PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

Zeleniak, Ann E.; Huang, Wei; Fishel, Melissa L.; Hill, Reuben

doi:10.1016/j.neo.2017.10.004

Cited by 15 publications

(18 citation statements)

References 66 publications

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“…A previous study uncovered a potential novel connection between the PTEN tumor suppressor and MTSS1, showing that PTEN regulates both MTSS1 protein level and stability . We next investigated whether PTEN affected MTSS1 expression in SGC‐7901 cells.…”

Section: Resultsmentioning

confidence: 98%

Metastasis suppressor protein 1 regulated by PTEN suppresses invasion, migration, and EMT of gastric carcinoma by inactivating PI3K/AKT signaling

Wang

Zhao

Cao

et al. 2018

J of Cellular Biochemistry

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Epithelial-mesenchymal transition (EMT) is a crucial event for cancer progression and metastasis. Metastasis suppressor protein 1 (MTSS1) is a metastasis suppressor in several cancers. In this study, we elucidated the potential physiological function of MTSS1 in the invasion and migration of gastric cancer (GC), and its distinct role in EMT and subsequently determined the potential molecular mechanism. We observed that MTSS1 expression was downregulated in GC tissues and several GC cell lines (SGC-7901, MGC-803, MKN-28, MKN-45, and BGC-823). Importantly, forced expression of MTSS1 drastically diminished the cell viability in both SGC-7901 and MKN-45 cells. Moreover, overexpression of MTSS1 attenuated the invasion ability of these two cell lines. In addition to the invasive capability, introduction of MTSS1 led to a loss of migratory potential. Furthermore, augmentation of MTSS1 exhibited the typical EMT phenotype switch, accompanied by enhanced the expression of vimentin and N-cadherin and reduced E-cadherin expression. Interestingly, MTSS1 also repressed transforming growth factor beta 1 (TGF-β1)induced EMT. Our mechanistic investigations revealed that MTSS1 was positively regulated by the phosphatase and tensin homolog (PTEN), and it functioned as a tumor suppressor, possibly by inactivating the phosphoinositide 3-kinase (PI3K)/vakt murine thymoma viral oncogene (AKT) pathway in GC cells. Collectively, our data provide insight into an important role for MTSS1 in suppressing tumor cell invasion, migration and EMT, which indicates that MTSS1 may act as a prospective prognostic biological marker and a promising therapeutic target for GC.

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Section: Resultsmentioning

confidence: 98%

Metastasis suppressor protein 1 regulated by PTEN suppresses invasion, migration, and EMT of gastric carcinoma by inactivating PI3K/AKT signaling

Wang

Zhao

Cao

et al. 2018

J of Cellular Biochemistry

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“…The above data indicated that the enrichment of MTA2 was dependent on the NuRD complex. Among these target genes, PTEN has been reported to be one of the most powerful tumor repressor gene in numerous cancer types including PDAC 32,33 . Therefore, we explored whether PTEN was functionally linked to the downstream target of MTA2.…”

