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

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 TNFinduced 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.

The Antitriple Negative Breast cancer Efficacy of Spatholobus suberectus Dunn on ROS‐Induced Noncanonical Inflammasome Pyroptotic Pathway

“…In the present study, survival analysis using the KM Plotter revealed that the low transcription levels of caspase-4 and 9 are related to low relapse-free survival in BCa. This study was consistent with earlier investigations in which researchers concluded that the caspase family is operated as new prognostic indicators in various cancers, including breast [ 79 ], gastric [ 80 ], ovary [ 81 ], and renal [ 82 ]. TNM plot analysis showed that the expression of caspase-4 and GSDME was significantly inhibited in clinical tissues in normal (113), tumor (1097), and metastatic (07) states, which was consistent with the earlier investigation [ 47 ].…”

The LncRNA CASC11 Promotes Colorectal Cancer Cell Proliferation and Migration by Adsorbing miR-646 and miR-381-3p to Upregulate Their Target RAB11FIP2

“…miR-381-3p also functions as a tumour suppressor in non-small-cell lung cancer (34), oral squamous cell carcinoma (35), breast cancer (36), and cervical cancer (37). However, Zhao et al (38) demonstrated that miR-381-3p can promote renal cell carcinoma by inhibiting apoptosis and necrosis. However, miR-381-3p has not been reported in CRC-related research.…”

Beneficial role of microRNA‑328‑3p in fracture healing by enhancing osteoblastic viability through the PTEN/PI3K/AKT pathway

“…Bone regeneration is the key to fracture healing, which involves the proliferation, apoptosis and differentiation of osteoblasts ( 20 ), implying that methods that regulate osteoblastic activity may assist fracture healing. miRNAs have important regulatory effects on various cellular processes, such as cell proliferation, migration, invasion, differentiation and apoptosis ( 21 ). Emerging studies have focused on deregulated miRNAs during fracture healing, which are expected to promote the development of novel strategies to accelerate healing by improving osteoblastic viability.…”