Ferroptosis is a regulated form of cell death driven by small molecules or conditions that induce lipid-based reactive oxygen species (ROS) accumulation. This form of iron-dependent cell death is morphologically and genetically distinct from apoptosis, necroptosis, and autophagy. miRNAs are known to play crucial roles in diverse fundamental biological processes. However, to date no study has reported miRNA-mediated regulation of ferroptosis. Here we show that miR-137 negatively regulates ferroptosis by directly targeting glutamine transporter SLC1A5 in melanoma cells. Ectopic expression of miR-137 suppressed SLC1A5, resulting in decreased glutamine uptake and malondialdehyde (MDA) accumulation. Meanwhile, antagomir-mediated inactivation of endogenous miR-137 increased the sensitivity of melanoma cells to erastin- and RSL3-induced ferroptosis. Importantly, knockdown of miR-137 increased the antitumor activity of erastin by enhancing ferroptosis both in vitro and in vivo. Collectively, these data indicate that miR-137 plays a novel and indispensable role in ferroptosis by inhibiting glutaminolysis and suggest a potential therapeutic approach for melanoma.

/pdf/mir-137-regulates-ferroptosis-by-targeting-glutamine-2zlxm476e3.pdf

miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma

MicroRNAs (miRNAs) play a critical role in regulating various biological processes, such as cell differentiation and immune modulation by binding to their target genes. miR-223 is a miRNA with important functions and has been widely investigated in recent years. Under certain physiological conditions, miR-223 is regulated by different transcription factors, including sirtuin1 (Sirt1), PU.1 and Mef2c, and its biological functions are mediated through changes in its cellular or tissue expression. This review paper summarizes miR-223 biosynthesis and its regulatory role in the differentiation of granulocytes, dendritic cells (DCs) and lymphocytes, macrophage polarization, and endothelial and epithelial inflammation. In addition, it describes the molecular mechanisms of miR-223 in regulating lung inflammation, rheumatoid arthritis, enteritis, neuroinflammation and mastitis to provide insights into the existing molecular regulatory networks and therapies for inflammatory diseases in humans and animals.

miR-223: An Effective Regulator of Immune Cell Differentiation and Inflammation.

Lung squamous cell carcinoma (LUSC) is often diagnosed at the advanced stage with poor prognosis. The mechanisms of its pathogenesis and prognosis require urgent elucidation. This study was performed to screen potential biomarkers related to the occurrence, development and prognosis of LUSC to reveal unknown physiological and pathological processes. Using bioinformatics analysis, the lung squamous cell carcinoma microarray datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were analyzed to identify differentially expressed genes (DEGs). Furthermore, PPI and WGCNA network analysis were integrated to identify the key genes closely related to the process of LUSC development. In addition, survival analysis was performed to achieve a prognostic model that accomplished good prediction accuracy. Three hundred and thirty–seven up–regulated and 119 down-regulated genes were identified, in which four genes have been found to play vital roles in LUSC development, namely CCNA2, AURKA, AURKB, and FEN1. The prognostic model contained 5 genes, which were all detrimental to prognosis. The AUC of the established prognostic model for predicting the survival of patients at 1, 3, and 5 years was 0.692, 0.722, and 0.651 in the test data, respectively. In conclusion, this study identified several biomarkers of significant interest for additional investigation of the therapies and methods of prognosis of lung squamous cell carcinoma.

https://www.mdpi.com/1422-0067/21/8/2994/pdf

Identification of Key Genes Related to Lung Squamous Cell Carcinoma Using Bioinformatics Analysis.

Spinal cord injuries are common and troublesome disorder, which is mediated by various signal pathways and mechanisms. MK2 is also involved in numerous inflammatory diseases including spinal cord injury. The role of microRNA-137 (miR-137) and its detailed working mechanism in spinal cord injuries remain unclear. In the present study, we found that an elevated MK2 but a decreased miR-137 was expressed in serum specimens of patients with spinal cord injury and in hydrogen peroxide-treated C8-D1A and C8-B4 cells. Meanwhile, we suggested that upregulation of miR-137 could inhibit the expression of TNF-α and IL-6, two markers of inflammatory response after SCI, and apoptosis in hydrogen peroxide-treated C8-D1A and C8-B4 cells. Furthermore, we verified that MK2 was a direct target of miR-137 thorough a constructed luciferase assay. Even further, we elucidated that miR-137 could suppress the inflammatory response and apoptosis via negative regulation of MK2. Finally, through an animal model trial performed using mice, we demonstrated the protective effect of how miR-137 works on inflammatory response and apoptosis after spinal cord injury. Considering all the forementioned, our findings revealed that miR-137 inhibited inflammatory response and apoptosis after spinal cord injury via the targeting of MK2. The outcomes of the present study might indicate a new target in molecular treatment of SCI.

