TY - JOUR
T1 - E74-Like Factor 3 Is a Key Regulator of Epithelial Integrity and Immune Response Genes in Biliary Tract Cancer
AU - Suzuki, Masami
AU - Saito-Adachi, Mihoko
AU - Arai, Yasuhito
AU - Fujiwara, Yuko
AU - Takai, Erina
AU - Shibata, Shinsuke
AU - Seki, Masahide
AU - Rokutan, Hirofumi
AU - Maeda, Daichi
AU - Horie, Masafumi
AU - Suzuki, Yutaka
AU - Shibata, Tatsuhiro
AU - Kiyono, Tohru
AU - Yachida, Shinichi
N1 - Funding Information:
D. Maeda reportsgrantsfromTakara Bio,Inc. outside thesubmittedwork. T.Kiyono reports grants, personal fees, and non-financial supportfrom National Cancer Center, as well as grants from Ministry of Education, Science and Culture of Japan during the conduct of the study. S. Yachida reports grants from Ministry of Education, Science and Culture ofJapan, Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Japan Agency for Medical Research and Development, Joint Research Project of the Institute of Medical Science, University of Tokyo, and Yasuda Medical Foundation during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
We are grateful to Risa Usui, Chiho Kohno, Takako Ishiyama, Drs. Mamoru Kato, Hiromi Nakamura, and Yasushi Totoki (National Cancer Center Research Institute) for technical assistance. The authors thank Dr. Hiroyuki Miyoshi (RIKEN, BioR-esource Center) for providing lentiviral constructs. The authors thank Dr. Shohei Koyama (National Cancer Center) and for helpful discussions. This work was supported by the following grants: grants-in-aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (16H04701 to T. Kiyono; A17H04275 to S. Yachida); Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University; Japan Agency for Medical Research and Development (JP20ck0106558); Joint Research Project of the Institute of Medical Science, University of Tokyo (2020); Yasuda Medical Foundation; Yakult Bio-Science Foundation; Princess Takamatsu Cancer Research Fund; and Takeda Science Foundation (to S. Yachida).
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - The transcription factor E74-like factor 3 (ELF3) is inactivated in a range of cancers, including biliary tract cancer (BTC). Here, we investigated the tumor-suppressive role of ELF3 in bile duct cells by identifying several previously unknown direct target genes of ELF3 that appear to be implicated in biliary duct carcinogenesis. ELF3 directly repressed ZEB2, a key regulator of epithelial–mesenchymal transition, and upregulated the expression of CGN, an integral element in lumen formation. Loss of ELF3 led to decreased cell–cell junctions and enhanced cell motility. ALOX5 and CXCL16 were also identified as additional direct targets of ELF3; their corresponding proteins 5-lipox-ygenase and CXCL16 play a role in the immune response. Conditioned medium from cells overexpressing ELF3 significantly enhanced the migration of natural killer cells and CD8þ T cells toward the conditioned medium. Gene expression profiling for BTC expressing high levels of ELF3 revealed significant enrichment of the ELF3-related genes. In a BTC xenograft model, activation of ELF3 increased expression of ELF3-related genes, enhanced the tubular structure of the tumors, and led to a loss of vimentin. Overall, our results indicate that ELF3 is a key regulator of both epithelial integrity and immune responses in BTC. Significance: Thease finding shows that ELF3 regulates epithelial integrity and host immune responses and functions as a tumor suppressor in biliary tract cancer.
AB - The transcription factor E74-like factor 3 (ELF3) is inactivated in a range of cancers, including biliary tract cancer (BTC). Here, we investigated the tumor-suppressive role of ELF3 in bile duct cells by identifying several previously unknown direct target genes of ELF3 that appear to be implicated in biliary duct carcinogenesis. ELF3 directly repressed ZEB2, a key regulator of epithelial–mesenchymal transition, and upregulated the expression of CGN, an integral element in lumen formation. Loss of ELF3 led to decreased cell–cell junctions and enhanced cell motility. ALOX5 and CXCL16 were also identified as additional direct targets of ELF3; their corresponding proteins 5-lipox-ygenase and CXCL16 play a role in the immune response. Conditioned medium from cells overexpressing ELF3 significantly enhanced the migration of natural killer cells and CD8þ T cells toward the conditioned medium. Gene expression profiling for BTC expressing high levels of ELF3 revealed significant enrichment of the ELF3-related genes. In a BTC xenograft model, activation of ELF3 increased expression of ELF3-related genes, enhanced the tubular structure of the tumors, and led to a loss of vimentin. Overall, our results indicate that ELF3 is a key regulator of both epithelial integrity and immune responses in BTC. Significance: Thease finding shows that ELF3 regulates epithelial integrity and host immune responses and functions as a tumor suppressor in biliary tract cancer.
UR - http://www.scopus.com/inward/record.url?scp=85100429341&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100429341&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-2988
DO - 10.1158/0008-5472.CAN-19-2988
M3 - Article
AN - SCOPUS:85100429341
SN - 0008-5472
VL - 81
SP - 489
EP - 500
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -
