Insulin-like growth factor 2 mRNA-binding protein 1 promotes cell proliferation <i>via</i> activation of AKT and is directly targeted by microRNA-494 in pancreatic cancer

Wan, Baishun; Cheng, Ming Huei; Zhang, Ling

doi:10.3748/wjg.v25.i40.6063

Cited by 36 publications

(39 citation statements)

References 23 publications

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“…For this study, we focused on the PoRs (Figure 3A), since these represent factors that may promote dedifferentiation and diseases progression and may thus present therapeutic targets eligible for treatment by inhibition, as proposed for LIN28B [29] and other RBPs. Among the 44 PoRs were proteins previously implicated in PDAC progression, e.g., IGF2BP1-3 [13][14][15][16][17], IFIT3 [30], EXO1 [21], or PTBP3 [23]. However, there were also proteins that, to the best of our knowledge, have not yet been associated with oncogenic potential in pancreatic cancer, e.g., OAS proteins, RBM34 or DQX1.…”

Section: Transcriptional Regulation Of Rbps In Pdacmentioning

confidence: 96%

“…Despite the lack of systematic investigation of RBPs in PDAC, ample evidence suggests substantial impact of some RBPs in this malignancy. For example, all three members of the insulin-like growth factor 2 mRNA binding protein family (IGF2BPs) have recently been described as being upregulated and associated with a poor prognosis in pancreatic cancer [13][14][15][16][17]. Furthermore, inactivation of the histone deacetylase SIRT6 was reported to accelerate PDAC progression in mouse models due to upregulation of LIN28B [18].…”

Section: Introductionmentioning

confidence: 99%

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RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma

Glaß

Michl

Hüttelmaier

2020

IJMS

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Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations cannot explain the heterogeneity in therapeutic responses observed in PDAC patients, which limits efficiency of current therapeutic strategies. Instead, recent classifications of PDAC tumor samples are based on transcriptomics data and thus include information about epigenetic, transcriptomic, and post-transcriptomic deregulations. RNA binding proteins (RBPs) are important post-transcriptional regulators involved in every aspect of the RNA life cycle and thus considerably influence the transcriptome. In this study, we systematically investigated deregulated expression, prognostic value, and essentiality reported for RBPs in PDAC or PDAC cancer models using publicly available data. We identified 44 RBPs with suggested oncogenic potential. These include various proteins, e.g., IGF2 mRNA binding proteins (IGF2BPs), with reported tumor-promoting roles. We further characterized these RBPs and found common patterns regarding their expression, interaction, and regulation by microRNAs. These analyses suggest four prime candidate oncogenic RBPs with partially validated target potential: APOBEC1, IGF2BP1 and 3, and OASL.

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Section: Transcriptional Regulation Of Rbps In Pdacmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma

Glaß

Michl

Hüttelmaier

2020

IJMS

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“…By binding different mRNAs, IGF2BPs decide the fate of those mRNAs by controlling their localization, stability, and translation [40]. Many studies have reported the role of IGF2BPs in cell proliferation, cell invasion, tumorigenesis, and embryogenesis [40][41][42][43][44][45][46][47][48][49][50][51]. IGF2BPs have also been found in sheep trophoblast cells suggesting their role in rapid proliferation of these cells [52].…”

Section: Introductionmentioning

confidence: 99%

Trophectoderm-Specific Knockdown of LIN28 Decreases Expression of Genes Necessary for Cell Proliferation and Reduces Elongation of Sheep Conceptus

Ali

Stenglein

Spencer

et al. 2020

IJMS

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LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferation. We hypothesized that the LIN28-let-7 axis regulates proliferation-associated genes in sheep trophectoderm in vivo. Day 9-hatched sheep blastocysts were incubated with lentiviral particles to deliver shRNA targeting LIN28 specifically to trophectoderm cells. At day 16, conceptus elongation was significantly reduced in LIN28A and LIN28B knockdowns. Let-7 miRNAs were significantly increased and IGF2BP1-3, HMGA1, ARID3B, and c-MYC were decreased in trophectoderm from knockdown conceptuses. Ovine trophoblast (OTR) cells derived from day 16 trophectoderm are a useful tool for in vitro experiments. Surprisingly, LIN28 was significantly reduced and let-7 miRNAs increased after only a few passages of OTR cells, suggesting these passaged cells represent a more differentiated phenotype. To create an OTR cell line more similar to day 16 trophectoderm we overexpressed LIN28A and LIN28B, which significantly decreased let-7 miRNAs and increased IGF2BP1-3, HMGA1, ARID3B, and c-MYC compared to control. This is the first study showing the role of the LIN28-let-7 axis in trophoblast proliferation and conceptus elongation in vivo. These results suggest that reduced LIN28 during early placental development can lead to reduced trophoblast proliferation and sheep conceptus elongation at a critical period for successful establishment of pregnancy.

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“…First, IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1) plays significant roles in carcinogenesis, including tumor cell proliferation and growth, invasion, and chemoresistance, and is associated with poor overall survival and metastasis in various types of human cancers [30]. This gene was also reported to be upregulated and associated with a poor prognosis in pancreatic cancer patients [31]. It inhibits pancreatic cancer cell growth in vitro and in vivo via the AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Multiomics profile and prognostic gene signature of m6A regulators in uterine corpus endometrial carcinoma

et al. 2020

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Uterine corpus endometrial carcinoma (UCEC) is the most common type of gynecologic malignancy worldwide. Despite advances in the treatments of UCEC, its incidence and mortality rates are still increasing. N6-methyladenosine (m6A) is the most common form of RNA modification and has attracted increasing interest in cancer pathogenesis and progression. Thus, we aimed to identify the landscape of m6A regulators and build a prognostic gene signature in UCEC. In this study, we first analyzed copy number variations (CNVs), single nucleotide variations (SNVs) and gene expression profiles as well as matched clinical information of UCEC patients from The Cancer Genome Atlas (TCGA) database. Next, we determined that CNVs in m6A regulatory genes had a significant negative impact on patient survival. The mRNA expression levels of a total of 16 m6A regulators were significantly correlated with different CNV patterns. Using univariate Cox regression analysis, IGF2BP1, KIAA1429, IGF2BP3, YTHDF3, and IGF2BP2 were found to be closely associated with UCEC patient survival outcomes. Based on the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression models, we built a 3-gene (IGF2BP3, KIAA1429 and IGF2BP1) signature of m6A regulators with prognostic value in UCEC that could effectively predict patient prognosis (log-rank test p-value < 0.0001). In addition, risk scores were significantly different between patients stratified by tumor stage, SNV, and CNV. Multivariate Cox regression analysis suggested that risk score might be an independent prognostic indicator for the overall survival of patients with UCEC (p-value < 0.05). Gene enrichment analysis indicated that high IGF2BP1 gene expression is associated with cytoplasmic stress granules. KIAA1429 gene expression is associated with cellular nucleic acid metabolism. The expression of the IGF2BP3 gene is associated with RNA binding processes. In conclusion, we determined that genetic alterations in m6A regulatory genes could be effective and reliable biomarkers for UCEC prognosis prediction.

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Insulin-like growth factor 2 mRNA-binding protein 1 promotes cell proliferation via activation of AKT and is directly targeted by microRNA-494 in pancreatic cancer

Cited by 36 publications

References 23 publications

RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma

RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma

Trophectoderm-Specific Knockdown of LIN28 Decreases Expression of Genes Necessary for Cell Proliferation and Reduces Elongation of Sheep Conceptus

Multiomics profile and prognostic gene signature of m6A regulators in uterine corpus endometrial carcinoma

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