Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer

// Gianluigi Mazzoccoli 1 , Tommaso Colangelo 2, * , Anna Panza 3, * , Rosa Rubino 1, * , Cristiana Tiberio 1 , Orazio Palumbo 4 , Massimo Carella 4 , Domenico Trombetta 5 , Annamaria Gentile 3 , Francesca Tavano 3 , Maria Rosa Valvano 3 , Clelia Tiziana Storlazzi 6 , Gemma Macchia 6 , Angelo De Cata 1 , Giovanni Bisceglia 7 , Daniele Capocefalo 8, * , Vittorio Colantuoni 2, # , Lina Sabatino 2, # , Ada Piepoli 9, # , Tommaso Mazza 8 1 Division of Internal Medicine and Chronobiology Unit, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy 2 Department of Sciences and Technologies, University of Sannio, Benevento, Italy 3 Division of Gastroenterology and Research Laboratory, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy 4 Medical Genetics Service, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy 5 Oncology-Research Laboratory, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy 6 Department of Biology, University of Bari, Bari, Italy 7 Department of Surgical Sciences, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy 8 Bioinformatics Unit, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy 9 Division 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 Correspondence to: Gianluigi Mazzoccoli, email: g.mazzoccoli@operapadrepio.it Tommaso Mazza, email: t.mazza@css-mendel.it Keywords: miRNA-mRNA, clock genes, circadian, colorectal cancer Received: April 29, 2016      Accepted: May 29, 2016      Published: June 14, 2016 ABSTRACT 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.