LRH1 as a driving factor in pancreatic cancer growth

Abstract

Liver receptor homolog 1 (LRH1), directs the development and differentiation of embryonic pancreas, and is overexpressed in pancreatic cancer (PC). We hypothesized that LRH1 promotes PC growth. Cell proliferation and tumorigenicity in nude mice were compared between empty vector-transfected (control) and stable LRH1-overexpressed PC cell lines. The subsequent tumor burden, vasculature development, and histologic features were evaluated. LRH1 overexpression enhanced the expression of downstream target genes (cyclin D1/E1) and stimulated cell proliferation in PC cell lines. LRH1 upregulated cyclin E1 truncated T1/T2 isoforms expression which may occur through ERα—calpain1 signaling. Compared with the control, LRH1 overexpressing stable cells generated tumors with increased weight, proliferation index and enhanced angiogenesis. Cyclin D1/E1 and calpain1 were overexpressed in human PC tumors compared to adjacent normal pancreas. These observations demonstrate that LRH1 promotes PC growth and angiogenesis, suggesting that LRH1 is a driving factor in tumorigenesis and may serve as a potential therapeutic target.

Aspartate β-hydroxylase expression promotes a malignant pancreatic cellular phenotype

“…We prepared lentiviral mediated stable transfection of ASPH that localized to the cell surface in MIA PaCa2 cells (Fig. 1f) with very low endogenous levels of ASPH as described [7, 8]. Empty vector transfected cells served as the control.…”

“…We established two stable MIA PaCa2 cell lines with overexpression of ASPH, and three stable AsPC-1 cell lines with knockdown of ASPH by specific shRNAs using the lentiviral system (GeneCopoeia, #EX-Z8758-Lv105 and # HSH011500-HIVU6, respectively) as described [7, 8]. Three shRNAs sequences used to target ASPH were as follows: [HSH011500-1-HIVU6 (OS217501)] cttctccatgaaatggtac, [HSH011500-2-HIVU6 (OS217502)] ctggaacctgaagtatctc, and ([HSH011500-3-HIVU6 (OS217503)] cctgaggataatcctgtag.…”

“…Assays to measure PC cell migration, invasion and colony formation were performed as described previously [7, 8]. …”

Liver receptor homolog-1 (LRH-1): a potential therapeutic target for cancer

“…16 Similarly, LRH-1 is associated with pancreatic cancer initiation and metastasis, 15,53,54 suggesting potential for this nuclear receptor in the treatment of pancreatic cancer. Interestingly, LRH-1 has been proposed to play a dual role in pancreatic ductal adenocarcinoma (PDA), the most common type of pancreatic cancer.…”

“…57,58 Lin et al hypothesizes that LRH-1 is a driving factor that is shared between pancreatic embryogenesis and oncogenesis. 54 Of equal importance, recent studies have shown that LRH-1 can promote pancreatic cancer metastasis. 15,53 Pancreatic cancer cells originating from metastatic tumors have significantly higher expression of LRH-1 than in primary tumor cells.…”