MiR-137 inhibited inflammatory response and apoptosis after spinal cord injury via targeting of MK2.

ABSTRACT NLRP3 inflammasome mainly controls interleukin-1β (IL-1β) secretion, leading to cell death called pyroptosis constituting a major antiviral host defense and inflammatory diseases upon viral infection. The RAF-MEK1/2-ERK1/2 cascade and downstream c-Jun/Fos and Activator protein-1 (AP1) signaling pathway control the degree of inflammatory response. Influenza A virus (IAV) infection is known to stimulate NLRP3 inflammasome activation and inflammatory responses. Nevertheless, the detailed mechanism by which IAV induces NLRP3 inflammasome activation involved in transcription of pro-IL-1β mRNA remains elusive. In our study, we found that IAV infection promotes pro-IL-1β mRNA transcription and activates NLRP3 inflammasome. Detailed studies reveal that type I interferon (IFN-α/IFN-β) as well as U0126 (a selective inhibitor of MEK-1 and MEK-2) typically inhibit IAV-mediated NLRP3 inflammasome activation via downregulating pro-IL-1β mRNA. Moreover, knock-down of c-Jun decreases pro-IL-1β mRNA and inhibits NLRP3 inflammasome activation upon IAV infection. Overall, the findings uncover that AP-1 signaling pathway promotes NLRP3 inflammasome activation upon IAV infection, which provides a new idea for the therapy of NLRP3 inflammasome-associated inflammatory diseases.

https://www.tandfonline.com/doi/pdf/10.1080/21505594.2022.2040188?needAccess=true

AP-1 signaling pathway promotes pro-IL-1β transcription to facilitate NLRP3 inflammasome activation upon influenza A virus infection

STIM1 mediates IAV-induced inflammation of lung epithelial cells by regulating NLRP3 and inflammasome activation via targeting miR-223

Aim The purpose of the present study was to explore the function and mechanism of tensin 1 (TNS1) in non-small cell lung cancer (NSCLC) progression. Methods The expression of TNS1 in NSCLC cells and tissues was assessed by RT-PCR and Western blot. Besides, Kaplan-Meier survival analysis was recruited to explore the association between TNS1 and NSCLC. Cell growth was analyzed by MTT and flow cytometry assay, while cell metastasis was determined by wound healing and transwell assays. The targeting relationship between TNS1 and miR-152 was assessed by luciferase activity assays. And Western blot was employed to determine the expression of related proteins of Akt/mTOR/RhoA pathway. Results TNS1 level was boosted in NSCLC cells and tissues, related to the prognosis of NSCLC patients. Furthermore, it was proved that TNS1 promoted the growth and metastasis of NSCLC cells via Akt/mTOR/RhoA pathway. And miR-152 targeted TNS1 to affect the progression of NSCLC. Conclusion miR-152/TNS1 axis inhibits the progression of NSCLC by Akt/mTOR/RhoA pathway.

/pdf/mir-152-tns1-axis-inhibits-non-small-cell-lung-cancer-50sowvj2pe.pdf

miR-152/TNS1 axis inhibits non-small cell lung cancer progression through Akt/mTOR/RhoA pathway.

