miR-668: A Dual-Role microRNA in Disease and Therapy
image: Pan-cancer expression analysis of miR-668-3p To explore the pan-cancer expression pattern of miR-668-3p, we retrieved the TCGA (Pan-Cancer) dataset from the UCSC Xena database (https://xenabrowser.net/). Subsequently, we extracted the expression data of the mature miR-668-3p chain in each sample. We filtered out samples with 0 expression, performed a log2(x + 1) transformation, excluded cancer types without corresponding control samples, and obtained the expression data for 15 cancer types. BRCA: breast invasive carcinoma; CESC: cervical cancer; CHOL: cholangiocarcinoma; COAD: colon adenocarcinoma; COADREAD: colon and rectal cancer; CRC: colorectal cancer; ESCA: esophageal carcinoma; GBMLGG: glioblastoma and low-grade glioma; GC: gastric cancer; HCC: hepatocellular carcinoma; KICH: kidney chromophobe; KIRC: kidney clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; NHSC: head and neck squamous cell carcinoma; NSCLC: non-small cell lung cancer; PAAD: pancreatic cancer; PCPG: pheochromocytoma and paraganglioma; PRAD: prostate adenocarcinoma; READ: rectum adenocarcinoma; STAD: stomach cancer; THCA: thyroid carcinoma; THYM: thymoma.
Credit: Qu-rui Wang, Jin-ze Shen, Jia-hua Si, Xin-ming Su, Jian-qiao Shentu, Ze-hua Wang, Shi-wei Duan.
MicroRNA-668 (miR-668) has emerged as a critical regulatory molecule with pleiotropic effects across multiple physiological and pathological processes. This small non-coding RNA demonstrates remarkable context-dependent functionality, exhibiting both protective and pathogenic roles depending on the tissue environment and disease state. The current understanding of miR-668 reveals its involvement in fundamental cellular processes including proliferation, apoptosis, mitochondrial dynamics, and inflammatory responses.
In the context of cancer biology, miR-668 displays a particularly complex duality. It functions as a potent oncogenic driver in certain malignancies, most notably in hepatocellular carcinoma and breast cancer, where it promotes tumor progression through multiple mechanisms. These include suppression of tumor suppressor genes like BTG2 (B-cell translocation gene 2) and FHIT (fragile histidine triad), activation of pro-survival NF-κB signaling, and enhancement of radiation resistance. Paradoxically, in other cellular contexts such as normal human keratinocytes, miR-668 appears to exert tumor-suppressive effects, highlighting the importance of cellular microenvironment in determining its functional outcomes.
The protective functions of miR-668 become particularly evident in ischemic conditions affecting various organs. In acute kidney injury and myocardial infarction models, miR-668 serves as a crucial mediator of cellular protection by maintaining mitochondrial integrity through regulation of MTFP1 (mitochondrial fission process 1) and modulating inflammatory responses via SDF-1 (stromal cell-derived factor 1) signaling. This mitochondrial stabilization function appears to be a conserved mechanism that contributes to its cytoprotective effects across different tissue types.
The regulation of miR-668 expression itself represents a complex network of molecular interactions. Hypoxic conditions induce its expression through HIF-1α (hypoxia-inducible factor 1-alpha), while hormonal factors like erythropoietin can modulate its levels in neurological contexts. Additionally, miR-668 participates in competitive endogenous RNA (ceRNA) networks, where it is sponged by various circular RNAs and long non-coding RNAs, adding another layer to its regulatory complexity.
From a clinical perspective, miR-668 shows significant promise as both a diagnostic biomarker and therapeutic target. Its expression patterns correlate with disease progression and treatment outcomes in several cancers, particularly in gastric and hepatic malignancies. The development of pharmacological modulators, such as melatonin and pterostilbene, that can influence miR-668 activity opens new avenues for therapeutic intervention. However, the dualistic nature of miR-668's functions necessitates careful consideration in therapeutic development to ensure targeted, tissue-specific effects.
Future research directions should focus on elucidating the precise molecular switches that determine miR-668's functional outcomes in different contexts, developing more sophisticated delivery systems for miR-668 modulation, and conducting comprehensive clinical trials to validate its utility in various disease settings. The continued investigation of this multifaceted microRNA promises to yield important insights into fundamental biological processes and may lead to novel therapeutic strategies for a range of human diseases.