Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer.
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.
Division of Internal Medicine and Chronobiology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Gianluigi
G
Mazzoccoli
Department of Sciences and Technologies, University of Sannio, Benevento, Italy.
Tommaso
T
Colangelo
Division of Gastroenterology and Research Laboratory, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Anna
A
Panza
Division of Internal Medicine and Chronobiology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Rosa
R
Rubino
Division of Internal Medicine and Chronobiology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Cristiana
C
Tiberio
Medical Genetics Service, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Orazio
O
Palumbo
Medical Genetics Service, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Massimo
M
Carella
Oncology-Research Laboratory, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Domenico
D
Trombetta
Division of Gastroenterology and Research Laboratory, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Annamaria
A
Gentile
Division of Gastroenterology and Research Laboratory, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Francesca
F
Tavano
Division of Gastroenterology and Research Laboratory, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Maria Rosa
MR
Valvano
Department of Biology, University of Bari, Bari, Italy.
Clelia Tiziana
CT
Storlazzi
Department of Biology, University of Bari, Bari, Italy.
Gemma
G
Macchia
Division of Internal Medicine and Chronobiology Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Angelo
A
De Cata
Department of Surgical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Giovanni
G
Bisceglia
Bioinformatics Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Daniele
D
Capocefalo
Department of Sciences and Technologies, University of Sannio, Benevento, Italy.
Vittorio
V
Colantuoni
Department of Sciences and Technologies, University of Sannio, Benevento, Italy.
Lina
L
Sabatino
Division of Epidemiology and Health Statistics, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Ada
A
Piepoli
Bioinformatics Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
Tommaso
T
Mazza
D000368:Aged; D000369:Aged, 80 and over; D056926:CLOCK Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D059467:Transcriptome
D035683:MicroRNAs; D056926:CLOCK Proteins
circadian; clock genes; colorectal cancer; miRNA-mRNA