MCPIP1 Selectively Destabilizes Transcripts Associated with an Antiapoptotic Gene Expression Program in Breast Cancer Cells That Can Elicit Complete Tumor Regression

Abstract

The ability of cancer cells to evade apoptosis is dictated by a shift in the balance between pro- and anti-apoptotic gene expression programs. Monocyte chemotactic protein induced protein 1 (MCPIP1) is a zinc finger RNA binding protein with important roles in mediating inflammatory responses. Overexpression of MCPIP1 in different cancer cell types has been implicated in eliciting an antitumor response, but a direct role of MCPIP1 in apoptosis has not been established. In this study, we demonstrate that MCPIP1 functions as a potent tumor suppressor that induces apoptosis of breast tumor cells by selectively enhancing mRNA decay of anti-apoptotic gene transcripts including Bcl2L1, Bcl2A1, RelB, Birc3, and Bcl3. Mechanistically, MCPIP1 physically interacted with a stem-loop structure in the 3'UTR of these transcripts through its PIN domain, causing mRNA destabilization. Furthermore, we found that MCPIP1 expression was repressed in breast tumor cells, and overexpression of MCPIP1 induced apoptosis, whereas its depletion enhanced cancer cell proliferation. Moreover, MCPIP1 induction in vivo resulted in complete regression of established tumors and a significant reduction in metastatic disease. Notably, low MCPIP1 expression in tumor samples from breast cancer patients was strongly associated with poor survival over 13 years of follow up. Collectively, our results highlight MCPIP1 is a new tumor suppressor in breast cancer that induces cell death by tipping the balance in favor of pro-apoptotic gene expression.

MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression

“…In our models, low MCPIP1 levels significantly increased the cell proliferation, tumor growth, and tumor weight of ccRCC. In contrast, MCPIP1 overexpression decreases the proliferation in vitro and reduced tumor growth in vivo as it was demonstrated for breast cancer (22). Interestingly, the analysis of tumors generated by cells carrying a point mutation of D141 (D141N) that completely abolishes MCPIP1 RNase activity (13) demonstrated that the loss of endoribonuclase activity of MCPIP1 significantly increased tumor growth in both investigated models.…”

“…It has been already demonstrated that MCPIP1 regulates the viability and proliferation of neuroblastoma (20), HeLa, HepG2 (19), ccRCC (25), and breast cancer cells (21). Previous findings have demonstrated that MCPIP1 degrades the mRNA of antiapoptotic gene transcripts in breast cancer cells, leading to apoptosis and tumor regression (22). Moreover, the same study showed that MCPIP1 expression in breast cancer samples was reduced compared with that in healthy tissue, and low MCPIP1 expression was associated with tumor progression and poor survival (22).…”

“…Previous findings have demonstrated that MCPIP1 degrades the mRNA of antiapoptotic gene transcripts in breast cancer cells, leading to apoptosis and tumor regression (22). Moreover, the same study showed that MCPIP1 expression in breast cancer samples was reduced compared with that in healthy tissue, and low MCPIP1 expression was associated with tumor progression and poor survival (22). Our group has already demonstrated that ccRCC tumors have a lower level of MCPIP1 than normal renal tissues, and MCPIP1 overexpression decreases viability and proliferation of ccRCC cells (25).…”

“…Recently, it has been shown that MCPIP1 is involved in the regulation of viability and proliferation in numerous cancer cell lines (19)(20)(21). Moreover, MCPIP1 overexpression in breast cancer cells induces apoptosis in vitro and reduces tumor growth and metastatic disease in vivo (22). Interestingly, some studies have suggested that MCPIP1 may promote endothelial cell angiogenesis by increasing the secretion of angiogenic factors, such as VEGF and hypoxia-inducible factor 1-alpha (HIF1a; refs.…”

MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma

“…The main physiological function of the protein is negative regulation of inflammation [Jura et al, 2012]. Roles of MCPIP1 in differentiation and apoptosis have also been described in mesenchymal stem cells and breast cancer [Labedz-Maslowska et al, 2015;Lu et al, 2016].…”