Table 1.

Comparative summary of in vitro studies investigating miR-218 function in lung cancer

Mechanistic category	Targets	Comparative summary of miR-218 function in NSCLC cells	References
Apoptosis and cell-survival signaling	Bcl-2, BMI-1, YY1, PTEN, Mcl-1, Survivin, PARP, Caspase-3, Bax	Across these studies, miR-218 overexpression reduces the expression of multiple anti-apoptotic proteins (Bcl-2, BMI-1, Mcl-1, Survivin) while increasing pro-apoptotic markers (cleaved PARP, Caspase-3, Bax), leading to reduced cell viability and enhanced apoptosis. Conversely, loss of miR-218 has the opposite effect, supporting its consistent pro-apoptotic and tumor-suppressive roles	[64,72,75]
JAK-STAT proliferative signaling	IL-6R, JAK3	miR-218 decreases IL-6R and JAK3 levels, resulting in suppressed cytokine-driven proliferation. This links miR-218 to the inhibition of IL-6/STAT-type growth signaling in NSCLC	[56]
Growth-factor receptor signaling	EGFR	By targeting EGFR, miR-218–5p reduces receptor expression and downstream signaling, thereby suppressing cell migration and proliferation	[73]
Cell motility and structural support	PXN, RPTPa, CDCP1	PXN, RPTPa, and CDCP1 are proteins that promote cancer cell adhesion, motility and dissemination. Across these studies, miR-218 overexpression decreases their expression, leading to reduced migration, invasion and, in some models, diminished tumor growth and colony formation	[74,76–78]
EMT, invasion and metastasis	Robo1, Ecop, TRIM9, HMGB1, CDH2/N-cadherin, Slug, ZEB2, Robo1, CDCP1, HS3ST3B1	Multiple independent studies demonstrated that miR-218 downregulates EMT drivers at different levels, including surface receptors (Robo1, CDCP1, HS3ST3B1), transcriptional regulators (Slug, ZEB2), mesenchymal markers (CDH2) and pro-invasive factors (Ecop, HMGB1, TRIM9). Across these targets, miR-218 consistently reduces EMT marker expression as well as cell migration and invasion, indicating that inhibition of EMT and metastatic potential is a central function of miR-218 in NSCLC	[76,77,79–85]
Transcriptional growth control	MEF2D	By suppressing MEF2D, miR-218 inhibits lung cancer cell growth, supporting its broader role in limiting cancer progression	[86]
Metabolic regulation and stress response	SHMT1, ERO1A, GLUT1	miR-218 affects several metabolic pathways: it reduces GLUT1-mediated glucose uptake, interferes with folate/one-carbon metabolism through SHMT1, and disrupts oxidative and ER stress responses via ERO1A. Across these pathways, miR-218 consistently limits metabolic activity, reduces tumor growth, and suppresses angiogenesis	[87–89]
Chemotherapy sensitivity (platinum agents)	RUNX2, Bcl-2/BMI-1/Mcl-1/Survivin axis	miR-218 improves the response to cisplatin by downregulating RUNX2 and enhances carboplatin-induced cell death by reducing survival-related proteins. Overall, miR-218 acts as a sensitizer to platinum-based drugs by weakening resistance pathways	[64,72,75,90]
Targeted therapy resistance (EGFR-TKI)	HOXA1	In gefitinib-resistant NSCLC, restoration of miR-218 levels decreases HOXA1 levels, reducing proliferation and promoting gefitinib-induced apoptosis, indicating that loss of miR-218 contributes to resistance to EGFR-TKIs	[65]
Radiation response and DNA-damage repair	PRKDC	miR-218 directly suppresses PRKDC, a key DNA repair enzyme, leading to increased unrepaired DNA damage, enhanced apoptosis, and greater radiosensitivity, including in radiation-resistant models	[91]

Bcl-2: B-cell lymphoma; BMI-1: B lymphoma Mo-MLV insertion region 1 homolog; YY1: Yin Yang 1; PTEN: phosphatase and tensin homolog; Mcl-1: myeloid cell leukemia sequence 1; PARP: poly-ADP ribose polymerase; JAK: Janus kinase; STAT: signal transducer and activator of transcription; IL-6 - Interleukin-6; EGFR: epidermal growth factor receptor; PXN: paxillin; RPTPα: receptor protein tyrosine phosphatase alpha; CDCP1: CUB-domain-containing protein 1; Robo1: roundabout homolog 1; Ecop: EGFR-coamplified and -overexpressed protein; TRIM9: tripartite motif 9; CDH2: N(Neural)-cadherin; ZEB2: Zinc finger E-box-binding homeobox 2; HS3ST3B1: Heparan sulfate D-glucosamine 3-O-sulfotransferase 3B1; MEF2D: myocyte enhancer factor 2D; SHMT1: serine hydroxymethyltransferase 1; ERO1A: endoplasmic reticulum oxidoreductase 1 alpha; GLUT1: glucose transporter 1; RUNX2: Runt-related transcription factor 2; HOXA1: homeobox A1; PRKDC: protein kinase, DNA-activated, catalytic subunit; NSCLC: non-small-cell lung cancer; EMT: epithelial-mesenchymal transition; IL-6R: interleukin-6 receptor; EGFR-TKI: EGFR-tyrosine kinase inhibitor.