Smoking‐Induced M2‐TAMs, via circEML4 in EVs, Promote the Progression of NSCLC through ALKBH5‐Regulated m6A Modification of SOCS2 in NSCLC Cells

Abstract

Lung cancer is a commonly diagnosed disease worldwide, with non-small cell lung cancers (NSCLCs) accounting for ≈ 85% of cases. Cigarette smoke is an environmental exposure promoting progression of NSCLC, but its role is poorly understood. This study reports that smoking-induced accumulation of M2-type tumor-associated macrophages (M2-TAMs) surrounding NSCLC tissues promotes malignancy. Specifically, extracellular vesicles (EVs) from cigarette smoke extract (CSE)-induced M2 macrophages promoted malignancy of NSCLC cells in vitro and in vivo. circEML4 in EVs from CSE-induced M2 macrophages is transported to NSCLC cells, where it reduced the distribution of ALKBH5 in the nucleus by interacting with Human AlkB homolog H5 (ALKBH5), resulting in elevated N6-methyladenosine (m6A) modifications. m6A-seq and RNA-seq revealed suppressor of cytokine signaling 2 (SOCS2)-mediated activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway by regulating m6A modification of SOCS2 via ALKBH5. Down-regulation of circEML4 in EVs from CSE-induced M2 macrophages reversed EVs-enhanced tumorigenicity and metastasis in NSCLC cells. Furthermore, this study found that smoking patients showed an increase in circEML4-positive M2-TAMs. These results indicate that smoking-induced M2-TAMs via circEML4 in EVs promote the NSCLC progression through ALKBH5-regulated m6A modification of SOCS2. This study also reveals that circEML4 in EVs from TAMs acts as a diagnostic biomarker for NSCLC, especially for patients with smoking history.

Prognostic factors and predictive model construction in patients with non-small cell lung cancer: a retrospective study

“…Smoking status is also considered a potential risk factor for disease progression. Cheng et al (40)found that smoking has the potential to accelerate tumor progression, a phenomenon attributed to the smoking-induced accumulation of M2-tumor-associated macrophages (M2-TAMs) around non-small cell lung cancer tissue. In addition, radiation therapy is considered to be one of the most effective methods of tumor control.…”

Functional roles of circular RNAs in lung injury

“…Lower circCIMT expression was associated with DNA damage in the mouse lung tissue and blood after Cd exposure, which contributing to the acquisition of tumor characteristics of lung epithelial cells ( Li et al, 2023 ). What’s more, smoking-induced M2 macrophages via circEML4 in extracellular vesicles promote the non small cell lung cancer progression through ALKBH5-regulated m6A modification of SOCS2, which leading to the activation of JAK-STAT pathway ( Cheng et al, 2023 ). Similarly, CircTMEM30A was highly expressed in COPD patients with lung cancer, and it regulated the expression of TNFα through miR-130a, thereby promoting the progression of COPD and lung cancer ( Shen et al, 2023 ).…”

Roles and mechanisms of circular RNA in respiratory system cancers

“…Besides its involvement in various physiological and autoimmune diseases, circRNA also plays an important role in the onset and progression of various malignant tumors ( 54 ), cell proliferation ( 55 ), cell apoptosis, and metastasis ( 56 ). With advancements in bioinformatics technology, an increasing number of circRNAs have been shown to play different biological functions in various cancer systems via multiple pathways ( 57 , 58 ).…”