Transforming Growth Factor-β Promotes Liver Tumorigenesis in Mice via Up-regulation of Snail

Moon, Hyuk; Ju, Hye Lim; Chung, Sook In; Cho, Kyung Joo; Eun, Jung Woo; Nam, Suk Woo; Han, Kwang Hyub; Calvisi, Diego F.; Ro, Simon Weonsang

doi:10.1053/j.gastro.2017.07.014

Cited by 76 publications

(71 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Upregulated CDH11 in GC increases NF-κB activity and promotes the nuclear localization of NF-κB p65, leading to cell invasion and metastasis. In the present study, to further determine how CDH11 promoted GC progression, 45 molecules associated with CDH11 were analyzed using the STRING database, and the results demonstrated that these molecules were primarily involved in cell adhesion (35,36) and migration (37,38). KEGG analysis revealed that the identified molecules were enriched in multiple cancer-associated signaling pathways such as the PI3K-Akt (39), Wnt/β-catenin (40) and HIF-1 signaling pathway (41).…”

Section: Univariate Analysismentioning

confidence: 90%

Clinical and prognostic association of oncogene cadherin 11 in gastric cancer

et al. 2020

View full text Add to dashboard Cite

The abnormal expression of cadherin-11 (CDH11) affects the progression of several types of cancer. However, the expression pattern and prognostic value of CDH11 in gastric cancer (GC) have not been reported. In the present study, the expression of CDH11 in patients with GC and its effect on their survival were analyzed using public cancer databases. The expression of CDH11 in GC tissues was significantly higher compared with that in normal gastric tissues. The expression of CDH11 was higher in advanced GC compared with early GC, and increased CDH11 was associated with tumor progression and poor prognosis in patients with GC. The high level of methylation in the promoter of CDH11 in GC tissues was not sufficient to reverse the upregulation of CDH11 caused by transcriptional activation. Finally, the expression pattern and prognostic significance of CDH11 in GC were validated using data from patients with GC recruited for the present study. Collectively, the present results demonstrated that CDH11 was upregulated in GC tissues, and suggested that high CDH11 expression may be associated with progression and poor prognosis in GC.

show abstract

Section: Univariate Analysismentioning

confidence: 90%

Clinical and prognostic association of oncogene cadherin 11 in gastric cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…On the one hand, SMAD4-deficient Kras G12D pancreatic mouse models showed rapid development of pancreatic tumors (32), while restoration of SMAD4 induced apoptosis (32) and inhibited tumorigenesis in Smad4-defective cancer cells (33). On the other hand, knockdown of SMAD4 significantly reduced liver tumorigenesis in mice (34). The molecular mechanism of this duality is yet to be solved.…”

Section: Discussionmentioning

confidence: 99%

BRK Phosphorylates SMAD4 for proteasomal degradation and inhibits tumor suppressor FRK to control SNAIL, SLUG and metastatic potential

Miah

Banks

Ogunbolude

et al. 2018

Preprint

View full text Add to dashboard Cite

RUNNING TITLE: BRK Regulates FRK and EMT via SMAD4 Phosphorylation and degradation. AbstractThe tumor-suppressing function of SMAD4 is frequently subverted during mammary tumorigenesis, leading to cancer growth, invasion, and metastasis. A long-standing concept is that SMAD4 is not regulated by phosphorylation but ubiquitination. Interestingly, our search for signaling pathways regulated by BRK, a non-receptor protein tyrosine kinase that is up-regulated in ~80% of invasive ductal breast tumors, led us to discover that BRK competitively binds and phosphorylates SMAD4, and regulates TGF-β/ SMAD4 signaling pathway. A constitutively active BRK (BRK-Y447F), phosphorylates SMAD4 resulting in its recognition by the ubiquitinproteasome system, which accelerates SMAD4 degradation. In agreement, we also observed an inverse protein expression pattern of BRK and SMAD4 in a panel of breast cancer cell lines and breast tumors. Activated BRK mediated degradation of SMAD4 causes the repression of tumor suppressor genes FRK that was associated with increased expression of mesenchymal markers and decreased cell adhesion ability. Thus, our data suggest that combination therapies targeting activated BRK signaling may have synergized the benefits in the treatment of SMAD4 repressed cancers. Therefore, our data propose that combination therapies which includes targeting activated BRK signaling may synergize the benefits in the treatment of SMAD4 deficient cancers. Results Components of the TGF-β/SMAD pathway are potential BRK targetsBRK is overexpressed in most breast cancer cell lines and tumors(21) , (5), and importantly, BRK is activated in the plasma membrane of human breast tumors(22). To substantiate the overexpression of BRK in most major cancer types, we interrogated the gene expression database, GENT (Gene Expression across Normal and Tumors;http://medicalgenome.kribb.re.kr/GENT/reference.php). We found that the expression of BRK mRNA was significantly higher (p≤ 0.05) in all five cancer types that we queried compared to their respective non-cancerous tissues (Figure 1A). Having confirmed that BRK overexpression is prevalent in cancers, we next sought to identify BRK targets.In this study, we focused on the constitutively-active form of BRK, BRK-Y447F (termed BRK-YF from here on). We have previously demonstrated that BRK-YF displayed higher kinase activity than BRK-WT when ectopically and stably expressed in HEK293 cells(5). To decipher the role of activated BRK in cellular signal transduction pathways, we expressed GFP-tagged, or SNAP-FLAG tagged BRK-WT and BRK-YF constructs in HEK293 cells and evaluated their global kinase activity by analyzing cell lysates by Western blotting. When we visualized phosphorylated proteins using the PY20 anti-phosphotyrosine antibody, we confirmed that BRK-YF showed higher kinase activity than BRK-WT (Figure 1B).

show abstract

“…(1) In cancers like HCC, TGF-β-SMAD signaling can be either tumor-suppressing or tumor-promoting. (1,5,6) The complexity of this pathway makes it extremely hard to target for cancer therapy.…”

Section: See Article On Page 1549mentioning

confidence: 99%

“…In addition, many other proteins—including the SMAD3 adaptor spectrin beta, nonerythrocytic 1 (SPTBN1); the TGFBR‐associated protein Smad anchor for receptor activation; and the SMAD corepressors SNO/SKI—function as positive or negative regulators of TGF‐β signaling . In cancers like HCC, TGF‐β–SMAD signaling can be either tumor‐suppressing or tumor‐promoting . The complexity of this pathway makes it extremely hard to target for cancer therapy.…”

mentioning

confidence: 99%

“…There are chances that TICs survived from DEN‐induced DNA damage through p53 mutations. A recent study from Moon et al reported that the TGF‐β signaling pathway inhibits HCC progression driven by oncogenic H‐RasG12V, while it promotes HCC growth in the context of p53 deficiency through the regulation of Snail in transposon‐based mouse models of HCC . Further analysis is needed regarding the p53 status of the TICs isolated from mice with DEN‐induced liver damage.…”

mentioning

confidence: 99%

See 1 more Smart Citation