ASPP2 suppresses invasion and TGF-β1-induced epithelial–mesenchymal transition by inhibiting Smad7 degradation mediated by E3 ubiquitin ligase ITCH in gastric cancer

Gen, Yasuyuki; Yasui, Kohichiroh; Kitaichi, Tomoko; Iwai, Naoharu; Terasaki, Kei; Dohi, Osamu; Hashimoto, Hikaru; Fukui, Hayato; Inada, Yutaka; Fukui, Akifumi; Jo, Masayasu; Moriguchi, Michihisa; Nishikawa, Taichiro; Umemura, Atsushi; Yamaguchi, Kanji; Konishi, Hiroyuki; Naito, Yuji; Itoh, Yoshito

doi:10.1016/j.canlet.2017.04.002

Cited by 28 publications

(25 citation statements)

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“…ASPP2 (apoptosis-stimulating p53-binding protein 2), encoded by TP53BP2 gene, is considered to play a crucial role on apoptosis genesis via binding to p53 family and enhancing their transcriptional activities towards pro-apoptosis gene [33][34][35]. Interestingly, in addition to promoting cell apoptosis via binding to p53, ASPP2 has recently been confirmed to function in p53-independent manners and the aberrant expression of ASPP2 is involved in numerous cellular functions in tumors, not only cell apoptosis but also cell metastasis, senescence, and autophagy [18,[36][37][38][39]. Similarly, it has been reported that ASPP2 is downregulated in majority of human tumors, such as hepatocellular carcinoma, pancreatic cancer, and breast cancer [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

“…ASPP2 can potentiate Ras signaling and even convert its oncogenic role to tumor-suppressive role on cell apoptosis and senescence [44,45]. In gastric cancer, ASPP2 inhibited ubiquitin-dependent degradation of Smad7 by interacting with ITCH, leading to the suppression of TGF-β1-Smad2/3 signaling, which reduced migration and invasion of gastric cancer cells both in vitro and in vivo [37]. Currently, ASPP2 as a tumor suppressor involved in the cell apoptosis and EMT process in breast cancer has attracted much more attention [18,46].…”

Section: Discussionmentioning

confidence: 99%

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Mir-30b-5p Promotes Proliferation, Migration, and Invasion of Breast Cancer Cells via Targeting ASPP2

Song

Xie

et al. 2020

BioMed Research International

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Triple-negative breast cancer (TNBC) is the most aggressive subtypes of breast cancer, which has few effective targeted therapies. Various sources of evidence confirm that microRNAs (miRNAs) contribute to the progression and metastasis of human breast cancer. However, the molecular mechanisms underlying the changes in miRNAs expression and the regulation of miRNAs functions have not been well clarified. In this study, we found that the expression of miR-30b-5p was upregulated in breast cancer tissues and breast cancer cell lines, compared to paracancer tissues and normal breast cell lines. Moreover, induced overexpression of miR-30b-5p promoted the MDA-MB-231 and HCC 1937 cell growth, migration, and invasion and reduced the cellular apoptosis. Further studies confirmed that miR-30b-5p could directly target ASPP2 and then activate the AKT signaling pathway. Our results suggested that miR-30b-5p could act as a tumor promoter in TNBC. The newly identified miR-30b-5p/ASPP2/AKT axis represents a novel therapeutic strategy for treating TNBC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mir-30b-5p Promotes Proliferation, Migration, and Invasion of Breast Cancer Cells via Targeting ASPP2

Song

Xie

et al. 2020

BioMed Research International

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“… 28 , 29 Among the known pathways, TGF-β signaling plays a central role in the development and progression of GC. 30 , 31 There are three isoforms of TGF-β in mammalian cells, including the most abundant TGF-β1, and the uncommon isoforms: TGF-β2 and TGF-β3. 32 The TGF-β/SMAD pathway is initiated by TGF-β1 binding to its type II receptor (TβRII).…”

Section: Discussionmentioning

confidence: 99%

MFAP2 promotes epithelial–mesenchymal transition in gastric cancer cells by activating TGF-β/SMAD2/3 signaling pathway

Wang¹,

Wang²,

Cai³

et al. 2018

OTT

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IntroductionMicrofibril-associated protein 2 (MFAP2) is an extracellular matrix protein that interacts with fibrillin to modulate the function of microfibrils. MFAP2 has been reported to play a significant role in obesity, diabetes, and osteopenia, and has been shown to be upregulated in head and neck squamous cell carcinoma. However, the molecular function and prognostic value of MFAP2 have never been reported in gastric cancer (GC) or any other tumors.MethodsThe current study investigated the expression patterns, prognostic significance, functional role, and possible mechanisms of MFAP2 in GC.ResultsWe demonstrated that MFAP2 was overexpressed in GC tissues, and its overexpression was significantly correlated with poor overall and disease-free survival in patients with GC. Moreover, we found that MFAP2 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) phenotype in GC cells. MFAP2 might modulate EMT of GC cells by activating the TGF-β/SMAD2/3 signaling pathway.ConclusionThese findings provide novel evidence that MFAP2 plays a crucial role in the progression of GC. Therefore, MFAP2 may be a promising prognostic marker and a potent anticancer agent.

