Dataset Information

MEIS2 promotes cell migration and invasion in colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) is one of the most common types of malignancy worldwide. Distant metastasis is a key cause of CRC?associated mortality. MEIS2 has been identified to be dysregulated in several types of human cancer. However, the mechanisms underlying the regulatory role of MEIS2 in CRC metastasis remain largely unknown. For the first time, the present study demonstrated that MEIS2 serves a role as a promoter of metastasis in CRC. In vivo and in vitro experiments revealed that knockdown of MEIS2 significantly suppressed CRC migration, invasion and the epithelial?mesenchymal transition. Furthermore, microarray and bioinformatics analyses were performed to investigate the underlying mechanisms of MEIS2 in the regulation of CRC metastasis. Additionally, it was identified that a high expression of MEIS2 was significantly associated with a shorter overall survival time for patients with CRC. The present study demonstrated that MEIS2 may serve as a novel biomarker for CRC.

SUBMITTER: Wan Z

PROVIDER: S-EPMC6549210 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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MEIS2 promotes cell migration and invasion in colorectal cancer.

Wan Ziang Z Chai Rui R Yuan Hang H Chen Bingchen B Dong Quanjin Q Zheng Boan B Mou Xiaozhou X Pan Wensheng W Tu Yifeng Y Yang Qing Q Tu Shiliang S Hu Xinye X

Oncology reports 20190515 1

Colorectal cancer (CRC) is one of the most common types of malignancy worldwide. Distant metastasis is a key cause of CRC‑associated mortality. MEIS2 has been identified to be dysregulated in several types of human cancer. However, the mechanisms underlying the regulatory role of MEIS2 in CRC metastasis remain largely unknown. For the first time, the present study demonstrated that MEIS2 serves a role as a promoter of metastasis in CRC. In vivo and in vitro experiments revealed that knockdown of ...[more]

PMID: 31115559

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Project description:BackgroundMetastasis is the major cause of cancer-related death. Forkhead Box M1 (FoxM1) is a master regulator of tumor metastasis. This study aims to identify new FoxM1 targets in regulating tumor metastasis using bioinformatics tools as well as biological experiments.MethodsIllumina microarray was used to profile WT and PTTG1 knockout HCT116 cells. R2 Genomics Analysis was used to identify PTTG1 as a potential FoxM1 targeted gene. Luciferase reporter array, EMSA and Chromatin Immunoprecipitation (ChIP) were used to determine the binding of FoxM1 to PTTG1 promoter. Boyden chamber assay was used to evaluate the effects of FoxM1-PTTG1 on cell migration and invasion. Splenic-injection induced liver metastasis model was used to evaluate the effects of FoxM1-PTTG1 on liver metastasis of colorectal cancer.ResultsAnalyses of multiple microarray datasets derived from human colorectal cancer indicated that correlation levels of FoxM1 and pituitary tumor transforming gene (PTTG1) are highly concordant (R = 0.68 ~ 0.89, p = 2.1E-226 ~ 9.6E-86). FoxM1 over-expression increased and knock-down decreased PTTG1 expression. Luciferase reporter assay identified that the -600 to -300 bp region of PTTG1 promoter is important for FoxM1 to enhance PTTG1 promoter activity. EMSA and ChIP assays confirmed that FoxM1 directly binds to PTTG1 promoter at the -391 to -385 bp region in colorectal cancer cells. Boyden chamber assay indicated that both FoxM1 and PTTG1 regulate migration and invasion of HCT116 and SW620 colorectal cancer cells. Further in vivo assays indicated that PTTG1 knock out decreased the liver metastasis of FoxM1 over-expressing HCT116 cells. Microarray analyses identified 662 genes (FDR < 0.05) differentially expressed between WT and PTTG1(-/-) HCT116 cells. Among them, dickkopf homolog 1 (DKK1), a known WNT pathway inhibitor, was suppressed by PTTG1 and FoxM1.ConclusionsPTTG1 is a FoxM1 targeted gene. FoxM1 binds to PTTG1 promoter to enhance PTTG1 transcription, and FoxM1-PTTG1 pathway promotes colorectal cancer migration and invasion.

Project description:BackgroundHypoxic microenvironments play a significant role in the progression of colorectal cancer (CRC). Silencing information regulator 1 (SIRT1), a class III histone deacetylase, modulates the multiple biological behaviors of cancer. However, its role in CRC remains unclear. This study aims to explore the role of SIRT1 in CRC migration and invasion under hypoxia.MethodsSIRT1 protein and mRNA levels were detected by Western blotting and real-time PCR in CRC cells exposed to hypoxia (1% O2). The migration and invasion abilities of SW480 and HCT116 cells with SIRT1 overexpression or knockdown were studied with transwell assays, and the results were confirmed by those of treatment with specific SIRT1 activator (SRT1720) and inhibitor (EX527). The dual-luciferase reporter systems with a series of SIRT1 promoter truncations were used to analyze their transcriptional activities, respectively. After a bioinformatic analysis of potential transcription factors, the direct interaction between the transcription factor and SIRT1 promoter was determined by chromatin immunoprecipitation (ChIP) assays. Western blot and real-time PCR assays were used to detect the activation and acetylation levels of the NF-κB pathway.ResultsThe protein and mRNA levels of SIRT1 were significantly decreased under hypoxia, and these effects were replicated by cobalt chloride treatment. Hypoxia promoted cell migration and invasion, which were impeded by the overexpression or activation of SIRT1 and promoted by the knockdown or inhibition of SIRT1. The dual-luciferase reporter gene and ChIP analyses revealed that the core regulatory elements located 100 bp upstream of the SIRT1 promoter and early growth response factor 1 (EGR1) could interact with this DNA sequence. Subsequent rescue experiments suggested that EGR1 was essential for hypoxia-mediated SIRT1 transcriptional suppression. Western blot analyses demonstrated that SIRT1 overexpression eliminated the p65 acetylation induced by hypoxia along with the decreased MMP-2/-9, suggesting that NF-κB was a direct downstream target of SIRT1 and might regulate cell migration and invasion through MMP-2/-9.ConclusionsOur results establish for the first time that EGR1 plays an important role in regulating SIRT1 expression under hypoxia. Hypoxia promotes CRC cell migration and invasion in a SIRT1-dependent manner. And a potential SIRT1/NF-κB/MMP-2/-9 axis modulates this process.

Dataset Information

MEIS2 promotes cell migration and invasion in colorectal cancer.

Publications

MEIS2 promotes cell migration and invasion in colorectal cancer.

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