ENTPD7
Ectonucleoside triphosphate diphosphohydrolase 7 (EC 3.6.1.15) (NTPDase 7) (Lysosomal apyrase-like protein 1) [LALP1]
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The aim of this study was to investigate the effects and mechanisms of ectonucleoside triphosphate phosphohydrolase-7 (ENTPD7) on lung cancer cells. The expression characteristics of ENTPD7 and its effect on the survival of lung cancer patients were analyzed by referring to The Cancer Genome Atlas (TCGA). Streptavidin-peroxidase (SP) staining was performed to detect the ENTPD7 protein in tumor tissues and adjacent tissues. Plasmid transfection technology was also applied to silence ENTPD7 gene. Crystal violet staining and flow cytometry were performed to determine cell proliferation and apoptosis. Tumor-bearing nude mice model was established to investigate the effect of sh-ENTPD7 on tumors. The results showed that patients with low levels of ENTPD7 had higher survival rates. ENTPD7 was up-regulated in lung cancer tissues and cells. Down-regulation of the expression of ENTPD7 inhibited proliferation but promoted apoptosis of lung cancer cell. Silencing ENTPD7 also inhibited the expression levels of Ras and Raf proteins and the phosphorylation of mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK). Tumor-bearing nude mice experiments showed that silencing ENTPD7 had an inhibitory effect on lung cancer cells. ENTPD7 was overexpressed in lung cancer cells. Down-regulating ENTPD7 could inhibit lung cancer cell proliferation and promote apoptosis via inhibiting the Ras/Raf/MEK/ERK pathway.
MeSH Terms
- Adult
- Aged
- Animals
- Apoptosis
- Apyrase
- Biomarkers
- Cell Line, Tumor
- Cell Proliferation
- Cells, Cultured
- Female
- Gene Expression Regulation, Neoplastic
- Gene Silencing
- Humans
- Lung Neoplasms
- MAP Kinase Signaling System
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- Mitogen-Activated Protein Kinases
- Plasmids
- Signal Transduction
- Survival Analysis
- raf Kinases
- ras Proteins
Keywords
- Ectonucleoside triphosphate phosphohydrolase-7
- Lung cancer
- Proliferation
- Senescence
Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16 and p21 transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers.
MeSH Terms
- Animals
- Apyrase
- Carcinoma, Hepatocellular
- Cell Line
- Cell Line, Tumor
- Cellular Senescence
- DNA-Binding Proteins
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Liver Neoplasms
- Male
- Mice
- Mice, Inbred C57BL
- Mutation
- RNA, Small Interfering
- Transcription Factors
Keywords
- ARID1B
- ENTPD7
- SWI/SNF
- cancer
- dNTP metabolism
- p53
- senescence