Abstract
Gene coexpression patterns can reveal gene collections with functional consistency. This study systematically constructs regulatory networks for pituitary tumours by integrating gene coexpression, transcriptional and posttranscriptional regulation. Through network analysis, we elaborate the incidence mechanism of pituitary adenoma. The Pearson’s correlation coefficient was utilized to calculate the level of gene coexpression. By comparing pituitary adenoma samples with normal samples, pituitary adenoma-specific gene coexpression patterns were identified. For pituitary adenoma-specific coexpressed genes, we integrated transcription factor (TF) and microRNA (miRNA) regulation to construct a complex regulatory network from the transcriptional and posttranscriptional perspectives. Network module analysis identified the synergistic regulation of genes by miRNAs and TFs in pituitary adenoma. We identified 142 pituitary adenoma-specific active genes, including 43 TFs and 99 target genes of TFs. Functional enrichment of these 142 genes revealed that the occurrence of pituitary adenoma induced abnormalities in intracellular metabolism and angiogenesis process. These 142 genes were also significantly enriched in adenoma pathway. Module analysis of the systematic regulatory network found that three modules contained elements that were closely related to pituitary adenoma, such as FGF2 and SP1, as well as transcription factors and miRNAs involved in the tumourigenesis. These results show that in the occurrence of pituitary adenoma, miRNA, TF and genes interact with each other. Based on gene expression, the proposed method integrates interaction information from different levels and systematically explains the occurrence of pituitary tumours. It facilitates the tracing of the origin of the disease and can provide basis for early diagnosis of complex diseases or cancer without obvious symptoms.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bottoni A., Zatelli M. C., Ferracin M., Tagliati F., Piccin D., Vignali C. et al. 2007 Identification of differentially expressed microRNAs by microarray: a possible role for microRNA genes in pituitary adenomas. J. Cell Physiol. 210, 370–377.
Care A., Felicetti F., Meccia E., Bottero L., Parenza M., Stoppacciaro A. et al. 2001 HOXB7: a key factor for tumor-associated angiogenic switch. Cancer Res. 61, 6532–6539.
Chen C. H., Xiao W. W., Jiang X. B., Wang J. W., Mao Z. G., Lei N. et al. 2013 A novel marine drug, SZ-685C, induces apoptosis of MMQ pituitary tumor cells by downregulating miR-200c. Curr. Med. Chem. 20, 2145–2154.
Chen H., Lee J. S., Liang X., Zhang H., Zhu T., Zhang Z. et al. 2008 Hoxb7 inhibits transgenic HER-2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis. Cancer Res. 68, 3637–3644.
D’Angelo D., Palmieri D., Mussnich P., Roche M., Wierinckx A., Raverot G. et al. 2012 Altered microRNA expression profile in human pituitary GH adenomas: down-regulation of miRNA targeting HMGA1, HMGA2, and E2F1. J. Clin. Endocrinol. Metab. 97, 1128–1138.
De Souza Setubal Destro M. F., Bitu C. C., Zecchin K. G., Graner E., Lopes M. A., Kowalski L. P. and Coletta R. D. 2010 Overexpression of HOXB7 homeobox gene in oral cancer induces cellular proliferation and is associated with poor prognosis. Int. J. Oncol. 36, 141–149.
Deng H., Guo Y., Song H., Xiao B., Sun W., Liu Z. et al. 2013 MicroRNA-195 and microRNA-378 mediate tumor growth suppression by epigenetical regulation in gastric cancer. Gene 518, 351–359.
Heaney A. P., Horwitz G. A., Wang Z., Singson R. and Melmed S. 1999 Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nat. Med. 5, 1317–1321.
Hiyama H., Kubo O., Kawamata T., Ishizaki R. and Hori T. 2002 Expression of cyclin kinase inhibitor p21/WAF1 protein in pituitary adenomas: correlations with endocrine activity, but not cell proliferation. Acta Neurochir. (Wien) 144, 481–488.
Hofland L. J., Feelders R. A., de Herder W. W. and Lamberts S. W. 2010 Pituitary tumours: the sst/D2 receptors as molecular targets. Mol. Cell Endocrinol. 326, 89–98.
Hou X. Z., Liu W., Fan H. T., Liu B., Pang B., Xin T. et al. 2010 Expression of hepatocyte growth factor and its receptor c-Met in human pituitary adenomas. Neuro. Oncol. 12, 799–803.
Jares P., Fernandez P. L., Campo E., Nadal A., Bosch F., Aiza G. et al. 1994 PRAD-1/cyclin D1 gene amplification correlates with messenger RNA overexpression and tumor progression in human laryngeal carcinomas. Cancer Res. 54, 4813–4817.
Kim K., Yoshida D. and Teramoto A. 2005 Expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor in pituitary adenomas. Endocr. Pathol. 16, 115–121.
Ko K. S., Peng H., Tang H., Cho M. G., Peng J., Aller M.-A. and Yang H. 2012 Recent advances of miRNA involvement in hepatocellular carcinoma and cholangiocarcinoma. J. Int. Med. 2, 135–162.
Kondo N., Toyama T., Sugiura H., Fujii Y. and Yamashita H. 2008 miR-206 expression is down-regulated in estrogen receptor alpha-positive human breast cancer. Cancer Res. 68, 5004–5008.
