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MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor
  1. Kar Lok Kong1,2,
  2. Dora Lai Wan Kwong1,2,
  3. Tim Hon-Man Chan1,2,
  4. Simon Ying-Kit Law3,
  5. Leilei Chen1,2,
  6. Yan Li1,2,
  7. Yan-Ru Qin4,
  8. Xin-Yuan Guan1,2,5
  1. 1Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
  2. 2Center for Cancer Research, The University of Hong Kong, Hong Kong, China
  3. 3Department of Surgery, The University of Hong Kong, Hong Kong, China
  4. 4Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
  5. 5State Key Laboratory of Oncology in Southern China, Cancer Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
  1. Correspondence to Xin-Yuan Guan, Department of Clinical Oncology, the University of Hong Kong, Room L10-56, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong, China; xyguan{at}hkucc.hku.hk

Abstract

Background To understand the involvement of micro-RNA (miRNA) in the development and progression of oesophageal squamous cell carcinoma (ESCC), miRNA profiles were compared between tumour and corresponding non-tumour tissues.

Methods miRCURY LNA array was used to generate miRNA expressing profile. Real-time quantitative PCR was applied to detectthe expression of miR-375 in ESCC samples and its correlation with insulin-like growth factor 1 receptor (IGF1R). Methylation-specific PCR was used to study the methylation status in the promoter region of miR-375. The tumour-suppressive effect of miR-375 was determined by both in-vitro and in-vivo assays.

Results The downregulation of miR-375 was frequently detected in primary ESCC, which was significantly correlated with advanced stage (p=0.003), distant metastasis (p<0.0001), poor overall survival (p=0.048) and disease-free survival (p=0.0006). Promoter methylation of miR-375 was detected in 26 of 45 (57.8%) ESCC specimens. Functional assays demonstrated that miR-375 could inhibit clonogenicity, cell motility, cell proliferation, tumour formation and metastasis in mice. Further study showed that miR-375 could interact with the 3′-untranslated region of IGF1R and downregulate its expression. In clinical specimens, the expression of IGF1R was also negatively correlated with miR-375 expression (p=0.008).

Conclusions This study demonstrates that miR-375 has a strong tumour-suppressive effect through inhibiting the expression of IGF1R. The downregulation of miR-375, which is mainly caused by promoter methylation, is one of the molecular mechanisms involved in the development and progression of ESCC.

  • Insulin-like growth factor 1 receptor
  • metastasis
  • microRNA-375
  • oesophageal squamous cell carcinoma

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Footnotes

  • Funding This work was supported by grants from Hong Kong Research Grant Council Central Allocation (HKUST 2/06C); the National Natural Science Foundation of China (30700820, 30772475 and 30971606); and Sun Yat-Sen University ‘Hundred Talents Program’ (85000-3171311).

  • Competing interests None.

  • Ethics approval Samples used in this study were approved by the committees for ethical review of research at the University of Hong Kong and the University of Zhengzhou.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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