Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling

Stoyanova, Tanya; Goldstein, Andrew S.; Cai, Houjian; Drake, Justin M.; Huang, Jiaoti; Witte, Owen N.

doi:10.1101/gad.196451.112

Cited by 118 publications

(148 citation statements)

References 61 publications

(66 reference statements)

Supporting

Mentioning

140

Contrasting

Order By: Relevance

“…Overexpression of Trop2 leads to upregulation of the β-catenin downstream target genes cyclin D1 and c-myc, and loss of β-catenin abolishes Trop2-driven self-renewal and transformation activity (61). These findings suggest that β-catenin signaling can be activated by multiple upstream events and play an important role in prostate cancer.…”

Section: Discussionmentioning

confidence: 76%

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Zong

Huang²,

Sankarasharma³

et al. 2012

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

Self Cite

View full text Add to dashboard Cite

Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AThook 2) an epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein alone is sufficient to induce dramatic hyperplasia and multifocal prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. Importantly, we find that this effect is predominantly mediated by increased Wnt/β-catenin signaling. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor in the stroma drives frank murine prostate adenocarcinoma in the adjacent epithelial tissues. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis.

show abstract

Section: Discussionmentioning

confidence: 76%

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Zong

Huang²,

Sankarasharma³

et al. 2012

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…7a). Like its close paralogue EpCAM (epithelial cell adhesion molecule), TROP2 is a nuclear signal transducer activated by regulated intramembrane proteolysis (47,48). TROP2Ex is first shed by proteolysis followed by intramembrane cleavage to release intracellular TROP2 (TROP2Ic).…”

Section: Resultsmentioning

confidence: 99%

Rapid Fine Conformational Epitope Mapping Using Comprehensive Mutagenesis and Deep Sequencing

Kowalsky

Faber

Nath

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: A new method using comprehensive mutagenesis libraries, yeast display, and deep sequencing is proposed to determine fine conformational epitopes for three antibody-antigen interactions. Results: For three separate antigens, the experimentally determined conformational epitope is consistent with orthogonal experimental datasets. Conclusion: We conclude that this new methodology is reliable and sound. Significance: With this new method, four antibody-antigen interactions can be mapped per day.

show abstract

“…Stoyanova et al 17 reported that trop2 promoted the stem-like properties and self-renewal ability of epithelial cancers via β-catenin signaling. In another study, Cubas et al 14 demonstrated that trop2 contributed to tumor pathogenesis by activating the ERK MAPK pathway.…”

Section: Discussionmentioning

confidence: 99%

Tumor-associated calcium signal transducer 2 regulates neovascularization of non-small-cell lung cancer via activating ERK1/2 signaling pathway

et al. 2017

View full text Add to dashboard Cite

Lung cancer, especially the non-small-cell lung cancer, is a highly aggressive vascular cancer with excessively activated signaling pathways. Tumor-associated calcium signal transducer 2, also known as trop2, was identified to be correlated with tumor proliferation and invasion of non-small-cell lung cancer; however, the biological role of trop2 in neovascularization of non-small-cell lung cancer remained elusive. In this study, we first verified that trop2 was overexpressed in non-small-cell lung cancer tissues as well as cell lines and that the increased expression of trop2 promoted non-small-cell lung cancer cell proliferation and invasion. Then, we expanded the biological role of trop2 by in vitro and in vivo angiogenesis assay. The tubular formation analysis revealed that trop2 promoted non-small-cell lung cancer angiogenesis in vitro, and the immunohistochemistry staining of vascular markers (CD31 and CD34) provided evidences that trop2 promoted in vivo neovascularization. The results of polymerase chain reaction array revealed that trop2 promoted the expression level of two well-known angiogenesis factors MMP13 and PECAM1. By screening the trop2-related signaling pathways, we observed that excessive angiogenesis was correlated with activation of ERK1/2 signaling pathway, and ERK1/2 inhibitor (U0126) could suppress the tubular formation ability induced by trop2 expression. These results suggested that trop2 facilitated neovascularization of non-small-cell lung cancer via activating ERK1/2 signaling pathway. Targeting trop2 might provide novel anti-angiogenesis strategy for non-small-cell lung cancer treatment.

show abstract

Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling

Cited by 118 publications

References 61 publications

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Rapid Fine Conformational Epitope Mapping Using Comprehensive Mutagenesis and Deep Sequencing

Tumor-associated calcium signal transducer 2 regulates neovascularization of non-small-cell lung cancer via activating ERK1/2 signaling pathway

Contact Info

Product

Resources

About