A combination of Wnt and growth factor signaling induces Arl4c expression to form epithelial tubular structures

Matsumoto, Shinji; Fujii, Shinsuke; Sato, Akira; Ibuka, Souji; Kagawa, Yutaka; Ishii, Masaru; Kikuchi, Akira

doi:10.1002/embj.201386942

Cited by 79 publications

(133 citation statements)

References 58 publications

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“…In qPCR validation experiments, all these genes were upregulated in RKO and/or HCT116 ZBED6 −/− cells, and the majority were significantly up-regulated upon siRNA-mediated knock-down of ZBED6 in HCT116 cells. Strikingly, two-MYBL1 (16) and SPTBN1 (17, 18)-were bona fide cancer genes, and six genes were linked to pathways involved in CRC: two [ARL4C (19) and TCF7] to the Wnt pathway, three [ARL4C (19), WWC1/KIBRA Genes with at least 1.5-fold change in the same direction in RKO and HCT116 ZBED6 −/− cells and a ChIP-seq peak with at least 30 reads in HCT116. RNA-seq fold-changes for RKO and HCT116 are given followed by the peak height of the nearest ZBED6 binding site.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells

Akhtar-Ali

Younis

Wallerman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-β, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.C olorectal cancers (CRCs) are caused by sequential mutations in driver genes of key cellular systems such as the Wnt, EGFR/Ras/MAPK, PI3K, TGFB, and TP53 pathways (1). Somatic mutations in the PI3K pathway members PIK3CA and PTEN occur late in CRC progression and contribute to increased tumor cell growth and invasivity (2-4). In CRC, overexpression of IGF2 is mutually exclusive with activating genomic alterations of the PI3K pathway genes PIK3CA and PIK3R1 (5). Further, IRS2 overexpression is mutually exclusive with IGF2 overexpression. The IRS2 gene is frequently amplified in CRCs (5) and encodes a protein that links IGF1R, a receptor for IGF1 and IGF2, with PI3K signaling. The importance of this pathway in colorectal tumorigenesis motivates studies to understand its regulation better.The ZBED6 (zinc finger, BED-type containing 6) transcription factor is a recently discovered negative regulator of IGF2 expression (6, 7). The intronless ZBED6 gene encodes two N-terminal zinc finger BED domains (8) and an hAT (hobo-Ac-Tam3) dimerization domain. Based on its primary structure, ZBED6 belongs to the hAT transposase family (9). The ZBED6 gene is located in the first intron of ZC3H11A and is transcribed as a composite transcript from the ZC3H11A promoter. An SNP (rs4951011) located in the 5′ UTR of ZBED6 recently was found to be associated with breast cancer susceptibility in a genome-wide association study (10). In pigs, a G-to-A mutation in the highly conserved CpG island in the thi...

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Section: Discussionmentioning

confidence: 99%

Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells

Akhtar-Ali

Younis

Wallerman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The formation of lamellipodia and filopodia (resulting in actin cytoskeleton reorganization), which are regulated by Rac and cdc42, respectively, contributes to cancer cell motility [18] . In a previous study, ADP-ribosylation factor-like 4C (ARL4C), a downstream factor of EGF signaling and Wnt signaling, was reported to promote cell motility by activating Rho GTPases [21] . We recently found that ARL4C is associated with PD in GC, possibly by promoting the invasive capacity of cancer cells via activation of both EMT and actin cytoskeleton reorganization [22] .…”

Section: The Detachment Of Cancer Cells From the Primary Tumormentioning

confidence: 99%

Molecular mechanism of peritoneal dissemination in gastric cancer

Hu¹,

Ito²,

Yanagihara³

et al. 2018

JCMT

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Peritoneal dissemination (PD) is the most common cause of metastasis in gastric cancer (GC). Because there are no standard treatments for PD, it is associated with a poor prognosis. Although clinicians have performed intraperitoneal chemotherapy for GC with PD, the outcome remains unsatisfactory. Therefore, the development of novel treatments and diagnostic tools for PD is expected to improve the prognosis of GC patients with PD. Notably, it is essential to elucidate the molecular mechanisms involved in the development of PD in GC. In this review, the molecular mechanisms of PD (three steps: detachment from the primary tumor, adaptation to the microenvironment of the peritoneal cavity, and attachment to peritoneal mesothelial cells) and new topics in GC are highlighted.

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“…We developed a new in vitro tubular formation assay using rat intestinal epithelial cells (IEC6 cells) in 3D Matrigel (Matsumoto et al, 2014). IEC6 cells formed cysts in 3D Matrigel, and simultaneous stimulation with Wnt3a and EGF induced tubular formation.…”

Section: Introductionmentioning

confidence: 99%

“…These morphological changes in the leading cells of tubular structures induced the nuclear localization of Yes-associated protein (YAP) and of transcriptional co-activator with PDZ-binding motif (TAZ), which are Hippo pathway transcriptional activators and play crucial roles in cell proliferation (Saucedo and Edgar, 2007), resulting in tubular formation. Owing to expression of Arl4c, MDCK cells formed tubular structures in response to HGF in 3D Matrigel culture, and Arl4c expression was also involved in elongation and budding of kidney ureteric buds of mouse embryos, suggesting the existence of a common mechanism regulating tube formation (Matsumoto et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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The P2Y2 receptor promotes Wnt3a- and EGF-induced epithelial tubular formation by IEC6 cells by binding to integrins

Ibuka

Matsumoto

Fujii

et al. 2015

Journal of Cell Science

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Epithelial tubular structures are essential units in various organs. Here, we used rat intestinal epithelial IEC6 cells to investigate tubulogenesis and we found that tubular formation was induced by a combination of Wnt3a and EGF signaling during threedimensional culture. Wnt3a and EGF induced the expression of the P2Y 2 receptor (P2Y 2 R, also known as P2RY2), and knockdown of P2Y 2 R suppressed tubular formation. A P2Y 2 R mutant that lacks nucleotide responsiveness rescued the phenotypes resulting from P2Y 2 R knockdown, suggesting that nucleotide-dependent responses are not required for P2Y 2 R functions in tubular formation. The ArgGly-Asp (RGD) sequence of P2Y 2 R has been shown to interact with integrins, and a P2Y 2 R mutant lacking integrin-binding activity was unable to induce tubular formation. P2Y 2 R expression inhibited the interaction between integrins and fibronectin, and induced cell morphological changes and proliferation. Inhibition of integrin and fibronectin binding by treatment with the cyclic RGD peptide and fibronectin knockdown induced tubular formation in the presence of EGF alone, but a fibronectin coat suppressed Wnt3a-and EGFinduced tubular formation. These results suggest that Wnt3a-and EGF-induced P2Y 2 R expression causes tubular formation by preventing the binding of integrins and fibronectin rather than by mediating nucleotide responses.

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A combination of Wnt and growth factor signaling induces Arl4c expression to form epithelial tubular structures

Cited by 79 publications

References 58 publications

Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells

Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells

Molecular mechanism of peritoneal dissemination in gastric cancer

The P2Y2 receptor promotes Wnt3a- and EGF-induced epithelial tubular formation by IEC6 cells by binding to integrins

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