Circular RNA ciRS-7 — A promising prognostic biomarker and a potential therapeutic target in colorectal cancer

Wenhao Weng, Qing Wei, Shusuke Toden, Kazuhiro Yoshida, Takeshi Nagasaka, Toshiyoshi Fujiwara, Sanjun Cai, Huanlong Qin, Yanlei Ma, Ajay Goel

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Purpose: Colorectal cancer is one of themost 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.

Original languageEnglish
Pages (from-to)3918-3928
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
Publication statusPublished - Jul 15 2017

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Colorectal Neoplasms
Biomarkers
Therapeutics
Mucous Membrane
HCT116 Cells
erbB-1 Genes
HT29 Cells
Survival
Porifera
Survival Analysis
circular RNA
Oncogenes
Neoplasms
Research Design
Multivariate Analysis
Animal Models
Phenotype
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Circular RNA ciRS-7 — A promising prognostic biomarker and a potential therapeutic target in colorectal cancer. / Weng, Wenhao; Wei, Qing; Toden, Shusuke; Yoshida, Kazuhiro; Nagasaka, Takeshi; Fujiwara, Toshiyoshi; Cai, Sanjun; Qin, Huanlong; Ma, Yanlei; Goel, Ajay.

In: Clinical Cancer Research, Vol. 23, No. 14, 15.07.2017, p. 3918-3928.

Research output: Contribution to journalArticle

Weng, Wenhao ; Wei, Qing ; Toden, Shusuke ; Yoshida, Kazuhiro ; Nagasaka, Takeshi ; Fujiwara, Toshiyoshi ; Cai, Sanjun ; Qin, Huanlong ; Ma, Yanlei ; Goel, Ajay. / Circular RNA ciRS-7 — A promising prognostic biomarker and a potential therapeutic target in colorectal cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 14. pp. 3918-3928.
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T1 - Circular RNA ciRS-7 — A promising prognostic biomarker and a potential therapeutic target in colorectal cancer

AU - Weng, Wenhao

AU - Wei, Qing

AU - Toden, Shusuke

AU - Yoshida, Kazuhiro

AU - Nagasaka, Takeshi

AU - Fujiwara, Toshiyoshi

AU - Cai, Sanjun

AU - Qin, Huanlong

AU - Ma, Yanlei

AU - Goel, Ajay

PY - 2017/7/15

Y1 - 2017/7/15

N2 - Purpose: Colorectal cancer is one of themost 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.

AB - Purpose: Colorectal cancer is one of themost 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.

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