The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

Tsuji, Shinnosuke; Kawasaki, Yuki; Furukawa, Shigeto; Taniue, Kenzui; Hayashi, Tomoatsu; Okuno, Masumi; Hiyoshi, Masaya; Kitayama, Joji; Akiyama, Tetsu

doi:10.1038/ncomms4150

Cited by 85 publications

(90 citation statements)

References 48 publications

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“…8D) may be specific to HT-29 cells or could occur in other cell types. We immunoblotted various cell lines with the phospho-Ser 37 antibody in comparison to affinity-purified antisera binding the nonphosphorylated peptide surrounding Ser 37 (see Materials and Methods) and to other commercial GATA6 antibodies (100, 118). In HCT-8 and DLD-1 colorectal cancer lines, AC16 cardiomyocytes (110), and MCF10A-5E breast epithelial cells (119), we observed the 60 and 75-kD forms of GATA6 L , which were phosphorylated to variable extents according to phospho-Ser 37 immunoreactivity (Fig.…”

Section: Resultsmentioning

confidence: 99%

TNF-insulin crosstalk at the transcription factor GATA6 is revealed by a model that links signaling and transcriptomic data tensors

Chitforoushzadeh

Sheng

et al. 2016

Sci. Signal.

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Signal -transduction networks coordinate transcriptional programs activated by diverse extracellular stimuli, such as growth factors and cytokines. Cells receive multiple stimuli simultaneously, and mapping how activation of the integrated signaling network affects gene expression is a challenge. We stimulated colon adenocarcinoma cells with various combinations of the cytokine tumor necrosis factor (TNF) and the growth factors insulin and epidermal growth factor (EGF) to investigate signal integration and transcriptional crosstalk. We quantitatively linked the proteomic and transcriptomic data sets by implementing a structured computational approach called tensor partial least squares regression. This statistical model accurately predicted transcriptional signatures from signaling arising from single and combined stimuli and also predicted time-dependent contributions of signaling events. Specifically, the model predicted that an early-phase, Akt-associated signal downstream of insulin repressed a set of transcripts induced by TNF. Through bioinformatics and cell-based experiments, we identified the Akt-repressed signal as glycogen synthase kinase 3 (GSK3)–catalyzed phosphorylation of Ser37 on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser37 promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin. Our analysis showed that predictive tensor modeling of proteomic and transcriptomic data sets can uncover pathway crosstalk that produces specific patterns of gene expression in cells receiving multiple stimuli.

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Section: Resultsmentioning

confidence: 99%

TNF-insulin crosstalk at the transcription factor GATA6 is revealed by a model that links signaling and transcriptomic data tensors

Chitforoushzadeh

Sheng

et al. 2016

Sci. Signal.

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“…Our data also imply that LGR5 is dispensable for tumour growth in these conditions, in contrast to recent reports using CRC cell lines knocked down for Gata6 (ref. 20). Gene set enrichment analysis also indicated a prominent enrichment in components of the transforming growth factor TGF-β superfamily, most of which belong to the BMP signalling pathway (Supplementary Table 3).…”

Section: Gata6mentioning

confidence: 95%

“…1b). Indeed, GATA6 has been very recently identified as a direct regulator of LGR5 expression in CRC cells 20 . We corroborated these findings through experiments of shRNA-mediated knockdown, overexpression and chromatin immunoprecipitation (ChIP) of GATA6 in CRC cells ( Fig.…”

Section: Screening For Genes That Regulate Stemness In Crcmentioning

confidence: 99%

The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression

et al. 2014

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Aberrant activation of WNT signalling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumour stem cell phenotype and identify the zinc-finger transcription factor GATA6 as a key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells whereas it restricts BMP signalling to differentiated tumour cells. Genetic deletion of Gata6 from mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumour stem cells. In human tumours, GATA6 competes with β-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been linked to increased susceptibility to development of CRC. Hence, GATA6 creates an environment permissive for CRC initiation by lowering the threshold of BMP signalling required for tumour stem cell expansion.

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“…Furthermore, there are other conflicting reports regarding the functional role of LGR5 in colon cancer tumorigenesis. Some studies reported that RSPO/LGR5 signaling has a tumor suppressive activity in colon cancer (8;13) whereas others showed that LGR5 promotes tumorigenicity (14). Therefore, the role of LGR5 in colon cancer tumorigenesis remains ambiguous, although in a transposon mutagenesis study RSPO2 scored second only to APC as a colon cancer tumor suppressor locus (15).…”

Section: Introductionmentioning

confidence: 99%

R-Spondin1/LGR5 Activates TGFβ Signaling and Suppresses Colon Cancer Metastasis

et al. 2017

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Leucine rich repeat containing G protein-coupled receptor 5 (LGR5), an intestinal stem cell marker, is known to exhibit tumor suppressor activity in colon cancer, the mechanism of which is not understood. Here we show that R-spondin 1 (RSPO1)/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFβ signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFβ receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFβ activation in colon cancer. Our study uncovers a novel crosstalk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis.

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The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

Cited by 85 publications

References 48 publications

TNF-insulin crosstalk at the transcription factor GATA6 is revealed by a model that links signaling and transcriptomic data tensors

TNF-insulin crosstalk at the transcription factor GATA6 is revealed by a model that links signaling and transcriptomic data tensors

The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression

R-Spondin1/LGR5 Activates TGFβ Signaling and Suppresses Colon Cancer Metastasis

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