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The expression of presenilin 1 enhances carcinogenesis and metastasis in gastric cancer.

ABSTRACT: Presenilin 1 (PS-1, encoded by PSEN1) is a part of the gamma- (?-) secretase complex. Mutations in PSEN1 cause the majority of cases of familial Alzheimer's disease (FAD). Although in recent years PS-1 has been implicated as a tumor enhancer in various cancers, nothing is known regarding its role in gastric cancer (GC). In the present study, we investigate the role and clinical significance of PS-1 in GC. We observed that PS-1 was significantly upregulated and amplified in GC tissues and cell lines, and its aberrant expression was positively correlated with lymph node metastasis and with poor overall survival. Furthermore, PS-1 promoted tumor invasion and metastasis of GC both in vitro and vivo without affecting the proliferation of GC cells (MGC-803 and MKN-45). The results of treatment with the ?-secretase inhibitor DAPT were consistent with the outcomes of PS-1 silencing. PS-1/?-secretase cleaves E-cadherin and releases its bound protein partner, ?-catenin, from the actin cytoskeleton, thereby allowing it to translocate into the nucleus and to activate the TCF/LEF-1 transcriptional activator, which may promote GC invasion and metastasis.In conclusion, PS-1 promotes invasion and metastasis in GC and may represent a novel prognostic biomarker and potential therapeutic target for GC treatment.

SUBMITTER: Li P

PROVIDER: S-EPMC4891148 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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The expression of presenilin 1 enhances carcinogenesis and metastasis in gastric cancer.

Li Ping P Lin Xi X Zhang Jun-Rong JR Li Yun Y Lu Jun J Huang Fei-Chao FC Zheng Chao-Hui CH Xie Jian-Wei JW Wang Jia-Bin JB Huang Chang-Ming CM

Oncotarget 20160301 9

Presenilin 1 (PS-1, encoded by PSEN1) is a part of the gamma- (γ-) secretase complex. Mutations in PSEN1 cause the majority of cases of familial Alzheimer's disease (FAD). Although in recent years PS-1 has been implicated as a tumor enhancer in various cancers, nothing is known regarding its role in gastric cancer (GC). In the present study, we investigate the role and clinical significance of PS-1 in GC. We observed that PS-1 was significantly upregulated and amplified in GC tissues and cell li ...[more]

PMID: 26872378

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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

The expression of presenilin 1 enhances carcinogenesis and metastasis in gastric cancer.

Publications

The expression of presenilin 1 enhances carcinogenesis and metastasis in gastric cancer.

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