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RNA-binding protein CIRBP mediates PKM2 intron retention to negatively regulate multiple myeloma progression and macrophage alternative activation

ABSTRACT: Multiple myeloma (MM) is a systemic malignancy characterized by the induction of osteolytic lesions. Cold-inducible RNA binding protein (CIRBP) has garnered attention in cancer research due to its dual role as either an oncogene or a tumor suppressor. In this study, publicly available single-cell RNA sequencing data, MM cell lines, and an in vivo xenograft model are utilized to assess the biological significance of CIRBP in MM. Analysis reveals frequent communication between MM cells and macrophages, alongside decreased CIRBP expression in patients. Functionally, CIRBP overexpression in MM cells inhibits short- and long-term viability, suppresses proliferation, and reduces tumor burden in vitro and in vivo. Furthermore, co-culture experiments confirm that CIRBP-expressing MM cells suppress macrophage chemotaxis and macrophage alternative activation, while CIRBP knockdown has opposite effects. Mechanistically, CIRBP binds to intron1 of pyruvate kinase M2 (PKM2) precursor messenger RNA (pre-mRNA), inhibiting its splicing and promoting its nonsense-mediated decay, ultimately leading to downregulation of PKM2. Elevated levels of PKM2 rescue the CIRBP-mediated suppression of macrophage chemotaxis and macrophage alternative activation. Our findings support the notion of CIRBP as a candidate tumor suppressor in MM and unveil a post-transcriptional regulatory mechanism governing PKM2-mediated macrophage plasticity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE339058 | GEO | 2026/09/18

REPOSITORIES: GEO

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Project description:Background: Albeit with well-recorded cytoprotective function, the study of stress protein CIRBP coping with cardiotoxicity during chemotherapy remains obscured. Here we report that CIRBP plays a critical role in safeguarding against chemo-induced cardiac apoptosis and dysfunction. Methods: Treating the immortalized human ventricular myocytes (T0519) and neonatal rat ventricular myocytes (NRVMs) with three regular chemotherapeutics (DOX/Cisplatin/5-FU), and DOX-induced cardiotoxic mouse model were leveraged to explore the cardioprotection of CIRBP during chemotherapy. We took advantage of AAV9 carrying CIRBP or shCIRBP expressive cassette under cTNT promoter to interfere with cardiac CIRBP expression. A conjoint analysis of transcriptomics and proteomics was performed within T0519 to identify the latent effector of CIRBP in regulating cardiomyocyte apoptosis. By contrast with the pan-opioid receptor Alvimopan (ALV), OGFR blocker Naltrexone (NTX) was introduced to disrupt CIRBP-OGFR signaling in an attempt to provide new insight in formulating efficacious cardioprotective scheme for tumor patients. Results: We discovered that CIRBP deficiency is involved in in-vivo and in-vitro cardiomyocyte apoptosis triggered by chemotherapeutic agents. Ectopic delivery of CIRBP in mouse myocardium significantly mitigates doxorubicin-induced cardiac apoptosis and malfunction. Opioid growth factor receptor (OGFR) was further highlighted as CIRBP downstream effector responsible for cardiomyocyte chemotherapeutical apoptosis. Mechanistically, CIRBP interacts with OGFR mRNA and represses OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced apoptosis relies largely on the regulation of CIRBP on OGFR. Naltrexone, an antagonist targeting OGFR of potency as well as certain opioid receptors, successfully rescues CIRBP ablation-rendered susceptibility to cardiac apoptosis and dyshomeostasis when exposed to DOX; while another antagonist Alvimopan, merely acting on opioid receptors, does not. Conclusions: Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction via dampening OGF/OGFR axis, shedding new light on the cardioprotection of tumor patients subjected to chemotherapy.

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RNA-binding protein CIRBP mediates PKM2 intron retention to negatively regulate multiple myeloma progression and macrophage alternative activation

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