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Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer
  1. Chenzhang Shi1,
  2. Yongzhi Yang1,
  3. Yang Xia2,
  4. Yoshinaga Okugawa3,
  5. Jun Yang2,
  6. Yong Liang2,
  7. Hongqi Chen2,
  8. Peng Zhang1,
  9. Feng Wang1,
  10. Huazhong Han2,
  11. Wen Wu1,
  12. Renyuan Gao1,
  13. Christoph Gasche4,
  14. Huanlong Qin1,
  15. Yanlei Ma1,
  16. Ajay Goel3
  1. 1Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
  2. 2Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  3. 3Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
  4. 4Division of Gastroenterology and Hepatology, Department of Medicine 4, Medical University Vienna, Vienna, Austria
  1. Correspondence to Huanlong Qin and Yanlei Ma, Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, 301 Yanchang Road, Shanghai 200072, China; hl-qin{at}hotmail.com and yanleima{at}live.cn Ajay Goel, Gastrointestinal Cancer Research Laboratory, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA; ajay.goel@baylorhealth.edu

Abstract

Objective miR-21 was found to be overexpressed in the colon tissues and serum of patients with UC and colorectal cancer (CRC); however, the exact roles of miR-21 in colitis-associated CRC remain unclear. The aim of our study was to investigate the biological mechanisms of miR-21 in colitis-associated colon cancer (CAC).

Design miR-21 expression was examined in the tumours of 62 patients with CRC from China and 37 colitis-associated neoplastic tissues from Japan and Austria. The biological functions of miR-21 were studied using a series of in vitro, in vivo and clinical approaches.

Results miR-21 levels were markedly upregulated in the tumours of 62 patients with CRC, 22 patients with CAC, and in a mouse model of CAC. Following azoxymethane and dextran sulfate sodium intervention, miR-21-knockout mice showed reduced expression of proinflammatory and procarcinogenic cytokines (interleukin (IL) 6, IL-23, IL-17A and IL-21) and a decrease in the size and number of tumours compared with the control mouse group. The absence of miR-21 resulted in the reduced expression of Ki67 and the attenuated proliferation of tumour cells with a simultaneous increase in E-cadherin and decrease in β-catenin and SOX9 in the tumours of CAC mice. Furthermore, the absence of miR-21 increased the expression of its target gene PDCD4 and subsequently modulated nuclear factor (NF)-κB activation. Meanwhile, miR-21 loss reduced STAT3 and Bcl-2 activation, causing an increase in the apoptosis of tumour cells in CAC mice.

Conclusions These observations provide novel evidence for miR-21 blockade to be a key strategy in reducing CAC.

  • CANCER
  • COLORECTAL CANCER

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