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An integrative transcriptomic analysis reveals p53 regulated miRNA, mRNA, and lncRNA networks in nasopharyngeal carcinoma

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Tumor Biology

Abstract

It has been reported that p53 dysfunction is closely related to the carcinogenesis of nasopharyngeal carcinoma (NPC). Recently, an increasing body of evidence has indicated that microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) participate in p53-associated signaling pathways and, in addition to mRNAs, form a complex regulation network to promote tumor occurrence and progression. The aim of this study was to elucidate the p53-regulated miRNAs, mRNAs, and lncRNAs and their regulating networks in NPC. Firstly, we overexpressed p53 in the NPC cell line HNE2 and performed transcriptomic gene expression profiling (GEP) analysis, which included miRNAs, mRNAs, and lncRNAs, using microarray technology at 0, 12, 24, and 48 h after transfection. There were 38 miRNAs (33 upregulated and 5 downregulated), 2107 mRNAs (296 upregulated and 1811 downregulated), and 1190 lncRNAs (133 upregulated and 1057 downregulated) that were significantly dysregulated by p53. Some of the dysregulated molecules were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Then, we integrated previously published miRNAs, mRNAs, and lncRNAs GEP datasets from NPC biopsies to investigate the expression of these p53 regulated molecules and found that 7 miRNAs, 218 mRNAs, and 101 lncRNAs regulated by p53 were also differentially expressed in NPC tissues. Finally, p53-regulated miRNA, mRNA, and lncRNA networks were constructed using bioinformatics methods. These miRNAs, mRNAs, and lncRNAs may participate in p53 downstream signaling pathways and play important roles in the carcinogenesis of NPC. Thorough investigations of their biological functions and regulating relationships will provide a novel view of the p53 signaling pathway, and the restoration of p53 functioning or its downstream gene regulating network is potentially of great value in treating NPC patients.

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Acknowledgments

This study was supported in part by grants from the National Natural Science Foundation of China (81172189, 81272298, 81372907, 81301757, 81472531, 81402009, 81572787, and 81528019) and the Natural Science Foundation of Hunan Province (14JJ1010 and 2015JJ1022).

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    1. Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China

      Zhaojian Gong, Zhaoyang Zeng, Pan Chen, Qianjin Liao, Bo Xiang, Ming Zhou, Xiaoling Li, Wei Xiong & Guiyuan Li

    2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China

      Zhaojian Gong, Qian Yang, Zhaoyang Zeng, Wenling Zhang, Bo Xiang, Ming Zhou, Xiaoling Li, Yong Li, Wei Xiong & Guiyuan Li

    3. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China

      Qian Yang, Zhaoyang Zeng, Xiayu Li, Hao Deng, Bo Xiang, Ming Zhou, Xiaoling Li, Wei Xiong & Guiyuan Li

    4. School of Nursing, Hunan Polytechnic of Environment and Biology, Hengyang, Hunan, China

      Qian Yang

    5. Clinical Research Institution, the First Affiliated Hospital, University of South China, Hengyang, Hunan, China

      Xuyu Zu

    6. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

      Yong Li

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    Supplemental Figure S1

    The expression of p53 was validated in HNE2 cells after transfection with TP53 gene plasmid. Real-time-PCR (a) and western blotting (b) were used to detect the mRNA and protein expression levels of p53 in HNE2 cells after transfection with TP53 gene plasmid, respectively. GAPDH was used as the control. (c) The p53 overexpression plasmid pCMV-p53 and luciferase reporter plasmid containing p53 binding sites used for assaying p53 transcriptional activity, the pp53-TA-luc, were cotransfected into HNE2 cells, and transcriptional activity of p53 from 0–48 h post-transfection was determined by luciferase assays. (GIF 42 kb) (GIF 134 kb)

    (TIFF 2451 kb)

    Supplemental Figure S2

    Networks of TP53-regulated genes in NPC cell line HNE2. Ingenuity Pathway Analysis software (IPA) was used to analyze p53 target genes. Four networks were identified. The main network is shown in Fig. 2c. The intensity of a node color indicates the degree of up-regulation (red). The meanings of the node shapes are indicated in the figure. (GIF 235 kb)

    (TIFF 4661 kb)

    Supplemental Figure S3

    Real-time PCR confirms the differentially expressed mRNA regulated by p53 in HNE2 cells. The expression levels of CDKN1A (a) and MDM2 (b) were confirmed in HNE2. The expression level of mRNAs at 0 h after TP53 transfection was used as the control and was normalized. The data are shown as the means of three independent experiments. *. P < 0.05; **, p < 0.01; ***, p < 0.001. (GIF 42 kb)

    (TIFF 601 kb)

    Supplemental Figure S4

    Construction of the miRNAs and their targeted mRNAs networks regulated by p53 through IPA software. Thirty-three up-regulated miRNAs and 1911 down-regulated mRNAs, as well as 5 down-regulated miRNAs and 296 up-regulated mRNAs, identified in p53 transfected HNE2 cells were entered into IPA software, and 2534 potential miRNAs-mRNAs pairs were identified among these differentially expressed miRNAs and mRNAs through the miRNA target screening strategy. The miRNA-mRNA interaction network was constructed by Cytoscape software. (GIF 349 kb)

    (TIFF 5936 kb)

    Supplemental Table S1

    The differentially expressed miRNAs in HNE2 cells after 0, 12, 24, and 48 h of transfection with the p53 expression vector pCMV-p53. (XLS 25 kb)

    Supplemental Table S2

    The differentially expressed mRNAs in HNE2 cells after 0, 12, 24, and 48 h of transfection with the p53 expression vector pCMV-p53 . (XLS 333 kb)

    Supplemental Table S3

    The differentially expressed lncRNAs in HNE2 cells after 0, 12, 24, and 48 h of transfection with the p53 expression vector pCMV-p53. (XLS 197 kb)

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    Gong, Z., Yang, Q., Zeng, Z. et al. An integrative transcriptomic analysis reveals p53 regulated miRNA, mRNA, and lncRNA networks in nasopharyngeal carcinoma. Tumor Biol. 37, 3683–3695 (2016). https://doi.org/10.1007/s13277-015-4156-x

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