LRH1 promotes pancreatic cancer metastasis.
The transcriptional factor liver receptor homolog 1 (LRH1) regulates pancreatic development, and may participate in pancreatic oncogenesis through activation of growth factor signaling transduction cascades. We measured transcriptional activity of β-catenin in response to LRH1 stimulation by a Topflash reporter assay. The pancreatic cancer (PC) phenotype was then characterized by cell migration, wound healing, invasion, and sphere formation in vitro, as well as tumor formation and distant metastatic spread in vivo. We compared results between vector control and LRH1-overexpressing stable PC cell lines. In addition, tumor burden, angiogenesis, histologic characteristics, and hepatic spread were assessed in orthotopic and experimental liver metastatic murine models. Expression of downstream LRH1 related genes was evaluated by Western blot and immunohistochemistry in PC cell lines and human tumor specimens. Specific inhibition of LRH1 expression and function was accomplished by shRNAs "knockdown" experiments. It was found that LRH1 enhanced transcriptional activity of β-catenin and the expression of downstream target genes (c-Myc, MMP2/9), as well as promoted migration, wound healing, invasion, and sphere formation of PC cell lines. Specific inhibition of LRH1 by shRNAs reduced cell migration, invasion, sphere formation and expression of c-Myc and MMP2/9 target genes. Mice injected with LRH1 overexpressing stable PC cells developed tumors with increased size and exhibited striking hepatic metastatic spread. More important, LRH1 was overexpressed in PC tumors compared to adjacent normal pancreas. Our findings demonstrate that LRH1 overexpression is associated with increased PC growth and metastatic spread, indicating that LRH1-targeted therapy could inhibit tumor progression.
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Pharmacy Building, 7 Greenhouse Road, Kingston, RI 02881, United States.
Qiushi
Q
Lin
Division of Gastroenterology and Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, United States.
Arihiro
A
Aihara
Division of Gastroenterology and Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, United States.
Waihong
W
Chung
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Pharmacy Building, 7 Greenhouse Road, Kingston, RI 02881, United States; Bacteriologic Laboratory, Harbin Center for Disease Control and Prevention, Harbin 150056, Heilongjiang Province, China.
Yu
Y
Li
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Pharmacy Building, 7 Greenhouse Road, Kingston, RI 02881, United States; Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang Province, China.
Xuesong
X
Chen
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Pharmacy Building, 7 Greenhouse Road, Kingston, RI 02881, United States.
Zheping
Z
Huang
Department of Occupational Health Assessment, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen 518001, Guangdong Province, China.
Shaofan
S
Weng
Division of Gastroenterology and Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, United States.
Rolf I
RI
Carlson
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Pharmacy Building, 7 Greenhouse Road, Kingston, RI 02881, United States.
Christina
C
Nadolny
Division of Gastroenterology and Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, United States.
Jack R
JR
Wands
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Pharmacy Building, 7 Greenhouse Road, Kingston, RI 02881, United States. Electronic address: xiaoqun_dong@mail.uri.edu.
Xiaoqun
X
Dong
D000818:Animals; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000166:cytology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000096:biosynthesis* / Q000235:genetics
C489427:MYC protein, human; C082631:NR5A2 protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D051176:beta Catenin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
Liver receptor homolog 1; MMP2; MMP9; Pancreatic cancer; c-Myc