IGF2BP2 promotes pancreatic carcinoma progression by enhancing the stability of B3GNT6 mRNA via m6A methylation

Abstract

BackgroundPancreatic carcinoma (PC) is a highly lethal cancer with an increasing mortality rate, its ve-year survival rate is only approximately 4%. N6-methyladenosine (m6A) modi cation is the most common posttranscriptional modi cation of RNA. However, its role in PC remains unclear. MethodsWe combined bioinformatic analysis with in vitro and in vivo experiments to investigate the expression pro le of methylation modulators and identify key m6A regulators in the progression of PC. Further study focused on exploring the target genes binding to the regulators through RIP and double uorescence staining. ResultsTCGA and Gene Expression Omnibus (GEO) analyses revealed an overall increasing trend in the expression of m6A regulators in PC, and consensus clustering analysis of m6A showed that the expression of regulators was negatively correlated with the survival rate. LASSO-Cox regression analysis revealed that IGF2BP2, METTL3, ALKBH5 and KIAA1429 were associated with hazard ratios (HR), but only IGF2BP2 was su ciently appropriate for the m6A survival prognosis model. The IHC and WB results veri ed high protein expression of IGF2BP2 in PC, and IGF2BP2 knockdown inhibited the proliferation and migration of PC cells. We predicted nine possible target mRNAs of IGF2BP2, and B3GNT6, which regulates three-dimensional serine or threonine structures to affect biosynthesis and metabolism, was veri ed via RIP and dual luciferase reporter assays to be observably methylated by IGF2BP2. In addition, IF staining con rmed the co-expression of IGF2BP2 and B3GNT6. The tumour-promoting effect of IGF2BP2 and its co-expression with B3GNT6 were veri ed in an animal model. Conclusions:Elevated m6A levels promote PC progression. IGF2BP2 is a credible marker and modulates B3GNT6 mRNA stability, indicating that IGF2BP2 is a potential prognostic marker and therapeutic target in PC progression. BackgroundPC has long been one of the most devastating and highly malignant tumours, with obvious resistance to radiotherapy and chemotherapy, the ve-year survival rate is only 4% 1 . In both the United States and China, the morbidity and mortality of PC are among the highest of all cancers 2 . Currently, the most common and effective treatment is surgery combined with radiochemotherapy and immunotherapy, but this regimen exhibits little therapeutic effect 3 . Considering that PC is characterized by a strong interstitial

m6A reader IGF2BP2 promotes M2 macrophage polarization and malignant biological behavior of bladder cancer by stabilizing NRP1 mRNA expression

“…Previous study had suggested that IGF2BP2 elevated FLT4 stability via m6A modification, thus accelerating angiogenesis and metastasis of lung adenocarcinoma cells [ 36 ]. Also, IGF2BP3 promoted pancreatic carcinoma cell proliferation and migration by improving B3GNT6 mRNA stability [ 37 ]. Here, we pointed out that IGF2BP2, as an m6A reader, recognized and bound to the m6A modified region of NRP1 transcript to enhance NRP1 mRNA stability.…”

FERMT1 Is a Prognostic Marker Involved in Immune Infiltration of Pancreatic Adenocarcinoma Correlating with m6A Modification and Necroptosis

“…In addition, only the high expression of IGF2BP2 and IGF2BP3 was linked to poor prognosis in PAAD. As the stabilizers of m 6 A methylation, IGF2BP2 and IGF2BP3 can enhance the stability of B3GNT6 and spermine synthase ( SMS ) mRNA and protein expression, respectively, to promote the progression of pancreatic cancer [ 39 , 40 ]. In light of these findings, we proposed that the FERMT1 may be modified by m 6 A to enhance mRNA stability, thereby accelerating the development of PAAD.…”

CircRNF121 facilitates ovarian cancer progression through modulating microRNA-153/IGF2BP2/B3GNT6 axis

“…B3GNT6, the protein that is essential for the synthesis of the core 3 structure of O-glycans, has been documented to be commonly dysregulated in many types of malignant tumors such as cervical cancer, prostate cancer and CRC 31 . Cao et al, showed that the oncogenic role of IGF2BP2 was mediated by modulating B3GNT6 mRNA stability 32 . Accordingly, B3GNT6 can affect EMT-MTE plasticity of CRC cells.…”