PMID- 28504692 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 2157-9024 (Print) IS - 2157-9024 (Electronic) IS - 2157-9024 (Linking) VI - 6 IP - 5 DP - 2017 May 15 TI - Mint3-mediated L1CAM expression in fibroblasts promotes cancer cell proliferation via integrin alpha5beta1 and tumour growth. PG - e334 LID - 10.1038/oncsis.2017.27 [doi] AB - Fibroblasts are some of the major cells in tumour tissues that influence tumour progression and drug resistance. However, our understanding on fibroblast-mediated tumour malignancy remains incomplete. Munc18-1-interacting protein 3 (Mint3) is known as an activator of hypoxia-inducible factor-1 (HIF-1) even during normoxia in cancer cells, macrophages and fibroblasts. Although Mint3 promotes ATP production via glycolysis by activating HIF-1 in cancer cells and macrophages, the biological role of Mint3-mediated HIF-1 activation in fibroblasts remains unclear. To address this, we examined whether Mint3 in fibroblasts contributes to tumour growth. Mint3 depletion in mouse embryonic fibroblasts (MEFs) decreased tumour growth of co-injected human breast cancer cells, MDA-MB-231 and epidermoid carcinoma A431 cells in mice. In MEFs, Mint3 also promoted cancer cell proliferation in vitro in a cell-cell contact-dependent manner. Mint3-mediated cancer cell proliferation depended on HIF-1, and further gene expression analysis revealed that the cell adhesion molecule, L1 cell adhesion molecule (L1CAM), was induced by Mint3 and HIF-1 in fibroblasts. Mint3-mediated L1CAM expression in fibroblasts stimulated the ERK signalling pathway via integrin alpha5beta1 in cancer cells, and promoted cancer cell proliferation in vitro and tumour growth. In cancer-associated fibroblasts (CAFs), knockdown of MT1-MMP, which promotes Mint3-mediated HIF-1 activation, or Mint3 decreased L1CAM expression. As MEFs, CAFs also promoted cancer cell proliferation in vitro, and tumour growth via Mint3 and L1CAM. In human breast cancer specimens, the number of fibroblasts expressing L1CAM, Mint3 and MT1-MMP was higher in cancer regions than in adjacent benign regions. In addition, more phospho-ERK1/2-positive cancer cells existed in the peripheral region surrounded by the stroma than in the central region of solid breast cancer nest. Thus, Mint3 in fibroblasts might be a good target for cancer therapy by regulating cancer cell-stromal cell communication. FAU - Nakaoka, H J AU - Nakaoka HJ AD - Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan. FAU - Tanei, Z AU - Tanei Z AD - Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan. AD - Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan. FAU - Hara, T AU - Hara T AD - Division of Cancer Cell Research, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan. FAU - Weng, J S AU - Weng JS AD - Division of Cancer Cell Research, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan. FAU - Kanamori, A AU - Kanamori A AD - Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan. FAU - Hayashi, T AU - Hayashi T AD - Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan. FAU - Sato, H AU - Sato H AD - Division of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan. FAU - Orimo, A AU - Orimo A AD - Department of Molecular Pathogenesis, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan. FAU - Otsuji, K AU - Otsuji K AD - Department of Breast and Endocrine Surgery, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan. FAU - Tada, K AU - Tada K AD - Department of Breast and Endocrine Surgery, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan. FAU - Morikawa, T AU - Morikawa T AD - Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan. FAU - Sasaki, T AU - Sasaki T AD - Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan. FAU - Fukayama, M AU - Fukayama M AD - Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan. FAU - Seiki, M AU - Seiki M AD - Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan. FAU - Murakami, Y AU - Murakami Y AD - Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan. FAU - Sakamoto, T AU - Sakamoto T AD - Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan. LA - eng PT - Journal Article DEP - 20170515 PL - United States TA - Oncogenesis JT - Oncogenesis JID - 101580004 PMC - PMC5523060 COIS- The authors declare no conflict of interest. EDAT- 2017/05/16 06:00 MHDA- 2017/05/16 06:01 PMCR- 2017/05/01 CRDT- 2017/05/16 06:00 PHST- 2017/03/07 00:00 [received] PHST- 2017/03/20 00:00 [accepted] PHST- 2017/05/16 06:00 [entrez] PHST- 2017/05/16 06:00 [pubmed] PHST- 2017/05/16 06:01 [medline] PHST- 2017/05/01 00:00 [pmc-release] AID - oncsis201727 [pii] AID - 10.1038/oncsis.2017.27 [doi] PST - epublish SO - Oncogenesis. 2017 May 15;6(5):e334. doi: 10.1038/oncsis.2017.27.