IGF2BP2 knockdown suppresses thyroid cancer progression by reducing the expression of long non-coding RNA HAGLR.

N6-methyladenosine (m6A), a common internal modification on RNAs, has been found to be closely linked with RNA biosynthesis/metabolism and cancer development. In this text, the roles and molecular mechanisms of m6A-bind protein IGF2BP2 in the development of thyroid cancer (TC) were investigated in vitro. IGF2BP2 and lncRNA HAGLR were screened out through multiple public databases such as TCGA, Ualcan, POSTAR2, Starbase, and GEPIA. Cell proliferative, migratory and invasive abilities were assessed by CCK-8, Transwell migration and invasion assays, respectively. Cell cycle distribution and cell apoptotic patterns were measured by flow cytometry. The interaction between HAGLR and IGF2BP2 was examined by RIP, RNA pull-down and luciferase assays and bioinformatics analysis. The effect of IGF2BP2 knockdown on the m6A level of HAGLR was explored by meRIP assay. IGF2BP2 was highly expressed in TC tumor tissues. IGF2BP2 knockdown weakened cell proliferative, migratory, and invasive abilities, and induced cell cycle arrest and cell apoptosis in TC cells. LncRNA HAGLR expression was markedly upregulated and positively associated with IGF2BP2 expression in TC tissues. IGF2BP2 knockdown reduced HAGLR expression and transcript stability in TC cells. IGF2BP2 regulated HAGLR expression in an m6A-dependent manner. HAGLR overexpression weakened the effects of IGF2BP2 loss on cell proliferation, migration, invasion, apoptosis, and cell cycle progression in TC cells. IGF2BP2 loss inhibited cell proliferation, migration and invasion, and induced cell apoptosis and cell cycle arrest by down-regulating HAGLR expression in an m6A-dependent manner in TC cells, providing some potential diagnostic and therapeutic targets for TC.

Dong L ，Geng Z ，Liu Z ，Tao M ，Pan M ，Lu X ... -  《-》

HAGLR, stabilized by m6A modification, triggers PTEN-Akt signaling cascade-mediated RPE cell pyroptosis via sponging miR-106b-5p.

Luo R ，Li L ，Han Q ，Fu J ，Xiao F ... -  《-》

m(6)A Modification of Long Non-Coding RNA HNF1A-AS1 Facilitates Cell Cycle Progression in Colorectal Cancer via IGF2BP2-Mediated CCND1 mRNA Stabilization.

Bian Y ，Wang Y ，Xu S ，Gao Z ，Li C ，Fan Z ，Ding J ，Wang K ... -  《Cells》

Bioinformatic identification reveals a m6A-binding protein, IGF2BP2, as a novel tumor-promoting gene signature in thyroid carcinoma.

N6-methyladenosine (m6A) modification plays a crucial role in thyroid carcinoma (THCA). Insulin-like growth factor 2 binding protein 2 (IGF2BP2) is a m6A-binding protein. We aimed to explore the effect of IGF2BP2 on the development of THCA. Differentially expressed genes (DEGs) were screened from GSE50901 and GSE60542 datasets. LinkedOmics, Genebank, and Sequence-based RNA Adenosine Methylation Site Predictor databases were employed to find potential m6A modification sites. Protein-protein interaction network and receiver-operating characteristic curves were applied to determine hub genes of THCA. ESTIMATE revealed the effect of IGF2BP2 on tumor immunity. The mRNA expression of IGF2BP2 was detected using real-time quantitative polymerase chain reaction. The viability, migration, and invasion were assessed by Cell Counting Kit-8, wound healing, and transwell assays. A total of 166 common DEGs were identified from GSE50901 and GSE60542 datasets. One m6A-related gene, IGF2BP2, was differentially expressed in THCA and selected as the research target. The hub genes (CD44, DCN, CXCL12, ICAM1, SDC4, KIT, CTGF, and FMOD) were identified with high prediction values for THCA. Subsequently, the target genes of IGF2BP2, SDC4, and ICAM1, which had potential m6A modification sites, were screened out based on the hub genes. IGF2BP2 was upregulated in THCA and IGF2BP2 expression was positively correlated with immune infiltration in THCA. Additionally, knockdown of IGF2BP2 inhibited the proliferation, invasion, and migration of THCA cells. IGF2BP2 has a contributory effect on the progression of THCA, which is a novel biomarker and a therapeutic target for THCA.

Xie Y ，Xiao J ，Ying Y ，Liu J ，Zhang L ，Zeng X ... -  《-》

RNA N6-methyladenosine reader IGF2BP2 promotes lymphatic metastasis and epithelial-mesenchymal transition of head and neck squamous carcinoma cells via stabilizing slug mRNA in an m6A-dependent manner.

Lymph node metastasis is the main cause of poor prognosis of head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression, and as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression and metastasis. However, not much is currently known about the functional roles of IGF2BP2 in HNSCC, and whether IGF2BP2 regulates lymphatic metastasis through m6A modification in HNSCC remains to be determined. The expression and overall survival (OS) probability of m6A-related regulators in HNSCC were analyzed with The Cancer Genome Atlas (TCGA) dataset and GEPIA website tool, respectively. The expression levels of IGF2BP2 were measured in HNSCC tissues and normal adjacent tissues. To study the effects of IGF2BP2 on HNSCC cell metastasis in vitro and in vivo, gain- and loss- of function methods were employed. RIP, MeRIP, luciferase reporter and mRNA stability assays were performed to explore the epigenetic mechanism of IGF2BP2 in HNSCC. We investigated 20 m6A-related regulators in HNSCC and discovered that only the overexpression of IGF2BP2 was associated with a poor OS probability and an independent prognostic factor for HNSCC patients. Additionally, we demonstrated that IGF2BP2 was overexpressed in HNSCC tissues, and significantly correlated to lymphatic metastasis and poor prognosis. Functional studies have shown that IGF2BP2 promotes both HNSCC cell migration as well as invasion via the epithelial-mesenchymal transition (EMT) process in vitro, and IGF2BP2 knockdown significantly inhibited lymphatic metastasis and lymphangiogenesis in vivo. Mechanistic investigations revealed that Slug, a key EMT-related transcriptional factor, is the direct target of IGF2BP2, and essential for IGF2BP2-regulated EMT and metastasis in HNSCC. Furthermore, we demonstrated that IGF2BP2 recognizes and binds the m6A site in the coding sequence (CDS) region of Slug and promotes its mRNA stability. Collectively, our study uncovers the oncogenic role and potential mechanism of IGF2BP2, which serves as a m6A reader, in controlling lymphatic metastasis and EMT in HNSCC, suggesting that IGF2BP2 may act as a therapeutic target and prognostic biomarker for HNSCC patients with metastasis.

Yu D ，Pan M ，Li Y ，Lu T ，Wang Z ，Liu C ，Hu G ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》