Microproteins in cancer: identification, biological functions, and clinical implications

Abstract

Cancer continues to be a major global health challenge, accounting for 10 million deaths annually worldwide.Since the inception of genome-wide cancer sequencing studies 20 years ago, a core set of ~700 oncogenes and tumor suppressor genes has become the basis for cancer research.However, this research has been based largely on an understanding that the human genome encodes ~19 500 protein-coding genes.Complementing this genomic landscape, recent advances have described numerous microproteins which are now poised to redefine our understanding of oncogenic processes and open new avenues for therapeutic intervention.This review explores the emerging evidence for microprotein involvement in cancer mechanisms and discusses potential therapeutic applications, with an emphasis on highlighting recent advances in the field. Microproteins emerge as a new area of study in cell biologyCancer arises as a result of an intricate interplay of genetic, epigenetic, and environmental forces, and often lacks a single, canonical genetic driver [1,2].Despite significant advancements in our understanding of cancer biology, gaps in our knowledge remain, particularly in recognizing and characterizing non-traditional molecular players.Recently, the study of microproteins has emerged as a promising area of research in cancer biology.These proteins, typically defined as being <100 amino acids long, have historically been overlooked due to technical limitations and biases in genome annotation [3][4][5].However, a newfound appreciation for microproteins raises a pivotal question: are we missing key molecular players in cancer biology?Advances in next-generation sequencing techniques, such as ribosome profiling, as well as enhanced sensitivity of mass spectrometry (MS)-based proteomics, have revealed extensive translation of short open reading frames (sORFs) into microproteins across the human genome, challenging previous assumptions about our genome's protein-coding potential.These sORFs can originate from diverse genomic contexts, including regions previously thought to be noncoding, such as 5 and 3 untranslated regions of mRNAs or long non-coding RNAs (lncRNAs).Additionally, alternative ORFs within known protein-coding genes but translated in a different reading frame can give rise to novel microproteins [6][7][8].Recent large-scale efforts have implicated microproteins in a wide range of biological functions, including cell survival, DNA repair, and gene regulation [7,[9][10][11][12][13][14][15][16][17][18][19].As the dysregulation of these basic cellular functions underpins cancer cell biology, the identification of microproteins in these processes suggests that they could also play crucial roles in oncogenesis.Despite increasing awareness of microproteins' functional significance, the field of microprotein research still grapples with substantial challenges in determining the mechanisms by which these small proteins influence cancer development.Several key questions remain.(i) Are Highlights Microproteins, historically overlooked, are emerging as key players in cancer biology.Advances in genomics and proteomics enable systematic identification of cancer-associated microproteins.Microproteins contribute to cancer pathogenesis, are an important source of cryptic cancer antigens, and may offer novel therapeutic targets.Harnessing the potential of microproteins could revolutionize cancer diagnostics, therapeutics, and immunotherapy.