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“…Mass spectrometry and protein analysis revealed that RASSF10 interacts and stabilizes the Apoptosis-Stimulating Protein of p53 2 (ASPP2) which is encoded by the TP53BP2 gene. ASPP2 is a tumor suppressor gene that controls epithelial plasticity and inhibits EMT [26,27]. Furthermore, we found that RASSF10, but not ASPP2, is frequently hypermethylated in human cancers and the loss of RASSF10 is associated with advanced tumor stages and impaired survival of cancer patients.…”

Section: Introductionmentioning

confidence: 85%

“…Our data indicate that knockdown of ASPP2 induces β-Catenin levels and phospho-SMAD2 under TGFβ treatment (Figure 9a). Previously it has been reported that ASPP2 suppresses TGFβ induced EMT by inhibiting Smad7 degradation [27]. SMAD7 prevents SMAD2/3 phosphorylation and is an important antagonist of TGFβ signaling [56].…”

Section: Discussionmentioning

confidence: 99%

RASSF10 Is a TGFβ-Target That Regulates ASPP2 and E-Cadherin Expression and Acts as Tumor Suppressor That Is Epigenetically Downregulated in Advanced Cancer

Richter

Küster

Woods

et al. 2019

Cancers

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The Ras Association Domain Family (RASSF) encodes members of tumor suppressor genes which are frequently inactivated in human cancers. Here, the function and the regulation of RASSF10, that contains a RA (Ras-association) and two coiled domains, was investigated. We utilized mass spectrometry and immuno-precipitation to identify interaction partners of RASSF10. Additionally, we analyzed the up- and downstream pathways of RASSF10 that are involved in its tumor suppressive function. We report that RASSF10 binds ASPP1 (Apoptosis-stimulating protein of p53) and ASPP2 through its coiled-coils. Induction of RASSF10 leads to increased protein levels of ASPP2 and acts negatively on cell cycle progression. Interestingly, we found that RASSF10 is a target of the EMT (epithelial mesenchymal transition) driver TGFβ (Transforming growth factor beta) and that negatively associated genes of RASSF10 are significantly over-represented in an EMT gene set collection. We observed a positive correlation of RASSF10 expression and E-cadherin that prevents EMT. Depletion of RASSF10 by CRISPR/Cas9 technology induces the ability of lung cancer cells to proliferate and to invade an extracellular matrix after TGFβ treatment. Additionally, knockdown of RASSF10 or ASPP2 induced constitutive phosphorylation of SMAD2 (Smad family member 2). Moreover, we found that epigenetic reduction of RASSF10 levels correlates with tumor progression and poor survival in human cancers. Our study indicates that RASSF10 acts a TGFβ target gene and negatively regulates cell growth and invasion through ASPP2. This data suggests that epigenetic loss of RASSF10 contributes to tumorigenesis by promoting EMT induced by TGFβ.

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ASPP2 suppresses invasion and TGF-β1-induced epithelial–mesenchymal transition by inhibiting Smad7 degradation mediated by E3 ubiquitin ligase ITCH in gastric cancer

Cited by 28 publications

References 40 publications

Mir-30b-5p Promotes Proliferation, Migration, and Invasion of Breast Cancer Cells via Targeting ASPP2

Mir-30b-5p Promotes Proliferation, Migration, and Invasion of Breast Cancer Cells via Targeting ASPP2

MFAP2 promotes epithelial–mesenchymal transition in gastric cancer cells by activating TGF-β/SMAD2/3 signaling pathway

RASSF10 Is a TGFβ-Target That Regulates ASPP2 and E-Cadherin Expression and Acts as Tumor Suppressor That Is Epigenetically Downregulated in Advanced Cancer

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ASPP2 suppresses invasion and TGF-β1-induced epithelial–mesenchymal transition by inhibiting Smad7 degradation mediated by E3 ubiquitin ligase ITCH in gastric cancer

Cited by 28 publications

References 40 publications

Mir-30b-5p Promotes Proliferation, Migration, and Invasion of Breast Cancer Cells via Targeting ASPP2

Mir-30b-5p Promotes Proliferation, Migration, and Invasion of Breast Cancer Cells via Targeting ASPP2

MFAP2 promotes epithelial&ndash;mesenchymal transition in gastric cancer cells by activating TGF-&beta;/SMAD2/3 signaling pathway

RASSF10 Is a TGFβ-Target That Regulates ASPP2 and E-Cadherin Expression and Acts as Tumor Suppressor That Is Epigenetically Downregulated in Advanced Cancer

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MFAP2 promotes epithelial–mesenchymal transition in gastric cancer cells by activating TGF-β/SMAD2/3 signaling pathway