeting IGF2BP2 [ 95 ].…”

“…M6A-RNA methylation refers to methylation of adenosine bases at position N6 in 3′UTRs near the stop codons but within the internal long exons [ 10 , 11 ]. Modified IGF2BP2 participates in the development and progression of multiple metabolic disease and cancers, including diabetes [ 2 ], obesity [ 12 ], fatty liver [ 13 ], breast cancer [ 14 ], colorectal carcinoma [ 15 ], esophageal adenocarcinoma [ 16 ], glioma [ 17 ], hepatocellular carcinoma [ 18 ], lung cancer [ 19 ], pancreatic cancer [ 20 ] and many others.…”

Cytoplasmic IGF2BP2 Protein Expression in Human Patients with Oral Squamous Cell Carcinoma: Prognostic and Clinical Implications

“…IGF2BP2 has been shown to promote tumor growth in cases of solid tumors and leukemia [22][23][24][25][26][27]. Recent research has identified IGF2BP2 as a potential oncogene, which, when overexpressed in liver cancer, causes excessive cell proliferation and invasion, resulting in a poor prognosis [28][29][30][31]. The overexpression of IGF2BP2 has also been shown to promote the development of glioblastoma multiforme by activating the IGF2/phosphoinositide 3-kinase (PI3K)/Akt pathway, thereby making glioblastoma resistant to temozolomide therapy [32].…”