MicroRNA-1291 targets the FOXA2-AGR2 pathway to suppress pancreatic cancer cell proliferation and tumorigenesis.
Pancreatic cancer is the fourth leading cause of cancer death in the United States. Better understanding of pancreatic cancer biology may help identify new oncotargets towards more effective therapies. This study investigated the mechanistic actions of microRNA-1291 (miR-1291) in the suppression of pancreatic tumorigenesis. Our data showed that miR-1291 was downregulated in a set of clinical pancreatic carcinoma specimens and human pancreatic cancer cell lines. Restoration of miR-1291 expression inhibited pancreatic cancer cell proliferation, which was associated with cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 sharply suppressed the tumorigenicity of PANC-1 cells in mouse models. A proteomic profiling study revealed 32 proteins altered over 2-fold in miR-1291-expressing PANC-1 cells that could be assembled into multiple critical pathways for cancer. Among them anterior gradient 2 (AGR2) was reduced to the greatest degree. Through computational and experimental studies we further identified that forkhead box protein A2 (FOXA2), a transcription factor governing AGR2 expression, was a direct target of miR-1291. These results connect miR-1291 to the FOXA2-AGR2 regulatory pathway in the suppression of pancreatic cancer cell proliferation and tumorigenesis, providing new insight into the development of miRNA-based therapy to combat pancreatic cancer.
Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA.
Mei-Juan
MJ
Tu
Department of Pharmaceutical Sciences, SUNY-Buffalo, Buffalo, NY 14214, USA.
Yu-Zhuo
YZ
Pan
Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Jing-Xin
JX
Qiu
Division of Hematology and Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA.
Edward J
EJ
Kim
Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA.
Ai-Ming
AM
Yu
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009088:Mucoproteins; D015513:Oncogene Proteins; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000378:metabolism
C502296:AGR2 protein, human; C496502:FOXA2 protein, human; C587958:MIRN1291 microRNA, human; D035683:MicroRNAs; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D051542:Hepatocyte Nuclear Factor 3-beta
AGR2; FOXA2; miR-1291; microRNA; pancreatic cancer