LRH1 promotes pancreatic cancer metastasis

Lin, Qiushi; Aihara, Arihiro; Chung, Waihong; Liu, Yu; Chen, Xuesong; Huang, Zheping; Weng, Shaofan; Carlson, Richard P.; Nadolny, Christina; Wands, Jack R.; Dong, Xiaoqun

doi:10.1016/j.canlet.2014.04.017

Cited by 39 publications

(58 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, NTF3 has also been shown to increase resistance to anoikis (33). LRH-1 as well has recently been implicated in pancreatic-cancer metastasis and breast-cancer development; these findings may demonstrate similar molecular underpinnings between cancer metastases (14,34,35). Another Rho member in our dataset that promotes metastasis in gastroenterological cancers is semaphorin 5A.…”

Section: Antiproliferative Mechanism Of Lrh-1 Inhibition Is Conservedsupporting

confidence: 52%

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Bayrer

Mukkamala

Sablin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Colorectal cancers (CRCs) account for nearly 10% of all cancer deaths in industrialized countries. Recent evidence points to a central role for the nuclear receptor liver receptor homolog-1 (LRH-1) in intestinal tumorigenesis. Interaction of LRH-1 with the Wnt/β-catenin pathway, highly active in a critical subpopulation of CRC cells, underscores the importance of elucidating LRH-1's role in this disease. Reduction of LRH-1 diminishes tumor burden in murine models of CRC; however, it is not known whether LRH-1 is required for tumorigenesis, for proliferation, or for both. In this work, we address this question through shRNA-mediated silencing of LRH-1 in established CRC cell lines. LRH-1 mRNA knockdown results in significantly impaired proliferation in a cell line highly expressing the receptor and more modest impairment in a cell line with moderate LRH-1 expression. Cell-cycle analysis shows prolongation of G0/G1 with LRH-1 silencing, consistent with LRH-1 cellcycle influences in other tissues. Cluster analysis of microarray gene expression demonstrates significant genome wide alterations with major effects in cell-cycle regulation, signal transduction, bile acid and cholesterol metabolism, and control of apoptosis. This study demonstrates a critical proproliferative role for LRH-1 in established colon cancer cell lines. LRH-1 exerts its effects via multiple signaling networks. Our results suggest that selected CRC patients could benefit from LRH-1 inhibitors.C olorectal cancer (CRC) accounts for nearly 10% of all cancer deaths in the United States. Much is understood about maintenance, but little is known about molecules driving initiation or metastasis of CRCs. Recent discoveries in animal and cellular models of CRC suggest a role for the nuclear receptor liver receptor homolog-1 (LRH-1, also known as NR5A2) (1).LRH-1, previously thought to be constitutively active, has a functional hormone-binding pocket that binds phosphatidylcholines (2, 3). The structure of the hormone-binding domain of LRH-1 has been determined with four different phospholipids in the binding pocket (4-6).LRH-1 is vital; knockout mouse embryos fail to undergo gastrulation (7). LRH-1 is expressed in the adult in the gastrointestinal tract, including liver and pancreas, and is also present in ovaries, where it regulates steroidogenesis (8). It is highly expressed in intestinal crypts where it is believed to play a role in intestinal epithelial cell renewal (9). LRH-1 has prominent roles in development, metabolism, stem-cell pluripotency, and tumorigenesis (10-14).LRH-1 figures prominently in WNT signaling in the intestine (9, 13). The WNT gene family is a large, conserved signaling pathway with roles in development, cellular homeostasis, and tumorigenesis (15). WNT signaling activates β-catenin, an important transcriptional coactivator that is active in over 80% of CRCs (16). LRH-1 physically binds to β-catenin and functions synergistically in the regulation of certain target genes, including cyclin E1 (9).LRH-1 and β-catenin contribute to ...

show abstract

Section: Antiproliferative Mechanism Of Lrh-1 Inhibition Is Conservedsupporting

confidence: 52%

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Bayrer

Mukkamala

Sablin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…15 The overexpression of LRH-1 can lead to a phenotype characterized by enhanced cell migration, wound healing, invasion, and sphere formation in pancreatic cancer cell lines. 53 LRH-1 has also been found to upregulate cyclins D1/E1 and c-Myc genes, as well as to promote pancreatic cancer cell proliferation and tumor growth in nude mice. 15,54 C-Myc is required for cell proliferation, which is also shown to be controlled by LRH-1.…”

Section: Lrh-1 and Pancreatic Cancermentioning

confidence: 95%

“…15 Overexpression of LRH-1 causes enhanced transcriptional activation of b-catenin and expression of downstream target genes c-Myc, MMP2, and MMP9 in pancreatic cancer cell lines. 53 Overexpression of LRH-1 also causes significant increases in pancreatic cancer cell migration, invasion, wound healing, and sphere formation. Similarly, specific inhibition of LRH-1 by shRNAs show significant reductions in cell migration, invasion, sphere formation, as well as in the expression of c-Myc and MMP2/9 target genes.…”

Section: Prox1mentioning

confidence: 99%

“…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. 15 Overexpression of LRH-1 causes enhanced transcriptional activation of b-catenin and expression of downstream target genes c-Myc, MMP2, and MMP9 in pancreatic cancer cell lines.…”

Section: Prox1mentioning

confidence: 99%

“…Similarly, specific inhibition of LRH-1 by shRNAs show significant reductions in cell migration, invasion, sphere formation, as well as in the expression of c-Myc and MMP2/9 target genes. 53 Two in vivo models, a murine orthotopic xenograft model and a hepatic metastasis model, were analyzed in terms of tumor growth and progression. Mice injected with stable pancreatic cancer cells overexpressing LRH-1 developed larger tumors and exhibited prominent hepatic metastatic spread compared to the vector control.…”

Section: Prox1mentioning

confidence: 99%

See 2 more Smart Citations

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

Nadolny

Dong

2015

Cancer Biology & Therapy

Self Cite

View full text Add to dashboard Cite

Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in various biological processes. This nuclear receptor has critical functions in embryonic development as well as in adult homeostasis. Although the physiological functions of LRH-1 in normal breast, pancreas, and intestine have been widely investigated, the dysregulation that occurs during pathological conditions is not well understood. LRH-1 has been implicated in pancreatic, breast, and gastrointestinal cancer, where it exerts its effect of initiation and progression by promoting cell proliferation and metastasis. In addition to mechanistic studies, LRH-1 agonists and antagonists are being explored. Identification and development of endogenous and synthetic ligands has been pursued using computational-based structural analysis. Through ligand identification and a thorough understanding of the pathological roles of LRH-1, new therapeutic avenues for cancer treatment based upon LRH-1 may be a desirable focus for further research.

show abstract

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

Michalek

Brunner

2020

IUBMB Life

View full text Add to dashboard Cite

Liver receptor homolog-1 (LRH-1, NR5A2) is an orphan nuclear receptor with widespread activities in the regulation of development, stemness, metabolism, steroidogenesis, and proliferation. Many of the LRH-1-regulated processes target the mitochondria and associated activities. While under physiological conditions, a balanced LRH-1 expression and regulation contribute to the maintenance of a physiological equilibrium, deregulation of LRH-1 has been associated with inflammation and cancer. In this review, we discuss the role and mechanism(s) of how LRH-1 regulates metabolic processes, cell survival, and cancer in a nuclear-mitochondrial crosstalk, and evaluate its potential as a pharmacological target.

show abstract

LRH1 promotes pancreatic cancer metastasis

Cited by 39 publications

References 29 publications

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

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

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

Contact Info

Product

Resources

About