Identification of β‑catenin target genes in colorectal cancer by interrogating gene fitness screening data

Zhao, Hao‐Min; He, Liang; Yin, Di; Song, Bin

doi:10.3892/ol.2019.10724

Cited by 7 publications

(6 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This included “direct” targets, as defined by the presence of TCF binding sites, and “indirect” targets, as obtained from large-scale β-catenin inactivation screening programs. β-catenin targets included the proto-oncogenes MYC and CCND1 , as well as the genes encoding the basic helix-loop-helix proteins ASCL2 and ITF-2B [39] . This dataset was interrogated in primary tumors and metastases.…”

Section: Resultsmentioning

confidence: 99%

Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer

et al. 2021

View full text Add to dashboard Cite

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2–driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from β-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of β-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/β-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2–centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer

et al. 2021

View full text Add to dashboard Cite

show abstract

“…ShRNA, transduced by lentivirus, can be expressed stably in infected cell lines [18][19][20]. Therefore, lentivirus-harboring shRNA can be packaged, concentrated, and infected into the targeted cells to produce efficient and long-term gene silencing [21][22][23]. In this study, the constructed lentiviral shRNA vectors were transfected into target cells.…”

Section: Discussionmentioning

confidence: 99%

Promotion of In Vitro Hair Cell-like Cell Differentiation from Human Embryonic Stem Cells through the Regulation of Notch Signaling

et al. 2021

View full text Add to dashboard Cite

The Notch signaling pathway plays an important role in otic neurogenesis by regulating the differentiation of inner ear hair cells and supporting cells. Notch-regulated differentiation is required for the regeneration of hair cells in the inner ear. The temporal expression pattern of Notch ligands and receptors during in vitro hair cell-like cell differentiation from human embryonic stem cells (hESCs) was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Subsequently, pAJ-U6-shRNA-CMV-Puro/GFP recombinant lentiviral vectors encoding short hairpin RNAs were used to silence JAG-1, JAG-2, and DLL-1, according to the temporal expression pattern of Notch ligands. Then, the effect of each ligand on the in vitro differentiation of hair cells was examined by RT-PCR, immunofluorescence, and scanning electron microscopy (SEM). The results showed that the individual deletion of JAG-2 or DLL-1 had no significant effect on the differentiation of hair cell-like cells. However, the simultaneous inhibition of both DLL-1 and JAG-2 increased the number of hair cell-like cells and decreased the number of supporting cells. JAG-2 and DLL-1 may have a synergistic role in in vitro hair cell differentiation.

show abstract

“…ShRNA, transduced by lentivirus, can be expressed stably in infected cell lines [19][20][21]. Therefore, lentivirus-harboring shRNA was packaged, concentrated, and infected into the targeted cells to produce e cient and long-term gene silencing [22][23][24]. In this study, the constructed lentiviral shRNA vector was transfected into target cells.…”

Section: Discussionmentioning

confidence: 99%

Promotion of in Vitro Hair Cell-like Cell Differentiation from Human Embryonic Stem Cells through the Regulation of Notch Signaling

Chen

Yang

Chen

et al. 2021

Preprint

View full text Add to dashboard Cite

Background Notch signaling mediates the committed induced differentiation of ear sensory cells and promotes the formation of a precise arrangement of mosaics between hair cells and supporting cells. Embryonic stem cells (ESCs) are pluripotent stem cells which have the potential to differentiate into cell lines through three germ layers. Therefore, it is necessary to study the effects of regulating Notch receptors and ligand expression on the in vitro differentiation equilibrium of hair cells and supporting cells from ESCs.Methods and Results The temporal ex-pression pattern of Notch ligands and receptors during in vitro hair cell-like cell differentia-tion from human embryonic stem cells (hESCs) was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Subsequently, pAJ-U6-shRNA-CMV-Puro/GFP recombinant lentiviral vectors, encoding short hairpin RNAs, were used to silence JAG-1, JAG-2, and DLL-1, according to the temporal expression pattern of Notch ligands. Then the effect of each ligand on the in vitro differentiation of hair cells was examined by RT-PCR, immunofluorescence, and scanning electron microscopy (SEM).Conclusions Results showed that JAG-1 played an important role in regulating hESC differentiation to otic progenitors. The individual deletion of JAG-2 or DLL-1 had no significant effect on the differentiation of hair cell-like cells. Although the simultaneous inhibition of both DLL-1 and JAG-2 could increase the number of hair cell-like cells, it decreased the number of supporting cells.

show abstract

Identification of β‑catenin target genes in colorectal cancer by interrogating gene fitness screening data

Cited by 7 publications

References 68 publications

Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer

Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer

Promotion of In Vitro Hair Cell-like Cell Differentiation from Human Embryonic Stem Cells through the Regulation of Notch Signaling

Promotion of in Vitro Hair Cell-like Cell Differentiation from Human Embryonic Stem Cells through the Regulation of Notch Signaling

Contact Info

Product

Resources

About