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Several important micropeptides encoded by noncoding RNAs have been identified in recent years; however, there have never been any reports of micropeptides in head and neck squamous cell carcinoma (HNSCC). Here we report the discovery and characterization of a human endogenous peptide named micropeptide inhibiting actin cytoskeleton (MIAC). Comprehensive analysis of the TCGA (The Cancer Genome Atlas) database (n = 500), clinical fresh samples (n = 94), and tissue microarrays (n = 60) revealed that lower MIAC expression is correlated with poor overall survival of HNSCC patients. Meanwhile, RNA-sequencing analysis of 9657 human tissues across 32 cancer types from TCGA cohorts found that MIAC is significantly associated with the progression of 5 other different tumors. Mechanistically, MIAC directly interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC. Collectively, the mechanism investigation and evaluation of MIAC activity in vivo and in vitro highlights that MIAC plays an important role in HNSCC tumorigenesis.

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Advanced analytic techniques, such as ribosome profiling and mass spectrometry, as well as improved bioinformatics technology, have promoted the field of genome annotation forward and have identified thousands of likely coding short open reading frames (sORFs) in the human genome. The discovery of sORFs and their products allows us to realize that the complexity of the human genome is far greater than previously assumed. Here, we provide a review of human micropeptides encoded by various transcripts such as mitochondrial rRNAs, long noncoding RNAs, circular RNAs, upstream of mRNAs, and so on.