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TUSC3: a novel tumour suppressor gene and its functional implications.

ABSTRACT: The tumour suppressor candidate 3 (TUSC3) gene is located on chromosome region 8p22 and encodes the 34 kD TUSC3 protein, which is a subunit of the oligosaccharyl transferase responsible for the N-glycosylation of nascent proteins. Known to be related to autosomal recessive mental retardation for several years, TUSC3 has only recently been identified as a potential tumour suppressor gene. Based on the structure and function of TUSC3, specific mechanisms in various diseases have been investigated. Several studies have demonstrated that TUSC3 is an Mg2+ -transporter involved in magnesium transport and homeostasis, which is important for learning and memory, embryonic development and testis maturation. Moreover, dysfunction or deletion of TUSC3 exerts its oncological effects as a modulator by inhibiting glycosylation efficiency and consequently inducing endoplasmic reticulum stress and malignant cell transformation. In this study, we summarize the advances in the studies of TUSC3 and comment on the potential roles of TUSC3 in diagnosis and treatment of TUSC3-related diseases, especially cancer.

SUBMITTER: Yu X

PROVIDER: S-EPMC5571513 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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TUSC3: a novel tumour suppressor gene and its functional implications.

Yu Xinshuang X Zhai Chunjuan C Fan Yujun Y Zhang Jiandong J Liang Ning N Liu Fengjun F Cao Lili L Wang Jia J Du Juan J

Journal of cellular and molecular medicine 20170308 9

The tumour suppressor candidate 3 (TUSC3) gene is located on chromosome region 8p22 and encodes the 34 kD TUSC3 protein, which is a subunit of the oligosaccharyl transferase responsible for the N-glycosylation of nascent proteins. Known to be related to autosomal recessive mental retardation for several years, TUSC3 has only recently been identified as a potential tumour suppressor gene. Based on the structure and function of TUSC3, specific mechanisms in various diseases have been investigated. ...[more]

PMID: 28272772

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Project description:BackgroundMicroRNA-7 (miR-7) has been reported to be a tumour suppressor gene. However, whether it has a role in the growth of non-small-cell lung cancer (NSCLC) and what is its target involved in the tumour growth is still under investigation.MethodsNSCLC tissue sample, NSCLC cell lines and tissue microarray were investigated in this study. Total RNA, miRNA and protein were used for RT-PCR and western blot analysis. Immunohistochemistry was performed in tissues microarray. Cell culture and intervention experiments were performed in vitro and in vivo. Bioinformatics prediction, western blot and luciferase assay were identified the target of miR-7.ResultsIn this study, we found that the expression of miR-7 was significantly downregulated not only in NSCLC cell lines, but also in human NSCLC tissues compared with the matched adjacent tissues. Restoration of its expression through miR-7 mimics in A549 and H1299 NSCLC cells inhibited cell proliferation, colony formation, and cell-cycle progression in vitro. More importantly, the tumorigenicity in nude mice was reduced after administration of miR-7 in vivo. In advance, through bioinformatic analysis, luciferase assay and western blot, we identified a novel target of miR-7, PA28gamma (a proteasome activator) to be enrolled in the regulation with tumour. PA28gamma mRNA and protein levels are markedly upregulated in NSCLC cell lines and tumour samples, exhibiting a strong inverse relation with that of miR-7. In addition, knockdown of PA28gamma induced similar effects as overexpression of miR-7 in NSCLC cells. Furthermore, miR-7 overexpression or silencing of PA28gamma reduced the cyclinD1 expression at mRNA and protein level in NSCLC cell lines.ConclusionAll these findings strongly imply that the overexpression of PA28gamma resulted from miR-7 downexpression in NSCLC has an important role in promoting cancer cell progress and consequently results in NSCLC growth. Thus, strategies targeting PA28gamma and/or miR-7 may become promising molecular therapies in NSCLC treatment.

Project description:We report that the odd-skipped related 1 (OSR1) gene encoding a zinc-finger transcription factor was preferentially methylated in gastric cancer by genome-wide methylation screening. OSR1 expression was frequently silenced or down-regulated in gastric cancer cell lines. OSR1 expression was also significantly down-regulated at both mRNA and protein levels in primary gastric cancer tissues compared with adjacent normal tissues. The silencing or down-regulation of OSR1 was closely associated with promoter hypermethylation. Overexpression of OSR1 significantly inhibited cell growth, arrested the cell cycle, and induced apoptosis in the gastric cancer cell lines AGS, MKN28, and MGC803. Conversely, knockdown of OSR1 by OSR1-short hairpin RNA significantly enhanced cell growth, promoted the cell cycle, and inhibited apoptosis in the normal gastric epithelial cell line GES1. The dual-luciferase reporter assay revealed that OSR1 activated p53 transcription and repressed the T-cell factor (TCF)/lymphoid enhancer factor (LEF). Complementary DNA expression array and western blotting showed that OSR1 increased the expression of nuclear p53, p21, Fas, and death receptor-5, and suppressed the expression of cyclin D1 and cyclin-dependent kinase 4 in the p53 signalling pathway. In addition, OSR1 suppressed the expression of cytoplasmic β-catenin, TCF-1, and LEF1 in the Wnt/β-catenin signalling pathway. OSR1 methylation was detected in 51.8% of primary gastric cancer patients (85 of 164) by bisulphite genomic sequencing. Multivariate Cox regression analysis showed that OSR1 methylation was an independent predictor of poor survival. Kaplan-Meier survival curves revealed that OSR1 methylation was associated with shortened survival in TNM stage I-III patients. In conclusion, OSR1 acts as a functional tumour suppressor through the transcriptional activation of p53 and repression of TCF/LEF in gastric cancer. Detection of OSR1 methylation may serve as a potential biomarker of the early stage of gastric cancer.

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TUSC3: a novel tumour suppressor gene and its functional implications.

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TUSC3: a novel tumour suppressor gene and its functional implications.

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