ABSTRACT
Despite recent advances in cancer management, colorectal cancer (CRC) remains the third most common cancer and a major health-care problem worldwide. MicroRNAs have recently emerged as key regulators of cancer development and progression by targeting multiple cancer-related genes; however, such regulatory networks are not well characterized in CRC. Thus, the aim of this study was to perform global messenger RNA (mRNA) and microRNA expression profiling in the same CRC samples and adjacent normal tissues and to identify potential miRNA-mRNA regulatory networks. Our data revealed 1273 significantly upregulated and 1902 downregulated genes in CRC. Pathway analysis revealed significant enrichment in cell cycle, integrated cancer, Wnt (wingless-type MMTV integration site family member), matrix metalloproteinase, and TGF-ß pathways in CRC. Pharmacological inhibition of Wnt (using XAV939 or IWP-2) or TGF-ß (using SB-431542) pathways led to dose- and time-dependent inhibition of CRC cell growth. Similarly, our data revealed up- (42) and downregulated (61) microRNAs in the same matched samples. Using target prediction and bioinformatics, ~77% of the upregulated genes were predicted to be targeted by microRNAs found to be downregulated in CRC. We subsequently focused on EZH2 (enhancer of zeste homolog 2 ), which was found to be regulated by hsa-miR-26a-5p and several members of the let-7 (lethal-7) family in CRC. Significant inverse correlation between EZH2 and hsa-miR-26a-5p (R(2)=0.56, P=0.0001) and hsa-let-7b-5p (R(2)=0.19, P=0.02) expression was observed in the same samples, corroborating the belief of EZH2 being a bona fide target for these two miRNAs in CRC. Pharmacological inhibition of EZH2 led to significant reduction in trimethylated histone H3 on lysine 27 (H3K27) methylation, marked reduction in cell proliferation, and migration in vitro. Concordantly, small interfering RNA-mediated knockdown of EZH2 led to similar effects on CRC cell growth in vitro. Therefore, our data have revealed several hundred potential miRNA-mRNA regulatory networks in CRC and suggest targeting relevant networks as potential therapeutic strategy for CRC.
Subject(s)
Colorectal Neoplasms/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , MicroRNAs/genetics , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adult , Aged , Base Sequence , Cell Movement/drug effects , Cell Movement/genetics , Cell Proliferation/drug effects , Cell Survival/drug effects , Colorectal Neoplasms/pathology , Enhancer of Zeste Homolog 2 Protein , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Regulatory Networks/drug effects , Genome, Human , Humans , Male , MicroRNAs/metabolism , Middle Aged , Molecular Sequence Data , Polycomb Repressive Complex 2/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
AIM: The safety and efficacy of laparoscopic surgery for colon cancer have been demonstrated in large, multicentre clinical trials. The study aimed to determine the use of laparoscopic surgery for rectal cancer in Ontario over a 7-year period. METHOD: We conducted a retrospective study examining rates of elective rectal cancer surgery among 10.5 million adults in Ontario, Canada, from 1 April 2002 to 31 March 2009. We linked the Canadian Institute for Health Information Discharge Abstract Database, the Registered Persons Database and the database of the Ontario Cancer Registry to assess procedures used over the period. Data on demographics were collected. Trends were assessed using time series analysis. RESULTS: Over the 7-year period, 8189 open and 1079 laparoscopic elective operations for rectal cancer were identified. The annual rate of laparoscopic rectal cancer procedures increased from 0.60 per 100,000 population in 2003 to 2.24 per 100,000 population in 2008 (P < 0.01). Laparoscopic patients were similar to open with respect to age (66.5 ± 11.8 vs 66.2 ± 12.1 years; standardized difference 0.02), gender (63.2%vs 59.4%; standardized difference 0.08), Charlson Comorbidity Index score (standardized difference < 0.1) and socioeconomic status (standardized difference < 0.1). CONCLUSION: Laparoscopic rectal cancer surgery rates are increasing in Ontario. Ongoing research regarding the long-term safety and effectiveness of the laparoscopic approach for rectal cancer surgeries may lead to greater increases in its utilization.
