MicroRNA-381-3p Functions as a Dual Suppressor of Apoptosis and Necroptosis and Promotes Proliferation of Renal Cancer Cells.

Cong Zhao,Jie Ju,Ying Yao,Tao Yang,Haoran Zhang,Xiaoliang Yu,Wei Zhang,Sudan He,Yifei Zhou,Qiao Ran

doi:10.3389/fcell.2020.00290

Abstract

Renal cell carcinoma (RCC) is the most common type of kidney cancer. It has a poor prognosis, with approximately 20–30% of patients developing recurrent and/or metastatic diseases that is relatively high resistant to conventional therapy. Resisting cell death is a hallmark of cancer cells. Apoptosis is a form of programmed cell death mediated by the activation of caspases. Necroptosis is a form of regulated necrosis that relies on the activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL), the substrate of RIPK3. Cancer cells often display apoptosis resistance via upregulation of anti-apoptotic genes and defective necroptosis due to the epigenetic silence of Ripk3. MicroRNAs (miRNAs) are non-coding small RNAs that are involved in numerous biological processes including cell proliferation, differentiation and death. In this study, we screened a set of ∼120 miRNAs for apoptosis-regulating miRNAs and identified miR-381-3p as a suppressor of TNF-induced apoptosis in various cancer cells. Ectopic expression of miR-381-3p inhibits the activation of caspase-8 and caspase-3. The expression level of miR-381-3p inversely correlates with the sensitivity of cancer cells to TNF-induced apoptosis. Moreover, we found that overexpression of miR-381-3p blocks TNF-induced necroptosis by inhibiting the activation of RIPK3 and MLKL. Of note, Kaplan-Meier Plotter analysis demonstrates that papillary RCC patients with high miR-381-3p expression have a lower overall survival than those with low expression level of miR-381-3p. Importantly, miR-381-3p overexpression promotes colony formation in human renal cancer cells. Thus, miR-381-3p acts as an oncogenic miRNA that counteracts both apoptotic and necroptotic signaling pathways. Our findings highlight miR-381-3p as a biomarker for predicting sensitivity to apoptosis and necroptosis, and as a possible therapeutic target for RCC.

Highlights

IntroductionCell death is crucial for the individual development and homeostasis maintenance
In multicellular organisms, cell death is crucial for the individual development and homeostasis maintenance
To identify miRNAs involved in the cellular response to apoptosis, we screened a set of ∼ 120 miRNAs to identify candidate miRNAs regulating TNF-induced apoptosis, which is known to be induced by the treatment of TNF-α plus Smac mimetic (Wang et al, 2008)

Summary

Introduction

Cell death is crucial for the individual development and homeostasis maintenance. Activation of mitochondria pathway results in the release of mitochondrial cytochrome c to the cytosol and subsequent assembly of the apoptosome, a protein complex comprised of cytochrome c, procaspase-9 and apoptotic protease activating factor-1 (Apaf-1) (Li et al, 1997). This event leads to the activation of caspase-9. RIPK1 forms a cytosolic protein complex (Complex II) with FADD and procaspase-8, leading to the activation of caspase-8 (Micheau and Tschopp, 2003; Wang et al, 2008). Activated caspase-9 or caspase-8 can cleave and activate the executor caspases such as caspase-3 and caspase-7, eventually leading to apoptosis

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Results

Conclusion