Dataset Information

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer.

ABSTRACT: ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.

SUBMITTER: Sun X

PROVIDER: S-EPMC5728182 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer.

Sun Xuxu X Wang Sam C SC Wei Yonglong Y Luo Xin X Jia Yuemeng Y Li Lin L Gopal Purva P Zhu Min M Nassour Ibrahim I Chuang Jen-Chieh JC Maples Thomas T Celen Cemre C Nguyen Liem H LH Wu Linwei L Fu Shunjun S Li Weiping W Hui Lijian L Tian Feng F Ji Yuan Y Zhang Shuyuan S Sorouri Mahsa M Hwang Tae Hyun TH Letzig Lynda L James Laura L Wang Zixi Z Yopp Adam C AC Singal Amit G AG Zhu Hao H

Cancer cell 20171101 5

ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in est ...[more]

PMID: 29136504

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Project description:BACKGROUND:In our previous study, we identified a candidate tumor suppressor gene, testin LIM domain protein (TES), in primary gastric cancer (GC). TES contains three LIM domains, which are specific interacting regions for the cell adhesion and cytoskeleton regulatory proteins. Mena is a known cytoskeleton regulator that regulates the assembly of actin filaments and modulates cell adhesion and motility by interacting with Lamellipodin (Lpd). Therefore, we hypothesized that TES plays a role as tumor suppressor in GC through interacting with Mena. This study aimed to investigate the tumor suppressive functions of TES in GC. METHODS:We explored the tumor suppressive effect of TES in GC by in vitro cell proliferation assay, colony formation assay, cell cycle analysis, Transwell assays, and in vivo tumorigenicity and metastasis assays. The interaction of TES and Mena was investigated through immunoprecipitation-based mass spectrometry. We also analyzed the expression of TES and Mena in 172 GC specimens using immunohistochemistry and investigated the clinicopathological and prognostic significance of TES and Mena in GC. RESULTS:TES suppressed GC cell proliferation and colony formation, induced cell cycle arrest, and inhibited tumorigenicity in vitro. Additionally, it inhibited GC cell migration and invasion in vitro and suppressed metastasis in vivo. TES interacted with Mena, and inhibited the interaction of Mena with Lpd. Transwell assays suggested that TES suppressed migration and invasion of GC cells in a Mena-dependent fashion. In GC patients with high Mena expression, the expression of TES was associated with tumor infiltration (P?=?0.005), lymph node metastasis (P?=?0.003), TNM stage (P?=?0.003), and prognosis (P?=?0.010). However, no significant association was observed in GC patients with low Mena expression. CONCLUSIONS:We believe that TES functions as a Mena-dependent tumor suppressor. TES represents a valuable prognostic marker and potential target for GC treatment.

Dataset Information

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer.

Publications

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer.

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