Section: Resultsmentioning

confidence: 99%

MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity

Liu

Wei

et al. 2019

Cell Death Dis

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Metastasis-associated protein 2 (MTA2) is a core subunit of the nucleosome remodeling and deacetylating (NuRD) complex and functions by mediating chromatin remodeling and gene silencing. However, its biological actions and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remain elusive. The aim of this study was to explore the function and regulation mechanism of MTA2 in PDAC. As shown in GEO, ICGC, and TCGA databases, a higher expression of MTA2 was noticed in the PDAC tissues than in the normal pancreatic tissues. Moreover, a higher expression level of MTA2 was associated with a shorter overall survival time in these public PDAC databases. We further investigated the underlying mechanisms of these observations by using a chromatin immunoprecipitation (ChIP)-based deep sequencing, luciferase reporter, and quantitative ChIP assays. We identified the repressive binding of MTA2 to the promoter of phosphatase and tensin homolog ( PTEN ). We also found that Snail recruited MTA2 and HDAC1 to suppress PTEN expression. Ectopic expression and knockdown of MTA2 were performed to evaluate the effects of this gene on PDAC cell proliferation, migration, and invasion. Using CCK-8, colony formation and transwell assays, and a xenograft tumor model, we revealed that MTA2 promoted PDAC cell proliferation, migration, and invasion in vitro and PDAC tumor growth in vivo by downregulation of PTEN. In benzyl isothiocyanate (BITC)-treated MIA Paca-2 cells and PANC-1 cells, MTA2 level decreased in a dose- and time-dependent manner with concomitant upregulation of PTEN level and downregulation of phosphorylated PI3K and AKT levels, providing evidence of the involvement of MTA2 and PTEN in the regulation of the PI3K/AKT pathway in BITC-mediated PDAC suppression. Collectively, these findings uncover a novel role for MTA2 in the regulation of PDAC progression and help to elucidate the mechanisms involved in this process.

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“…The further mechanism investigation demonstrates that MTSS1 could repress TGF-β1-induced EMT (Epithelial-Mesenchymal Transition), and MTSS1 could be positively regulated by PTEN (Phosphatase and tennis homolog) as a tumor suppressor by inactivating PI3K/AKT oncogenic pathway. In pancreatic ductal adenocarcinoma, Zeleniak reported PTEN could form a complex with MTSS1 in order to stabilize and protect MTSS1 from proteasomal degradation, eventually causinga significant decrease in cellular migration and invasion 30. Therefore, PTEN may play an important role in the influence of MTSS1 on tumor metastases.…”

Section: Discussionmentioning

confidence: 99%

<p>MTSS1 inhibits metastatic potential and induces G2/M phase cell cycle arrest in gastric cancer</p>

Liu¹,

Jiao²,

Hao³

et al. 2019

OTT

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Background: Metastasis suppressor 1 (MTSS1), a potential metastasis suppressor gene associated with tumor progression, may play an important role in cancer development. Our previous study demonstrated that MTSS1 was downregulated significantly when gastric cancer (GC) progressed and metastasized, suggesting that MTSS1 may be involved in the physiopathologic mechanism of GC. Purpose: The objective of this study was to evaluate the effect of MTSS1 expression on the biological behavior of gastric cancer cell both in vitro and in vivo . Materials and methods: The gain-and-loss function of MTSS1 in GC cells were analyzed after transfection with pEGFP-N1-MTSS1 and ShRNA431. Proliferation and invasion abilities were measured by means of plate clone formation assay and transwell assay. To further explore the underlying mechanism of MTSS1-induced tumor restrain, cell cycle distribution was analyzed using flow cytometry. Results: The results revealed that overexpression of MTSS1 significantly reduced proliferation, migration and invasion of GC cells in vivo and in vitro , while downregulation of MTSS1 had the opposite biological manifestations. Moreover, overexpression of MTSS1 induced accumulation of GC cells in G2/M phase, increased phosphorylated Cdc2 expression and decreased Cdc25C and cyclinB1 levels, suggesting MTSS1 could cause G2/M cell cycle arrest. Conclusion: Our data provided insight into an important role for MTSS1 in suppressing tumor cell proliferation, invasion and migration, indicating that MTSS, as a functional tumor suppressor in GC, could be a potential therapeutic target to prevent GC metastasis.

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PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

Cited by 15 publications

References 66 publications

Metastasis suppressor protein 1 regulated by PTEN suppresses invasion, migration, and EMT of gastric carcinoma by inactivating PI3K/AKT signaling

Metastasis suppressor protein 1 regulated by PTEN suppresses invasion, migration, and EMT of gastric carcinoma by inactivating PI3K/AKT signaling

MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity

<p>MTSS1 inhibits metastatic potential and induces G2/M phase cell cycle arrest in gastric cancer</p>

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