Circular RNA ciRS-7-A Promising Prognostic Biomarker and a Potential Therapeutic Target in Colorectal Cancer.
Purpose:Colorectal cancer is one of the most common malignancies worldwide. Recently, a novel circular RNA, ciRS-7, was proposed to be a potential miR-7 sponge. As miR-7, a putative tumor-suppressor, regulates the expression of several important drivers of colorectal cancer, we analyzed the clinical significance of ciRS-7 in colorectal cancer patients.Experimental Design:Initially, we evaluated the expression levels of ciRS-7 in a training cohort comprising of 153 primary colorectal cancer tissues and 44 matched normal mucosae. We subsequently confirmed its clinical relevance in an independent validation cohort (n= 165), and evaluated the effect of ciRS-7 on miR-7, and its target genes EGFR and RAF1. Functional analyses were performed in cell lines and an animal model to support clinical findings.Results:Our data revealed that ciRS-7 was significantly upregulated in colorectal cancer tissues compared with matched normal mucosae (P= 0.0018), and its overexpression was associated with poor patient survival (P= 0.0224 and 0.0061 in the training and validation cohorts, respectively). Multivariate survival analysis revealed that ciRS-7 emerged as an independent risk factor for overall survival (P= 0.0656 and 0.0324 in the training and validation cohorts, respectively). Overexpression of ciRS-7 in HCT116 and HT29 cells led to the blocking of miR-7 and resulted in a more aggressive oncogenic phenotype, and ciRS-7 overexpression permitted the inhibition of miR-7 and subsequent activation of EGFR and RAF1 oncogenes.Conclusions:CiRS-7 is a promising prognostic biomarker in colorectal cancer patients and may serve as a therapeutic target for reducing EGFR-RAF1 activity in colorectal cancer patients.Clin Cancer Res; 23(14); 3918-28. ©2017 AACR.
Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.|Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
Wenhao
W
Weng
Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
Qing
Q
Wei
Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
Shusuke
S
Toden
Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
Kazuhiro
K
Yoshida
Department of Gastroenterological Surgery and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Takeshi
T
Nagasaka
Department of Gastroenterological Surgery and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Toshiyoshi
T
Fujiwara
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Sanjun
S
Cai
Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China.
Huanlong
H
Qin
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Ajay.Goel@BSWHealth.org yanleima@fudan.edu.cn.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Yanlei
Y
Ma
Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas. Ajay.Goel@BSWHealth.org yanleima@fudan.edu.cn.
Ajay
A
Goel
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D000073888:Cell-Free Nucleic Acids / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*
D014408:Biomarkers, Tumor; D000073888:Cell-Free Nucleic Acids; D066246:ErbB Receptors; D035683:MicroRNAs; D019908:Proto-Oncogene Proteins c-raf; C549242:MIRN7-1 microRNA, human; C512478:EGFR protein, human