mda-7/IL-24 Expression Inhibits Breast Cancer through Upregulation of Growth Arrest-Specific Gene 3 (gas3) and Disruption of β1 Integrin Function

Abstract

Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressing MDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of b1 integrin with fibronectin. A mutated GAS3, which is unable to bind b1 integrin, was also unable to inhibit fibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of b1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of b1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P ¼ 1.02 Â 10 À9

Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

“…PMP22/gas3 overexpression was originally found to induce an apoptotic-like phenotype, 91 and recent studies have revealed that the induction of GAS3 inhibits breast cancer by inhibiting the attachment and proliferation of the tumor cells, at least in part by blocking the interaction of β1 integrin with fibronectin. 92 Indeed, the tumor-suppressive activity of GAS3 is related to the significantly increased metastasis-free survival of breast cancer patients. Another top molecule notably decreased upon acquisition of metformin resistance was the S100A14 (S100 calcium binding protein A14) gene (14-fold downregulation vs. metformin-naïve MCF-7 cells; Table 2).…”

The ‘melanoma-enriched’ microRNA miR-4731-5p acts as a tumour suppressor

“…PMP22 is expressed primarily in neural crest derived cell lineages (including melanocytes), however expression of PMP22 has also been associated with cell proliferation and survival in breast cancer [3–5]. To date no target genes of miR-4731 have been functionally validated.…”

A comparison of the gene expression profiles and pathway network analyses after treatment of Prostate cancer cell lines with different Ganoderma lucidum based extracts

“…IRF1 has similar expression profiles to IL24. Both IL24 and IRF1 are TSGs and exert anti-cancer activities via activation of STAT1 and STAT3 transcription factors [75,76,77,78]. Up-regulation of IL24 and IRF1 has anti-proliferative effects in breast and colon cancers [75,76,77,78].…”