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Mounting evidence has indicated that aberrantly expressed microRNAs (miRNAs) play key roles in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). Previous studies have shown that miR‐335‐5p can serve as a tumor suppressor or an oncogene in cancer. However, the clinical importance and biological effects of miR‐335‐5p in HNSCC have not been determined. Here, we investigated the expression pattern, functional role, and mechanisms of miR‐335‐5p in HNSCC. We showed a decreased expression of miR‐335‐5p in HNSCC samples from the TCGA and GEO databases. Consistently, we detected a downregulation of miR‐335‐5p in HNSCC cell lines and patient tissues. The expression of miR‐335‐5p was inversely correlated with advanced clinical TNM stage and lymph node metastasis in HNSCC patients. miR‐335‐5p overexpression inhibited HNSCC cell proliferation and induced apoptosis, while miR‐335‐5p inhibition had the opposite effects. miR‐335‐5p overexpression suppressed tumor growth in mice. Bioinformatic analyses and functional assays identified MAP3K2 as a target of miR‐335‐5p, and we showed that miR‐335‐5p downregulated mitogen‐activated protein kinase kinase kinase 2 (MAP3K2) expression in HNSCC cells. We found an inverse association between MAP3K2 and miR‐335‐5p expression in 38 pairs of HNSCC tissues. Furthermore, the effect of miR‐335‐5p overexpression on growth and metastasis as well as cell apoptosis in HNSCC cells could be partially rescued by MAP3K2 expression. Collectively, our data show that miR‐335‐5p inhibits the development of HNSCC by regulating MAP3K2 expression. Thus, these findings offer novel insights into a potential therapeutic strategy for HNSCC patients. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) have the ability to dictate tumor initiation, recurrence, and metastasis. Here, we examined the expression of a α 2 δ 1 + in laryngeal cancer tissues and further determined the effect of α 2 δ 1 on the migratory ability and tumorigenicity of laryngeal cancer cells. Immunofluorescence staining revealed that α 2 δ 1 was positive in 13 (13/16, 81.25%) cases in laryngeal squamous cell carcinoma (LSCC) tissues, 7 (7/16, 43.75%) cases in paracancerous tissues and only 2 (2/16, 12.5%) cases in normal tumor tissues. Our quantitative RT-PCR assays further showed that α 2 δ 1 + LSCC cells expressed significantly higher levels of stem cell-associated genes and drug efflux and resistance genes versus α 2 δ 1 - cells. Sphere-forming assays demonstrated higher sphere-forming efficiency in the α 2 δ 1 + versus α 2 δ 1 - subpopulation. Our Matrigel assays showed that α 2 δ 1 + cells exhibited significantly greater invasive and migratory ability than α 2 δ 1 - cells. Furthermore, the percentage of purified α 2 δ 1 + in TU686 and TU212 cells treated cisplatin or paclitaxel was significantly higher than that of the control group. Tumor xenograft assays revealed that the tumorigenicity of α 2 δ 1 + cells was much higher than α 2 δ 1 - cells. In conclusion, a α 2 δ 1 + subpopulation with CSC-like property was present in laryngeal cancer and possessed high self-renewal activity and was sufficient for tumor growth, differentiation, migration, invasion, and chemotherapeutic resistance. They could represent a promising therapeutic target for LSCC. [ABSTRACT FROM AUTHOR]

• CircRNA_100290 is significantly upregulated in LSCC tissues and cell lines. • CircRNA_100290 promotes cell growth, metastasis, and inhibits cell apoptosis. • CircRNA_100290 could sponge miR-136-5p. • RAP2C is a functional target of miR-136-5p. • CircRNA_100290/miR-136-5p/RAP2C axis plays a significant role in LSCC progression. Circular RNAs (circRNAs) exert critical functions in tumorigenesis and tumor development, but whether and how circRNAs contribute to laryngeal squamous cell carcinoma (LSCC) is unclear. In this study, we explored the function and mechanisms of circRNA_100290 in LSCC. Tissue samples were obtained from 40 patients with LSCC. The expression of circRNA_100290 and other targets was measured through quantitative reverse transcription-polymerase chain reaction and western blot analysis. Cell proliferation, colony-forming ability, and apoptosis were tested using CCK-8 assay and EdU assay, colony formation assay, and flow cytometry, respectively. Cell migration and invasion were detected by Transwell assay. Moreover, the interactions between circRNA_100290, miR-136-5p, and RAP2C were analyzed by bioinformatics, and verified by dual‐luciferase reporter assays. Here, we found that circRNA_100290 expression was significantly upregulated in LSCC tissues and cell lines compared with the normal controls. Expression of circRNA_100290 positively correlated with advanced TNM stage and lymph node metastasis in LSCC patients. In cell culture, upregulation of circRNA_100290 promoted LSCC cell proliferation, migration, and invasion, while it inhibited cell apoptosis; downregulating circRNA_100290 exerted the opposite effects. In vivo, circRNA_100290 overexpression dramatically promoted tumor growth. Mechanistically, circRNA_100290 may act as a sponge of miR-136-5p, and inhibiting miR-136-5p in LSCC cells indeed reversed the effects of circRNA_100290 downregulation. The RAS oncogene RAP2C was predicted to be a target of miR-136-5p, and downregulating RAP2C in LSCC cells partially reversed the oncogenic effects of circRNA_100290 overexpression or miR-136-5p decrease. Our findings suggest that circRNA_100290 promotes LSCC progression by targeting the miR-136-5p/RAP2C axis, which may lead to the identification of potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Abnormal expression of non-coding circular RNAs (circRNAs) have been reported in many types of tumors. circRNA have been suggested to be an ideal candidate biomarker for diagnostic and therapeutic implications in cancers. The aim of this study was to assess the circRNA expression profile of laryngeal squamous cell carcinomas (LSCC). The biopsy samples from patients with LSCC were obtained intra-operatively. The circRNA expression was performed using secondary sequencing. Among 10 patients with LSCC, 2 were well differentiated, 3 were moderately differentiated and 5 were adjunctive samples with normal and LSCC tissues. A total of 21,444 distinct circRNA candidates were detected. Among them, we defined the statistical criteria for selecting aberrant-expressed circRNA using a q-value of < 0.001 with a fold change of > 2.0 or < 0.5. A total of 29 circRNA were upregulated and 19 circRNA were downregulated significantly in the LSCC tissues. The intersection of these dysregulated circRNAs of normal-well differentiated set and normal-moderately differentiated set was then assessed to narrow the upregulated and downregulated circRNAs down to 18 and 5 respectively. Furthermore, an association of the circRNA-miRNA-mRNA was investigated, showing that 20 dysregulated circRNA successfully predicted an interaction with several cancer-related miRNAs. Finally, a further KEGG analysis showed that PPAR, Axon guidance, Wnt and Cell cycle signaling pathway were key putative pathways in the process of LSCC. hsa_circ:chr20:31876585–31,897,648 was found to be able to differentiate most of LSCC from the matching normal tissues. This observational study demonstrated dysregulation of circRNA in LSCC, which may have an impact on development of potential biomarkers in this disease. Validation of down-regulation of hsa_circ:chr20:31876585–31,897,648 in LSCC compared to each adjunctive tissue by Q-RT-PCR, indicating that hsa_circ:chr20:31876585–31,897,648 may be a novel promising tumor suppresser in LSCC. [ABSTRACT FROM AUTHOR]