Erythroid Differentiation Regulator 1, an Interleukin 18-Regulated Gene, Acts as a Metastasis Suppressor in Melanoma

Abstract

Erythroid differentiation regulator (Erdr1) was first discovered in mouse leukemia cell lines and functions as a stress-related survival factor. This study investigated whether Erdr1 regulates murine melanoma progression, as well as the mechanism involved in Erdr1-regulated metastasis. The expression of Erdr1 is negatively correlated with IL-18 expression, which has a pro-cancer effect in melanoma. To study the role of Erdr1 as an anti-cancer factor, cell migration, invasion, and proliferation were measured. Erdr1 overexpression markedly inhibited the level of cell migration, invasion, and proliferation in B16F10 cells in vitro. In addition, Erdr1 overexpression significantly suppressed melanoma lung colonization, metastasis, and tumor growth in vivo. To identify the factors involved in Erdr1-reduced metastasis, heat shock protein 90 (HSP90), a well-known stress protein and contributor to tumor metastasis, was examined. We found that HSP90 was significantly decreased in Erdr1-overexpressing cells. Functional analysis demonstrated that HSP90 small-interfering RNA transfection reduced the migration ability and metastasis of melanoma. In conclusion, Erdr1 shows a powerful anti-metastasis effect that leads to the ability to reduce the metastatic potential of murine malignant melanoma cells. Erdr1 is an anti-metastatic factor that may be a possible therapeutic target for treatment of melanoma.

Immunotherapeutic Approach for Better Management of Cancer - Role of IL-18

“…The expression of Erdr1 is negatively correlated with IL-18 expression. Erdr1 over expression markedly inhibited the level of cell migration, invasion, and proliferation in B16F10 cells in vitro (Jung et al, 2011). Selenium can prevent metastasis by inhibiting IL-18 gene expression in a dose-dependent manner.…”

ERDR1 enhances human NK cell cytotoxicity through an actin-regulated degranulation-dependent pathway

“…ERDR1 induces hemoglobin synthesis and is a stressrelated survival factor [17,18]. Recently, ERDR1 was reported to be a pro-apoptotic factor in human keratinocytes and an antimetastasis factor in mouse melanoma cells and human gastric cancer cells [19][20][21]. This study investigated whether ERDR1 has anti-cancer effects on immune cells, human primary NK cells, as well as cancer cells.…”

“…In human keratinocytes, ERDR1 is involved in cell growth and survival and is regarded as a pro-apoptotic factor [19]. Recently, ERDR1 expression is negatively regulated by IL-18, causing anti-metastatic functions in melanoma [20]. Additionally, ERDR1 inhibits gastric cancer cell migration and invasion [21].…”

Microbiota promotes systemic T-cell survival through suppression of an apoptotic factor

“…Erdr1 expression levels in splenic CD4+ T cells from IL-1R-and IL-18-deficient animals were similar to those of wild-type (WT) controls, indicating that Erdr1 is not regulated by these cytokines (Fig. 1C) (12). It is possible that microbiota composition could be different in these various knockout strains and account for the differential expression of Erdr1.…”

“…Erdr1 was originally identified in supernatants of B-cell leukemic cells and named for its hemoglobin-inducing activity on erythroid lines, but now has implicated roles in cellular survival, NK cytotoxicity, and metastasis; however, its function within T cells remains completely unexplored (11)(12)(13)(14)(15).…”