Mitochondrial substrate utilization and microrna-mediated drug resistance in head and neck cancer stem cells

Head and neck cancer (HNC) is one of the most common cancers worldwide, and squamous cell carcinoma is the most common pathology type of HNC. One of the major clinical issues in head and neck squamous cell carcinoma (HNSCC) is drug resistance and tumor recurrence. Cancer stem cells (CSCs) have been confirmed to be a critical factor in drug resistance and tumor recurrence. Mitochondria may contribute to the survival of CSCs under the harsh tumor microenvironment. In addition, microRNAs (miRNAs) have been reported to be a potential tool for diagnosis and treatment strategy in many types of cancers. This study aims to determine the unique mitochondrial- related miRNAs of HNSCC-CSC in drug resistance and tumor recurrence, investigate the unique metabolic phenotypes and utilization of mitochondria substrate in HNSCC-CSC, and explore the response of substrate utilization of mitochondria to unique miRNAs in HNSCC-CSC. Initially, 18 mitochondrial- associated miRNAs of HNSCC-CSCs were predicted by bioinformatic analysis. Secondly, has-let-7c-5p (let-7c-5p) was determined to be the potential mitochondrial-associated miRNA of HNSCC-CSCs related to drug resistance and tumor recurrence by the data mining analysis. Next, the HNSCC-CSCs model was developed using cell lines from the FADU, CAL-27, and nasopharyngeal cancer (NPC) patients, and the characteristics of HNSCC- CSCs including cell surface marker CD44, sphere cell formation, and chemotherapy resistance, were verified by the flow cytometer, sphere formation experiment, and Cell Counting Kit-8 (CCK8) Cell Viability Assay. Subsequently, let-7c-5p expression was identified to be significantly lower in HNSCC-CSCs compared to the source cell lines by RT-qPCR test. Meanwhile, the sphere formation efficiency of HNSCC-CSCs was significantly decreased after overexpressing let-7c-5p by transfection. Afterward, the metabolic phenotypes and the utilization of succinic acid were determined to be significantly different between HNSCC-CSCs and their source cell lines through the Mitochondrial Function Assays. Lastly, overexpressing let-7c-5p in HNSCC-CSC was observed to suppress mitochondrial respiration by reducing the utilization of succinic acid. In conclusion, let-7c-5p can maintain the stemness of HNSCC-CSCs by regulating the metabolic phenotype. The metabolic phenotype of HNSCC-CSCs displayed a complex model of glycolysis/mitochondrial respiratory, where mitochondrial respiratory plays a dominant role. The metabolic phenotype of HNSCC-CSCs can be switched by succinic acid, and let-7c-5p showed the potential ability to regulate it. However, this study only tested three typical cell lines of HNSCC, and the specific mechanism between let-7c-5p and succinic acid utilization in HNSCC-CSC needs to be further verified.

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