Leone V., D’Angelo D., Rubio I., de Freitas P. M., Federico A., Colamaio M. et al. 2011 miR-1 is a tumor suppressor in thyroid carcinogenesis targeting CCND2, CXCR4, and SDF-1 alpha. J. Clin. Endocrinol. Metab. 96, E1388–E1398.
Liu L., Chen L., Xu Y., Li R. and Du X. 2010 microRNA-195 promotes apoptosis and suppresses tumorigenicity of human colorectal cancer cells. Biochem. Biophys. Res. Commun. 400, 236–240.
Lubensky I. A., Debelenko L. V., Zhuang Z., Emmert-Buck M. R., Dong Q., Chandrasekharappa S. et al. 1996 Allelic deletions on chromosome 11q13 in multiple tumors from individual MEN1 patients. Cancer Res. 56, 5272–5278.
McCabe C. J., Khaira J. S., Boelaert K., Heaney A. P., Tannahill L. A., Hussain S. et al. 2003 Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour. Clin. Endocrinol. (Oxf) 58, 141–150.
Mizokami Y., Egashira N., Takekoshi S., Itoh J., Itoh Y., Osamura R. Y. and Matsumae M., 2008 Expression of MSX1 in human normal pituitaries and pituitary adenomas. Endocr. Pathol. 19, 54–61.
Mlika M., Azouz H., Chelly I., Said I. B., Jemel H., Haouet S. et al. 2011 Spindle cell oncocytoma of the adenohypophysis in a woman: a case report and review of the literature. J. Med. Case Rep. 5, 64.
Nishioka H., Tamura K., Iida H., Kutsukake M., Endo A., Ikeda Y. and Haraoka J. 2011 Co-expression of somatostatin receptor subtypes and estrogen receptor-alpha mRNAs by non-functioning pituitary adenomas in young patients. Mol. Cell Endocrinol. 331, 73–78.
Phan D., Cheng C. J., Galfione M., Vakar-Lopez F., Tunstead J., Thompson N. E. et al. 2004 Identification of Sp2 as a transcriptional repressor of carcinoembryonic antigen-related cell adhesion molecule 1 in tumorigenesis. Cancer Res. 64, 3072–3078.
Shan B., Gerez J., Haedo M., Fuertes M., Theodoropoulou M., Buchfelder M. et al. 2012 RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells. Endocr. Relat. Cancer 19, 13–27.
Shi X., Tao B., He H., Sun Q., Fan C., Bian L. et al. 2012 MicroRNAs-based network: a novel therapeutic agent in pituitary adenoma. Med. Hypotheses 78, 380–384.
Tfelt-Hansen J., Kanuparthi D. and Chattopadhyay N. 2006 The emerging role of pituitary tumor transforming gene in tumorigenesis. Clin. Med. Res. 4, 130–137.
Tong Y., Tan Y., Zhou C. and Melmed S. 2007 Pituitary tumor transforming gene interacts with Sp1 to modulate G1/S cell phase transition. Oncogene 26, 5596–5605.
Trivellin G., Butz H., Delhove J., Igreja S., Chahal H. S., Zivkovic V. et al. 2012 MicroRNA miR-107 is overexpressed in pituitary adenomas and inhibits the expression of aryl hydrocarbon receptor-interacting protein in vitro. Am. J. Physiol. Endocrinol. Metab. 303, 708–719.
Vender J. R., Laird M. D. and Dhandapani K. M. 2008 Inhibition of NFkappaB reduces cellular viability in GH3 pituitary adenoma cells. Neurosurgery 62, 1122–1127; discussion 1027–1028.
Vierimaa O., Georgitsi M., Lehtonen R., Vahteristo P., Kokko A., Raitila A. et al. 2006 Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312, 1228–1230.
Wang X., Southard R. C., Allred C. D., Talbert D. R., Wilson M. E. and Kilgore M. W. 2008 MAZ drives tumor-specific expression of PPAR gamma 1 in breast cancer cells. Breast Cancer Res. Treat. 111, 103–111.
Wu T., Li Y., Gong L., Lu J. G., Du X. L., Zhang W. D. et al. 2012 Multi-step process of human breast carcinogenesis: a role for BRCA1, BECN1, CCND1, PTEN and UVRAG. Mol. Med. Rep. 5, 305–312.
Yamasaki T., Yoshino H., Enokida H., Hidaka H., Chiyomaru T., Nohata N. et al. 2012 Novel molecular targets regulated by tumor suppressors microRNA-1 and microRNA-133a in bladder cancer. Int. J. Oncol. 40, 1821–1830.
Zhou C., Wawrowsky K., Bannykh S., Gutman S. and Melmed, S. 2009 E2F1 induces pituitary tumor transforming gene (PTTG1) expression in human pituitary tumors. Mol. Endocrinol. 23, 2000–2012.
Author information
Authors and Affiliations
Corresponding author
Additional information
[Gong J., Diao B., Yao G. J., Liu Y. and Xu G. J. 2013 Analysis of regulatory networks constructed based on gene coexpression in pituitary adenoma. J. Genet. 92, xx–xx]
Jie Gong and Bo Diao contributed equally to this work
Rights and permissions
About this article
Cite this article
GONG, J., DIAO, B., YAO, G.J. et al. Analysis of regulatory networks constructed based on gene coexpression in pituitary adenoma . J Genet 92, 489–497 (2013). https://doi.org/10.1007/s12041-013-0299-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12041-013-0299-y