IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer
Nadine Bley,Annekatrin Schott,Simon Müller,Danny Misiak,Marcell Lederer,Tommy Fuchs,Chris Alexander Aßmann,Markus Glaß,Christian Ihling,Andrea Sinz,Nikolaos Pazaitis,Claudia Wickenhauser,Martina Vetter,O Ungurs,Hans-Georg Strauss,Christoph Thomssen,Stefan Hüttelmaier +16 more
TLDR
It is shown that the IGF2 mRNA-binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HGSOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism, which reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signalling in ovarian cancer cells.Abstract:
Epithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HGSOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here, we show that the IGF2 mRNA-binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HGSOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in an RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signalling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation, only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rationale for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HGSOC.read more
Citations
More filters
Journal ArticleDOI
RNA m6A Modification in Cancers: Molecular Mechanisms and Potential Clinical Applications
Chang Gu,Xin Shi,Chenyang Dai,Feng Shen,Gaetano Rocco,Jiafei Chen,Zhengyu Huang,Chunji Chen,Chuan He,Tao Huang,Chang Chen +10 more
TL;DR: The underlying mechanisms of m6A modifications in tumorigenesis are emphasized and the potential m 6A regulators-associated therapeutic targets for tumor therapy are introduced.
Journal ArticleDOI
IGF2BP1, a Conserved Regulator of RNA Turnover in Cancer
Markus Glaß,Danny Misiak,Nadine Bley,Simon Müller,Sven Hagemann,Bianca Busch,Alexander Rausch,Stefan Hüttelmaier +7 more
TL;DR: In this paper, the authors present a set of genes and cancer hallmark pathways showing a conserved pattern of deregulation in dependence of IGF2BP1 expression in cancer cell lines, which confirm and expand previous findings on the pivotal role of the oncofetal IGF2 mRNA-binding protein 1 in promoting oncogenic gene expression by stabilizing target mRNAs in a mainly 3'UTR, m6A-, miRNA-, and potentially AU-rich element dependent manner.
Journal ArticleDOI
The role of Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as m6A readers in cancer
TL;DR: The up-to-date knowledges of IGF2BPs (IGF2BP1/2/3) as m6A readers in an m6a-modified manner in cancer progression are reviewed, and the oncogenic role of IGF 2BPs in cancer is discussed.
Journal ArticleDOI
The biological function of IGF2BPs and their role in tumorigenesis.
TL;DR: The insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) pertain to a highly conservative RNA-binding family that works as a post-transcriptional fine-tuner for target transcripts as discussed by the authors.
Journal ArticleDOI
Novel insights into m6A modification of coding and non-coding RNAs in tumor biology: From molecular mechanisms to therapeutic significance
Jinling Jia,Su-Yao Wu,Zimo Jia,Chang Wang,Chenxi Ju,Jinxiu Sheng,Fucheng He,Mingxia Zhou,Jing He +8 more
TL;DR: Current advances in m 6A modification and the regulatory mechanisms underlying mRNAs and ncRNAs in distinct cancer stages are highlighted and the therapeutic significance of m6A regulators in clinical cancer treatment is focused on.
References
More filters
Journal ArticleDOI
Expression of the RNA-binding protein IMP1 correlates with poor prognosis in ovarian carcinoma.
Martin Köbel,D Weidensdorfer,Claudia Reinke,Marcell Lederer,Wolfgang D. Schmitt,K Zeng,Christoph Thomssen,Steffen Hauptmann,Stefan Hüttelmaier +8 more
TL;DR: Phenotypic studies in ovarian carcinoma-derived ES-2 cells demonstrated that IMP1 knockdown affects proliferation and cell survival, and reduced proliferation was associated with decreased c-myc mRNA half-life, suggesting IMP1 as an oncogenic factor that is involved in promoting elevated proliferation by stabilizing the c- myc mRNA in ovarian cancers.
Journal ArticleDOI
IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors.
Simon Müller,Nadine Bley,Markus Glaß,Bianca Busch,Vanessa Rousseau,Danny Misiak,Tommy Fuchs,Marcell Lederer,Stefan Hüttelmaier +8 more
TL;DR: Findings indicate that IGF2BP1 enhances an aggressive tumor cell phenotype by antagonizing miRNA-impaired gene expression.
Journal ArticleDOI
The oncogenic triangle of HMGA2, LIN28B and IGF2BP1 antagonizes tumor-suppressive actions of the let-7 family.
Bianca Busch,Nadine Bley,Simon Müller,Markus Glaß,Danny Misiak,Marcell Lederer,Martina Vetter,Hans-Georg Strauß,Christoph Thomssen,Stefan Hüttelmaier +9 more
TL;DR: The targeting of the HMGA2-LIN28B-IGF2BP1 triangle is suggested as a promising strategy in cancer treatment because the expression of the triangle factors is inversely correlated with let-7 levels and promoted by LIN28B impairingLet-7 biogenesis.
Journal ArticleDOI
Subcellular localization and RNP formation of IGF2BPs (IGF2 mRNA-binding proteins) is modulated by distinct RNA-binding domains.
TL;DR: Analysis of the role of KH domains in IGF2BPs by the mutational GXXG-GEEG conversion of single KH domain loops in the context of full-length polypeptides indicates paralogue-dependent RNA-binding properties of IGF2 BPs which likely direct distinct cellular functions.
Journal ArticleDOI
Epithelial-mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways.
Dongdong Fang,Huijun Chen,Jessica Y. Zhu,Wei Wang,Yong Teng,Han Fei Ding,Qing Jing,Shi-Bing Su,Shuang Huang +8 more
TL;DR: It is shown that the presence of SOS1/EPS8/ABI1 complex is critical for sustained EMT traits of ovarian cancer cells and that cocktail of MEK1/2 and Src inhibitors represents an effective therapeutic strategy against ovarian cancer progression.