Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer
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Gianluigi Mazzoccoli1, Tommaso Colangelo2,*, Anna Panza3,*, Rosa Rubino1,*, Cristiana Tiberio1, Orazio Palumbo4, Massimo Carella4, Domenico Trombetta5, Annamaria Gentile3, Francesca Tavano3, Maria Rosa Valvano3, Clelia Tiziana Storlazzi6, Gemma Macchia6, Angelo De Cata1, Giovanni Bisceglia7, Daniele Capocefalo8,*, Vittorio Colantuoni2,#, Lina Sabatino2,#, Ada Piepoli9,#, Tommaso Mazza8
1Division of Internal Medicine and Chronobiology Unit, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy
2Department of Sciences and Technologies, University of Sannio, Benevento, Italy
3Division of Gastroenterology and Research Laboratory, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy
4Medical Genetics Service, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy
5Oncology-Research Laboratory, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy
6Department of Biology, University of Bari, Bari, Italy
7Department of Surgical Sciences, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy
8Bioinformatics Unit, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy
9Division of Epidemiology and Health Statistics, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy
*These junior authors contributed equally to this work
#These senior authors contributed equally to this work
Gianluigi Mazzoccoli, email: [email protected]
Tommaso Mazza, email: [email protected]
Keywords: miRNA-mRNA, clock genes, circadian, colorectal cancer
Received: April 29, 2016 Accepted: May 29, 2016 Published: June 14, 2016
Altered functioning of the biological clock is involved in cancer onset and progression. MicroRNAs (miRNAs) interact with the clock genes modulating the function of genetically encoded molecular clockworks. Collaborative interactions may take place within the coding-noncoding RNA regulatory networks. We aimed to evaluate the cross-talk among miRNAs and clock genes in colorectal cancer (CRC). We performed an integrative analysis of miRNA-miRNA and miRNA-mRNA interactions on high-throughput molecular profiling of matched human CRC tissue and non-tumor mucosa, pinpointing core clock genes and their targeting miRNAs. Data obtained in silico were validated in CRC patients and human colon cancer cell lines. In silico we found severe alterations of clock gene–related coding-noncoding RNA regulatory networks in tumor tissues, which were later corroborated by the analysis of human CRC specimens and experiments performed in vitro. In conclusion, specific miRNAs target and regulate the transcription/translation of clock genes and clock gene-related miRNA-miRNA as well as mRNA-miRNA interactions are altered in colorectal cancer. Exploration of the interplay between specific miRNAs and genes, which are critically involved in the functioning of the biological clock, provides a better understanding of the importance of the miRNA-clock genes axis and its derangement in colorectal cancer.
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