PMID- 28032929 OWN - NLM STAT- MEDLINE DCOM- 20170502 LR - 20220318 IS - 1349-7006 (Electronic) IS - 1347-9032 (Print) IS - 1347-9032 (Linking) VI - 108 IP - 3 DP - 2017 Mar TI - Downregulation of microRNA-100/microRNA-125b is associated with lymph node metastasis in early colorectal cancer with submucosal invasion. PG - 390-397 LID - 10.1111/cas.13152 [doi] AB - A majority of early colorectal cancers (CRCs) with submucosal invasion undergo surgical operation, despite a very low incidence of lymph node metastasis. Our study aimed to identify microRNAs (miRNAs) specifically responsible for lymph node metastasis in submucosal CRCs. MicroRNA microarray analysis revealed that miR-100 and miR-125b expression levels were significantly lower in CRC tissues with lymph node metastases than in those without metastases. These results were validated by quantitative real-time PCR in a larger set of clinical samples. The transfection of a miR-100 or miR-125b inhibitor into colon cancer HCT116 cells significantly increased cell invasion, migration, and MMP activity. Conversely, overexpression of miR-100 or miR-125b mimics significantly attenuated all these activities but did not affect cell growth. To identify target mRNAs, we undertook a gene expression array analysis of miR-100-silenced HCT116 cells as well as negative control cells. The Ingenuity Pathway Analysis, TargetScan software analyses, and subsequent verification of mRNA expression by real-time PCR identified mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 receptor (IGF1R) as direct, and Fas and X-linked inhibitor-of-apoptosis protein (XIAP) as indirect candidate targets for miR-100 involved in lymph node metastasis. Knockdown of each gene by siRNA significantly reduced the invasiveness of HCT116 cells. These data clearly show that downregulation of miR-100 and miR-125b is closely associated with lymph node metastasis in submucosal CRC through enhancement of invasion, motility, and MMP activity. In particular, miR-100 may promote metastasis by upregulating mTOR, IGF1R, Fas, and XIAP as targets. Thus, miR-100 and miR-125b may be novel biomarkers for lymph node metastasis of early CRCs with submucosal invasion. CI - (c) 2016 The Authors Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. FAU - Fujino, Yasuteru AU - Fujino Y AD - Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Takeishi, Shunsaku AU - Takeishi S AD - Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Nishida, Kensei AU - Nishida K AD - Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Okamoto, Koichi AU - Okamoto K AD - Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Muguruma, Naoki AU - Muguruma N AD - Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Kimura, Tetsuo AU - Kimura T AD - Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Kitamura, Shinji AU - Kitamura S AD - Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Miyamoto, Hiroshi AU - Miyamoto H AD - Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Fujimoto, Akiko AU - Fujimoto A AD - Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Higashijima, Jun AU - Higashijima J AD - Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Shimada, Mitsuo AU - Shimada M AD - Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Rokutan, Kazuhito AU - Rokutan K AD - Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. FAU - Takayama, Tetsuji AU - Takayama T AD - Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. LA - eng PT - Journal Article PL - England TA - Cancer Sci JT - Cancer science JID - 101168776 RN - 0 (FAS protein, human) RN - 0 (IGF1R protein, human) RN - 0 (MIRN100 microRNA, human) RN - 0 (MIRN125 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Somatomedin) RN - 0 (X-Linked Inhibitor of Apoptosis Protein) RN - 0 (XIAP protein, human) RN - 0 (fas Receptor) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.24.- (Matrix Metalloproteinases) SB - IM MH - Cell Line, Tumor MH - Cell Movement/*genetics MH - Cell Proliferation/*genetics MH - Colorectal Neoplasms/genetics/*pathology MH - HCT116 Cells MH - HT29 Cells MH - Humans MH - Lymphatic Metastasis/genetics MH - Matrix Metalloproteinases/*metabolism MH - MicroRNAs/biosynthesis/*genetics MH - RNA Interference MH - RNA, Small Interfering/genetics MH - Receptor, IGF Type 1 MH - Receptors, Somatomedin/genetics MH - TOR Serine-Threonine Kinases/genetics MH - X-Linked Inhibitor of Apoptosis Protein/genetics MH - fas Receptor/genetics PMC - PMC5378282 OTO - NOTNLM OT - Cancer invasion OT - colorectal cancer with submucosal invasion OT - lymph node metastasis OT - miR-100 OT - miR-125b EDAT- 2016/12/30 06:00 MHDA- 2017/05/04 06:00 PMCR- 2017/03/01 CRDT- 2016/12/30 06:00 PHST- 2016/08/24 00:00 [received] PHST- 2016/12/21 00:00 [revised] PHST- 2016/12/25 00:00 [accepted] PHST- 2016/12/30 06:00 [pubmed] PHST- 2017/05/04 06:00 [medline] PHST- 2016/12/30 06:00 [entrez] PHST- 2017/03/01 00:00 [pmc-release] AID - CAS13152 [pii] AID - 10.1111/cas.13152 [doi] PST - ppublish SO - Cancer Sci. 2017 Mar;108(3):390-397. doi: 10.1111/cas.13152.