PD-1 inhibitor inducing exosomal miR-34a-5p expression mediates the cross talk between cardiomyocyte and macrophage in immune checkpoint inhibitor–related cardiac dysfunction

Sun

et al. 2021

Front. Cell Dev. Biol.

Low back pain is tightly associated with intervertebral disc degeneration (IVDD) and aberrant nucleus pulposus (NP) is a critical cause. miRNAs N6-methyladenosine (m6A) modification accounts for the TNF-α-induced senescence of NP cells. The aim of this study was to investigate whether m6A modification regulates TNF-α-mediated cell viability, cell cycle arrest, and cell senescence and how it works. The results showed that METTL14 expression positively correlated with m6A and TNF-α expression in HNPCs. The knockdown of METTL14 led to the inhibition of the TNF-α-induced cell senescence. METTL14 overexpression promoted cell senescence. METTL14 regulated the m6A modification of miR-34a-5p and interacted with DGCR8 to process miR-34a-5p. The miR-34a-5p inhibitor inhibited the cell cycle senescence of HNPCs. miR-34a-5p was predicted to interact with the SIRT1 mRNA. SIRT1 overexpression counteracted the miR-34a-5p-promoted cell senescence. METTL14 participates in the TNF-α-induced m6A modification of miR-34a-5p to promote cell senescence in HNPCs and NP cells of IVDD patients. Downregulation of either METTL14 expression or miR-34a-5p leads to the inhibition of cell cycle arrest and senescence. SIRT1 mRNA is an effective binding target of miR-34a-5p, and SIRT1 overexpression mitigates the cell cycle arrest and senescence caused by miR-34a-5p.

Section: Discussionmentioning

confidence: 99%

N6-Methyladenosine Induced miR-34a-5p Promotes TNF-α-Induced Nucleus Pulposus Cell Senescence by Targeting SIRT1

Sun

et al. 2021

Front. Cell Dev. Biol.

Front. Cardiovasc. Med.

“…miRNAs also play an important role in ICI-induced cardiac injury. Specifically, the PD-1 inhibitor promote a large amount of miR-34a aggregation in cardiomyocytes by regulating the miR-34a/KLF4 and miR-34a/Pnuts signaling pathways to induce myocardial inflammation and promote myocardial aging ( 100 , 101 ). miRNAs are therefore potential therapeutic targets for ICI-induced cardiac injury.…”

Section: Emerging Biomarkersmentioning

confidence: 99%

Advances in Biomarkers for Detecting Early Cancer Treatment-Related Cardiac Dysfunction

Xiao

Wang

et al. 2021

With the gradual prolongation of the overall survival of cancer patients, the cardiovascular toxicity associated with oncology drug therapy and radiotherapy has attracted increasing attention. At present, the main methods to identify early cancer treatment-related cardiac dysfunction (CTRCD) include imaging examination and blood biomarkers. In this review, we will summarize the research progress of subclinical CTRCD-related blood biomarkers in detail. At present, common tumor therapies that cause CTRCD include: (1) Chemotherapy—The CTRCD induced by chemotherapy drugs represented by anthracycline showed a dose-dependent characteristic and most of the myocardial damage is irreversible. (2) Targeted therapy—Cardiovascular injury caused by molecular-targeted therapy drugs such as trastuzumab can be partially or completely alleviated via timely intervention. (3) Immunotherapy—Patients developed severe left ventricular dysfunction who received immune checkpoint inhibitors have been reported. (4) Radiotherapy—CTRCD induced by radiotherapy has been shown to be significantly associated with cardiac radiation dose and radiation volume. Numerous reports have shown that elevated troponin and B-type natriuretic peptide after cancer treatment are significantly associated with heart failure and asymptomatic left ventricular dysfunction. In recent years, a few emerging subclinical CTRCD potential biomarkers have attracted attention. C-reactive protein and ST2 have been shown to be associated with CTRCD after chemotherapy and radiation. Galectin-3, myeloperoxidas, placental growth factor, growth differentiation factor 15 and microRNAs have potential value in predicting CTRCD. In this review, we will summarize CTRCD caused by various tumor therapies from the perspective of cardio-oncology, and focus on the latest research progress of subclinical CTRCD biomarkers.

“…Interestingly, ncRNAs might also mediate side effects of ICI treatment. Xia et al revealed that ICIs induce exosomal trafficking of miR-34a-5p from macrophages to cause cardiac injury in vivo [ 320 ]. However, few studies have focused on the direct alterations of ncRNA profiles during ICI treatment, which might become a hot field in the near future.…”

Section: Noncoding Rnas Bridge Metabolites and Pro- Or Antitumor Immunitymentioning

confidence: 99%

Noncoding RNAs link metabolic reprogramming to immune microenvironment in cancers

et al. 2021

Altered metabolic patterns in tumor cells not only meet their own growth requirements but also shape an immunosuppressive microenvironment through multiple mechanisms. Noncoding RNAs constitute approximately 60% of the transcriptional output of human cells and have been shown to regulate numerous cellular processes under developmental and pathological conditions. Given their extensive action mechanisms based on motif recognition patterns, noncoding RNAs may serve as hinges bridging metabolic activity and immune responses. Indeed, recent studies have shown that microRNAs, long noncoding RNAs and circRNAs are widely involved in tumor metabolic rewiring, immune cell infiltration and function. Hence, we summarized existing knowledge of the role of noncoding RNAs in the remodeling of tumor metabolism and the immune microenvironment, and notably, we established the TIMELnc manual, which is a free and public manual for researchers to identify pivotal lncRNAs that are simultaneously correlated with tumor metabolism and immune cell infiltration based on a bioinformatic approach.