In vivo identification of tumor suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma

By J. Johansen, C. Cain, Linnaea E. Ostroff, Joseph E LeDoux. 2011

1,518 citations recorded by the source corpus.

Summary We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAFV600E to promote melanomagenesis.

Subfields: Cancer Research, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Yvonne Tay
2. Isidore Rigoutsos
3. P. Pandolfi
4. J. Lieberman
5. Lev M. Kats
6. L. Salmena
7. L. Poliseno

In Molecular Biology

1. P. Pandolfi
2. Yvonne Tay
3. Qian Li
4. Isidore Rigoutsos
5. Xuchen Zhang
6. Yi Zhong
7. Liyuan Wang
8. L. Salmena

Citations in the corpus

• Genetic dissection of mutual interference between two consecutive learning tasks in Drosophila (2022, background): “Although, we have much understanding of the molecular mechanisms of learning and memory for a single learning task (Johansen et al., 2011; Kandel et al., 2014), the molecular mechanisms that modulate the interferences between different tasks remain unclear.”
• Roles for microRNAs in conferring robustness to biological processes. (2012, neutral): “Karreth et al. (2011) and Tay et al. (2011) are able to observe miRNA inhibition when they use the format of these synthetic miRNA sponges in experiments that overexpress the 30 UTR of the purported ceRNA using transient plasmid transfection and a strong viral promoter rather than the endogenous…”
• Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp™ (2014, neutral): “However, such studies have used cancer cell lines with abnormal miRNA and ceRNA expression (Poliseno et al., 2010; Karreth et al., 2011), leaving their physiological relevance in primary cells unclear.”
• A temporal shift in the circuits mediating retrieval of fear memory (2015, background): “However, silencing (c) PL-BLA projections increased locomotion (F(1,12)= 12.”
• Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. (2014, neutral): “However, such studies have used cancer cell lines with abnormal miRNA and ceRNA expression (Poliseno et al., 2010; Karreth et al., 2011), leaving their physiological relevance in primary cells unclear.”
• The synaptic plasticity and memory hypothesis: encoding, storage and persistence (2014, background): “We may be getting very close to a true demonstration of mimicry in some brain structures with unambiguously defined CS and US inputs, most notably the amygdala in which learning follows Pavlovian principles (for review, see [14]).”