Control of the Human Osteopontin Promoter by ERRα in Colorectal Cancer

Abstract

Colorectal cancer is the second leading cause of death from cancer. Osteopontin (OPN) is a component of tumor extracellular matrix identified as a key marker of cancer progression. The estrogen-related receptor α (ERRα) has been implicated in endocrine-related cancer development and progression, possibly through modulation of cellular energy metabolism. Previous reports that ERRα regulates OPN expression in bone prompted us to investigate whether ERRα controls OPN expression in human colorectal cancer. Using a tissue microarray containing 83 tumor-normal tissue pairs of colorectal cancer samples, we found that tumor epithelial cells displayed higher staining for ERRα than normal mucosa, in correlation with elevated OPN expression. In addition, knocking down endogenous ERRα led to reduced OPN expression in HT29 colon cancer cells. Promoter analysis, inhibition of ERRα activity, and expression and mutation of potential ERRα response elements in the proximal promoter of human OPN showed that ERRα and its obligate co-activator, peroxisome proliferator-activated receptor γ co-activator-1 α, positively control human OPN promoter activity. Furthermore, chromatin immunoprecipitation experiments confirmed in vivo occupancy of the OPN promoter by ERRα in HT29 cells, suggesting that OPN is a direct target of ERRα in colorectal cancer. These findings suggest an additional mechanism by which ERRα participates in the development and progression of colorectal cancer, further supporting the relevance of targeting ERRα with antagonists as anticancer agents.

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer

“…As a positive regulator of EMT in several cancer types (16,27), ERRα may increase the number of CRC stem cells from residual cancer cells in patients with CRC following curative resection, thereby contributing to recurrence. A previous study revealed that ERRα, combined with PGC1α, activates the promoter of osteopontin (OPN) gene and leads to elevated OPN expression in CRC cells (29). OPN is a glycoprotein secreted by a variety of tissues and enhances cancer stem cell phenotypes in various cancer types (30,31).…”

OPN and αvβ3 Expression are Predictors of Disease Severity and Worse Prognosis in Hepatocellular Carcinoma

“…Moreover, OPN also may appear in biological fluids, including blood, urine and so on [6], [7]. OPN is a multifunctional secreted phosphorylated glycoprotein that promotes cellular chemotaxis, adhesion and migration and is associated with the occurrence, metastasis and prognosis of a variety of cancer types [8], [9], [10].…”

Effects of estrogen-related receptor alpha (ERRα) on proliferation and metastasis of human lung cancer A549 cells

“…The ERREs are different from those mediating the estrogenic response (estrogen response elements, EREs) [5] . Recent studies indicated that ERRα may interfere with the estrogen/androgen-related signaling pathways and then play an important role in the development of hormone-dependent cancers [6] .ERRα is found to express in multiple human cancer cells such as breast [7] , colorectal [8] , and ovarian [9] cancer cells. Its expression is positively correlated with the risk of recurrence and poor clinical outcomes of breast [10] and ovarian cancer [11] .…”

“…ERRα is found to express in multiple human cancer cells such as breast [7] , colorectal [8] , and ovarian [9] cancer cells. Its expression is positively correlated with the risk of recurrence and poor clinical outcomes of breast [10] and ovarian cancer [11] .…”