Overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with malignant potential in colorectal cancer

Iida,Michihisa; Hazama,Shoichi; Tsunedomi,Ryouichi; Tanaka,Hironori; Takenouchi,Hiroko; Kanekiyo,Shinsuke; Tokumitsu,Yukio; Tomochika,Shinobu; Tokuhisa,Yoshihiro; Sakamoto,Kazuhiko; Suzuki,Nobuaki; Takeda,Shigeru; Ueno,Tomio; Yamamoto,Shigeru; Yoshino,Shigefumi; Fujita,Koji; Kuroda,Masahiko; Nagano,Hiroaki

doi:10.3892/or.2018.6575

Overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with malignant potential in colorectal cancer

Authors:
- Michihisa Iida
- Shoichi Hazama
- Ryouichi Tsunedomi
- Hironori Tanaka
- Hiroko Takenouchi
- Shinsuke Kanekiyo
- Yukio Tokumitsu
- Shinobu Tomochika
- Yoshihiro Tokuhisa
- Kazuhiko Sakamoto
- Nobuaki Suzuki
- Shigeru Takeda
- Tomio Ueno
- Shigeru Yamamoto
- Shigefumi Yoshino
- Koji Fujita
- Masahiko Kuroda
- Hiroaki Nagano
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Affiliations: Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University School of Medicine, Ube, Yamaguchi 755‑8505, Japan, Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, Okayama 701‑0192, Japan, Department of Molecular Pathology, Tokyo Medical University, Tokyo 160‑8402, Japan
Published online on: July 13, 2018 https://doi.org/10.3892/or.2018.6575
Pages: 1621-1631

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Abstract

The cancer stroma is important in cancer development, however, whether the aberrant expression of microRNAs (miRNAs) in the cancer stroma is associated with cancer progression remains to be fully elucidated. The aim of the present study was to identify the miRNAs associated with liver metastasis in the cancer stroma of human colorectal cancer (CRC). Using laser capture microdissection, cancer stroma was obtained from the primary lesion of six patients with CRC with liver metastasis (CRCwLM) and six patients with CRC without liver metastasis (CRCwoLM), and miRNA microarray analysis was performed. Candidate miRNA expression status in the stroma was validated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis in 40 CRC cases (wLM, n=20; woLM, n=20), and the association between miRNA expression and clinicopathological factors was assessed in 101 advanced CRC samples. The localization of candidate miRNAs in CRCs was analyzed using in situ hybridization analysis (ISH). The microarray analysis identified six miRNAs with expression differing between the CRCwLM and CRCwoLM cancer stroma. Validation using RT‑qPCR analysis of the stroma showed that the expression levels of miR‑221 and miR‑222 in the cancer stroma were significantly higher in CRCwLM than in CRCwoLM. The RT‑qPCR analysis of 101 CRC samples showed that a high expression level of miR‑221 or miR‑222 in the cancer stroma was associated with liver metastasis, distant metastasis, and shorter overall survival rate of patients with CRC (P<0.05). Increased levels of miR‑221 and miR‑222 were observed in cancer cells and in fibroblasts in the stromal tissue in the ISH analysis. The results suggested that the overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with the metastatic activity and malignant potential in patients with CRC.

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