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A novel function of IMPA2, plays a tumor-promoting role in cervical cancer.

ABSTRACT: Discovery of genes and molecular mechanism involved in cervical cancer development would promote the prevention and treatment. By comparing gene expression profiles of cervical carcinoma in situ (CCIS) and adjacent normal tissues, we identified a potential cancer-promoting gene, IMPA2. This study aimed to elucidate the role of IMPA2 and underlying molecular mechanisms in cervical cancer progression. To do this expression of IMPA2 was compared between human cervical cancer and corresponding adjacent normal cervical tissues firstly. CCK-8 assay, clone formation assay, wound healing assay, transwell assay, and tumor formation in nude mice were performed to demonstrate the effect of IMPA2 in cervical cancer proliferation and metastasis. Further proteomic profiling and western blotting explored the molecular pathway involved in the IMPA2-regulating process. The results showed that IMPA2 gene expression was upregulated in cervical cancer. Consistently, silencing of IMPA2 suppressed tumor formation in BALB/c nude mice. Short hairpin RNA (shRNA)-mediated IMPA2 silencing significantly inhibited proliferation and colony-forming abilities of cervical cancer cells, while IMPA2 overexpression had little impact. Also, IMPA2 silencing suppressed cellular migration, but overexpression promoted migration. Proteomics analysis revealed the involvement of mitogen-activated protein kinase (MAPK) pathway in tumor-promoting action of IMPA2. Significantly, the inhibition of IMPA2 activated ERK phosphorylation, and its inhibitory effects can be restored by using selective ERK inhibitor, FR180204. In conclusion, IMPA2 acts as an oncogene in the proliferation and migration of cervical cancer. IMPA2 downregulated ERK phosphorylation to promote cervical cancer. These findings identify a new mechanism underlying cervical cancer and suggest a regulating effect of IMPA2 in MAPK signaling pathway.

SUBMITTER: Zhang K

PROVIDER: S-EPMC7224180 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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A novel function of IMPA2, plays a tumor-promoting role in cervical cancer.

Zhang Kan K Liu Lei L Wang Min M Yang Min M Li Xianping X Xia Xiaomeng X Tian Jingjing J Tan Shan S Luo Lingli L

Cell death & disease 20200514 5

Discovery of genes and molecular mechanism involved in cervical cancer development would promote the prevention and treatment. By comparing gene expression profiles of cervical carcinoma in situ (CCIS) and adjacent normal tissues, we identified a potential cancer-promoting gene, IMPA2. This study aimed to elucidate the role of IMPA2 and underlying molecular mechanisms in cervical cancer progression. To do this expression of IMPA2 was compared between human cervical cancer and corresponding adjac ...[more]

PMID: 32409648

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Project description:BackgroundGABPB1, the gene that encodes two isoforms of the beta subunit of GABP, has been identified as an oncogene in multiple malignant tumors. However, the role and mode of action of GABPB1 in malignant tumors, especially in lung cancer, are not well understood and need further research.MethodsOur research focused on examining the biological function of GABPB1 in NSCLC (Non-Small Cell Lung Cancer). We analysed tumor data from public databases to assess the expression of GABPB1 in NSCLC and its correlation with patient prognosis and investigated GABPB1 expression and methylation patterns in relation to the tumor microenvironment. In parallel, experiments were conducted using short hairpin RNA (shRNA) to suppress the GABPB1 gene in human lung cancer cells to evaluate the effects on cell proliferation, viability, and apoptosis.ResultsGABPB1 was widely expressed in various tissues of the human body. Compared to that in normal tissues, the expression of this gene was different in multiple tumor tissues. GABPB1 was highly expressed in lung cancer tissues and cell lines. Its expression was associated with molecular subtype and cellular signalling pathways, and a high level of GABPB1 expression was related to a poor prognosis in lung adenocarcinoma patients. The expression and methylation of GABPB1 affect the tumor microenvironment. After suppressing the expression of GABPB1 in both A549 and H1299 cells, we found a decrease in cell growth and expression, the formation of clones and an increase in the apoptosis rate.ConclusionsOur research verified that GABPB1 promotes the tumorigenesis of NSCLC and has an inhibitory effect on tumor immunity. The specific role of GABPB1 may vary among different pathological types of NSCLC. This molecule can serve as a prognostic indicator for lung adenocarcinoma, and its methylation may represent a potential breakthrough in treatment by altering the tumor immune microenvironment in lung squamous cell carcinoma. The role and mechanism of action of GABPB1 in NSCLC should be further explored.

Project description:BackgroundCervical cancer is a common leading cause of cancer related to women death worldwide. Cylindromatosis (CYLD) is known as an important tumor suppressor in various human cancers, and a deubiquitination enzyme (DUB) as well. Previously, we identified Skp2 as an E3 ligase of Aurora B ubiquitination, but the DUB of Aurora B still remains unknown.MethodsAurora B ubiquitination site is identified through in vivo ubiquitination assay. Activity of Aurora B and CENPA was detected by immunoblotting (IB) and immunofluorescence (IF) assay. Protein-to-protein interaction was investigated by immunoprecipitation (IP). Cell chromosome dynamics was monitored by live-cell time-lapse Imaging. Cancer cell proliferation, colony formation, apoptosis, and cell invasion and migration assays were also performed. Protein level was checked by immunohistochemical (IHC) staining in clinical cervical cancer samples.ResultsWe identified Lysine 115 (K115) as the main Aurora B ubiquitination site for Skp2. We could also detect an interaction of Aurora B with the DUB CYLD. We found that CYLD promoted deubiquitination of Aurora B, and regulated Aurora B activity and function as well. Compared with control, we found it took more time for the cells to finish cell mitosis with CYLD over-expression. Furthermore, we found that CYLD deficiency promoted cervical cancer cell proliferation, colony formation, cell migration and invasion, and inhibited apoptosis instead, whereas it is just opposite with CYLD over-expression. In clinical cervical cancer samples, we showed a negative correlation of CYLD expression with Aurora B activation and histological cancer cell invasion. Furthermore, there was less CYLD abundance and higher Aurora B activity in advanced cancer samples compared with early stage.ConclusionsOur findings uncover CYLD as a novel potential DUB of Aurora B, which inhibits Aurora B activation and its subsequent function in cell mitosis, and also provide more evidence for its tumor suppressor function in cervical cancer.

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A novel function of IMPA2, plays a tumor-promoting role in cervical cancer.

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A novel function of IMPA2, plays a tumor-promoting role in cervical cancer.

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