Jimin Min1,2,3, Tae-Su Han4, Yoojin Sohn3,5, Takahiro Shimizu2,3,5,6, Boram Choi1, Seong-Woo Bae1, Keun Hur7, Seong-Ho Kong8, Yun-Suhk Suh8, Hyuk-Joon Lee1,8, Jang-Seong Kim4, Jeong-Ki Min4, Woo-Ho Kim9, V Narry Kim10, Eunyoung Choi11,12,13, James R Goldenring14,15,16,17, Han-Kwang Yang18,19. 1. Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul, 03080, South Korea. 2. Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA. 3. Epithelial Biology Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, MRB IV 10435F, 2213 Garland Avenue, Nashville, TN, 37232, USA. 4. Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea. 5. Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. 6. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 7. Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea. 8. Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea. 9. Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea. 10. School of Biological Sciences, Seoul National University, Seoul, South Korea. 11. Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, TN, USA. eunyoung.choi@vumc.org. 12. Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA. eunyoung.choi@vumc.org. 13. Epithelial Biology Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, MRB IV 10435F, 2213 Garland Avenue, Nashville, TN, 37232, USA. eunyoung.choi@vumc.org. 14. Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, TN, USA. jim.goldenring@vumc.org. 15. Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA. jim.goldenring@vumc.org. 16. Epithelial Biology Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, MRB IV 10435F, 2213 Garland Avenue, Nashville, TN, 37232, USA. jim.goldenring@vumc.org. 17. Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. jim.goldenring@vumc.org. 18. Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul, 03080, South Korea. hkyang@snu.ac.kr. 19. Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea. hkyang@snu.ac.kr.
Abstract
BACKGROUND: Spasmolytic polypeptide-expressing metaplasia (SPEM) is considered a precursor lesion of intestinal metaplasia and intestinal-type gastric cancer (GC), but little is known about microRNA alterations during metaplasia and GC developments. Here, we investigate miR-30a expression in gastric lesions and identify its novel target gene which is associated with the intestinal-type GC. METHODS: We conducted in situ hybridization and qRT-PCR to determine miR-30a expression in gastric tissues. miR-30a functions were determined through induction or inhibition of miR-30a in GC cell lines. A gene microarray was utilized to confirm miR-30a target genes in GC, and siRNA-mediated target gene suppression and immunostaining were performed. The Cancer Genome Atlas data were utilized to validate gene expressions. RESULTS: We found down-regulation of miR-30a during chief cell transdifferentiation into SPEM. MiR-30a level was also reduced in the early stage of GC, and its level was maintained in advanced GC. We identified a novel target gene of miR-30a and ITGA2, and our results showed that either ectopic expression of miR-30a or ITGA2 knockdown suppressed GC cell proliferation, migration, and tumorigenesis. Levels of ITGA2 inversely correlated with levels of miR-30a in human intestinal-type GC. CONCLUSION: We found down-regulation of miR-30a in preneoplastic lesions and its tumor-suppressive functions by targeting ITGA2 in GC. The level of ITGA2, which functions as an oncogene, was up-regulated in human GC. The results of this study suggest that coordination of the miR-30a-ITGA2 axis may serve as an important mechanism in the development of gastric precancerous lesions and intestinal-type GC.
BACKGROUND:Spasmolytic polypeptide-expressing metaplasia (SPEM) is considered a precursor lesion of intestinal metaplasia and intestinal-type gastric cancer (GC), but little is known about microRNA alterations during metaplasia and GC developments. Here, we investigate miR-30a expression in gastric lesions and identify its novel target gene which is associated with the intestinal-type GC. METHODS: We conducted in situ hybridization and qRT-PCR to determine miR-30a expression in gastric tissues. miR-30a functions were determined through induction or inhibition of miR-30a in GC cell lines. A gene microarray was utilized to confirm miR-30a target genes in GC, and siRNA-mediated target gene suppression and immunostaining were performed. The Cancer Genome Atlas data were utilized to validate gene expressions. RESULTS: We found down-regulation of miR-30a during chief cell transdifferentiation into SPEM. MiR-30a level was also reduced in the early stage of GC, and its level was maintained in advanced GC. We identified a novel target gene of miR-30a and ITGA2, and our results showed that either ectopic expression of miR-30a or ITGA2 knockdown suppressed GC cell proliferation, migration, and tumorigenesis. Levels of ITGA2 inversely correlated with levels of miR-30a in humanintestinal-type GC. CONCLUSION: We found down-regulation of miR-30a in preneoplastic lesions and its tumor-suppressive functions by targeting ITGA2 in GC. The level of ITGA2, which functions as an oncogene, was up-regulated in human GC. The results of this study suggest that coordination of the miR-30a-ITGA2 axis may serve as an important mechanism in the development of gastric precancerous lesions and intestinal-type GC.
Authors: Ming Liu; Feifei Huang; Dan Zhang; Junyi Ju; Xiao-Bin Wu; Ying Wang; Yadong Wang; Yupeng Wu; Min Nie; Zhuchen Li; Chi Ma; Xi Chen; Jin-Yong Zhou; Renxiang Tan; Bo-Lin Yang; Ke Zen; Chen-Yu Zhang; Yu-Gen Chen; Quan Zhao Journal: Cancer Res Date: 2015-09-02 Impact factor: 12.701
Authors: Christine P Petersen; Victoria G Weis; Ki Taek Nam; Josane F Sousa; Barbara Fingleton; James R Goldenring Journal: Gastroenterology Date: 2014-02-15 Impact factor: 22.682