MCP-1/MCPIP-1 Signaling Modulates the Effects of IL-1β in Renal Cell Carcinoma through ER Stress-Mediated Apoptosis

Abstract

In renal cell carcinoma (RCC), interleukin (IL)-1β may be a pro-metastatic cytokine. However, we have not yet noted the clinical association between tumoral expression or serum level of IL-1β and RCC in our patient cohort. Herein, we investigate molecular mechanisms elicited by IL-1β in RCC. We found that IL-1β stimulates substantial monocyte chemoattractant protein (MCP)-1 production in RCC cells by activating NF-kB and AP-1. In our xenograft RCC model, intra-tumoral MCP-1 injection down-regulated Ki67 expression and reduced tumor size. Microarray analysis revealed that MCP-1 treatment altered protein-folding processes in RCC cells. MCP-1-treated RCC cells and xenograft tumors expressed MCP-1-induced protein (MCPIP) and molecules involved in endoplasmic reticulum (ER) stress-mediated apoptosis, namely C/EBP Homologous Protein (CHOP), protein kinase-like ER kinase (PERK), and calnexin (CNX). ER stress-mediated apoptosis in MCP-1-treated RCC cells was confirmed using Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Moreover, ectopic MCPIP expression increased PERK expression in Human embryonic kidney (HEK)293 cells. Our meta-analysis revealed that low MCP-1 levels reduce 1-year post-nephrectomy survival in patients with RCC. Immunohistochemistry indicated that in some RCC biopsy samples, the correlation between MCP-1 or MCPIP expression and tumor stages was inverse. Thus, MCP-1 and MCPIP potentially reduce the IL-1β-mediated oncogenic effect in RCC; our findings suggest that ER stress is a potential RCC treatment target.

Novel Prognostic Biomarkers in Gastric Cancer: CGB5, MKNK2, and PAPPA2

“…MAPK Interacting Serine/Threonine Kinase 2 (MKNK2) is a protein-coding gene, primarily associated with IL-1 signaling pathway and ERK signaling pathway. Interestingly, the interleukin-1 family is associated with the growth and metastasis of several cancers (21,22). The present study also Novel Biomarkers in Gastric Cancer found a positive correlation of MKNK2 with memory B cells, regulatory T cells (Tregs), and CD8 T cells in gastric cancer, all of which are reported to be strongly associated with tumors (23)(24)(25).…”

miR‐148a‐3p silences the CANX/MHC‐I pathway and impairs CD8+T cell‐mediated immune attack in colorectal cancer

“…40,41 IL-1β stimulation could enhance ER stress-induced apoptosis sensitivity in renal cell carcinoma through the induction of PERK and CANX expression. 41 The activation of the EFGR pathway could activate caspase-8-mediated cleavage to the CANX cytosolic domain. The cleaved CANX cytoplasmic domain moves into the nucleus where it binds to PIAS3 (a natural inhibitor of STAT3), thereby preventing PIAS3 from binding to STAT3.…”

“…These molecules are essential to the stable formation of DC and T‐cell synapses 39 . In addition, CANX expression may similarly increase the sensitivity to ER stress‐induced apoptosis 40,41 . IL‐1β stimulation could enhance ER stress‐induced apoptosis sensitivity in renal cell carcinoma through the induction of PERK and CANX expression 41 .…”

“…In addition, CANX expression may similarly increase the sensitivity to ER stress‐induced apoptosis 40,41 . IL‐1β stimulation could enhance ER stress‐induced apoptosis sensitivity in renal cell carcinoma through the induction of PERK and CANX expression 41 . The activation of the EFGR pathway could activate caspase‐8‐mediated cleavage to the CANX cytosolic domain.…”

Tanshinone IIA Inhibits Osteosarcoma Growth through a Src Kinase-Dependent Mechanism

“…Generally, tumorigenesis is identified at 2-3 weeks when the local tumor mass size was about l cm 3 . Tumor growth status was determined as follows [15]: poor tumor growth was defined as an average tumor weight of < l g or if the tumor weight was <400 mg in mice with 20% overall tumor weight. Nude mice with poor tumor growth that met these criteria were considered a failed model and were excluded.…”