Lung cancer is the leading cause of cancer-related mortality worldwide and cigarette smoking is reported to contribute to the lung cancer-related mortality. The present study aimed to investigate the molecular mechanism underlying nicotine-induced chemoresistance in lung cancer. The expression of microRNA (miR)-21-3p and its predicted target FOXO3a in lung cancer cells was detected via reverse transcription-quantitative PCR, in the presence or absence of nicotine. The regulatory effect of miR-21-3p and FOXO3a on lung cancer cell proliferation and apoptosis induced by docetaxel or cisplatin treatment was evaluated by performing Cell Counting Kit-8 and Annexin V/PI staining assays, respectively. The interaction between miR-21-3p and FOXO3a was analyzed by performing luciferase reporter assays and western blotting. FOXO3a overexpression rescue experiments were conducted in vitro and in vivo using a xenograft mouse model to assess the function of miR-21-3p/FOXO3a in lung cancer. Nicotine induced miR-21-3p expression in lung cancer cells in a dose-dependent manner. miR-21-3p downregulated FOXO3a expression by directly binding to the 3′-untranslated region of FOXO3a. Moreover, miR-21-3p knockdown sensitized lung cancer cells to docetaxel or cisplatin treatment. Mechanistically, FOXO3a was predicted as a direct target of miR-21-3p. FOXO3a overexpression promoted the chemosensitivity of lung cancer cells to docetaxel or cisplatin treatment. Furthermore, FOXO3a overexpression antagonized the regulatory function of miR-21-3p on docetaxel- or cisplatin-treated lung cancer cells. In the docetaxel- or cisplatin-treated lung cancer xenograft mouse model, miR-21-3p promoted chemoresistance via negatively regulating FOXO3a. Therefore, the present study demonstrated that nicotine-induced miR-21-3p promoted chemoresistance to docetaxel or cisplatin treatment via negatively regulating FOXO3a, which may serve as a novel therapeutic strategy for the treatment of patients with chemoresistant lung cancer.

/pdf/nicotine-induced-mir-21-3p-promotes-chemoresistance-in-lung-3nlmcqvt.pdf

Nicotine-induced miR-21-3p promotes chemoresistance in lung cancer by negatively regulating FOXO3a

A class of adhesion protein that occurs in the membrane with both extracellular and intracellular domain and play vital role in maintaining multicellularity is TRASK, also called CUB-domain containing protein1, CD318 (CDCP1). Specifically, in the current study, documented aggressive grades of lung cancers and distant metastatic tissues were examined for protein interactions of Trask and compared with lung cancer variants in situ. The intracellular domain of Trask has the ability to undergo tyrosine phosphorylation and thereafter undergo increased genomic expression, as well as interact with cytoskeletal proteins in the cell periphery and other local signal transduction machinery to induce invadopodia formation and distant metastasis. We incorporated proximity ligation assay to examine protein interactions of Trask in metastatic lung cancer tissues and compare with advanced and low-grade lung cancers restricted to the primary site of origins. Here, we provide direct evidence that activated Trask, which is a phosphorylated form, binds with cytoskeletal proteins actin and spectrin. These interactions were not seen in locally growing lung cancer and cancer in situ. These interactions may be responsible for invadopodia formation and breaking free from a multicellular environment. Functional studies demonstrated interaction between Trask and the STOCs Orai1 and Stim1. Calcium release from internal stores was highest in metastatic lung cancers, suggesting this mechanism as an initial stimulus for the cells to respond chaotically to external growth factor stimulation, especially in aggressive metastatic variants of lung cancers. Recently, inhibitors of STOCs have been identified, and preclinical evidence may be obtained whether these drugs may be of benefit in preventing the deadly consequences of lung cancer.

Significance of Trask protein interactions in brain metastatic cohorts of lung cancers

Leucine-rich repeat kinase 2 (LRRK2) plays an important role in a variety of inflammatory diseases, as well as peripheral and central immune responses. At present, there are few reports about the role of LRRK2 in lung cancer, and need to be further explored. The main purpose of this study is to explore the role and mechanism of LRRK2 in lung cancer. The results revealed that the expression of LRRK2 was increased in the tissues of lung cancer patient and lung cancer cells. Further studies found that interference with LRRK2 expression significantly induced the apoptosis, and promoted the expression of caspase-3, caspase-9, and Bax. More importantly, si-LRRK2 inhibited the expression of VEGF and P-gp, indicating inhibition of cell proliferation and drug resistance. What’s more, LRRK2 regulated TLR4/NF-κB signaling pathways and NLRP3 inflammasome, and TLR4/NF-κB pathways was involved in the molecular mechanism of LRRK2 on lung cancer cells. In conclusion, this study suggested that the mechanism of si-LRRK2 inhibiting the progression of lung cancer is to regulate the TLR4/NF-κB signaling pathways and NLRP3 inflammasome.

Knockdown of LRRK2 inhibits the progression of lung cancer by regulating TLR4/NF-κB pathways and NLRP3 inflammasome

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