The central dogma of life science posits that DNA is transcribed into messenger RNA (mRNA), which is then translated into proteins that execute biological functions, forming the fundamental operational framework of life activities. In contrast, non-coding RNAs (ncRNAs), which do not encode proteins, have long been considered to primarily serve regulatory functions. However, recent large-scale integrated transcriptomic and proteomic analyses have revealed widespread significant discrepancies between mRNA expression levels and the abundance of their corresponding proteins under both physiological and pathological conditions. This phenomenon suggests that the biological effects of mRNA may not necessarily rely entirely on its translation products, and the traditional static functional classification system centered on "protein function" may have systematically overlooked the potential for mRNA molecules themselves to exert independent functions.

Intercellular Adhesion Molecule 1 (ICAM1) is a classic transmembrane protein that plays important roles in tumorigenesis, development, and immune regulation. Previous studies have shown that ICAM1 is closely associated with tumor invasion, metastasis, and immune escape in various cancers. Yet, it can exhibit either pro-tumor or anti-tumor effects in different cancer types, and the molecular mechanisms underlying these functional differences have long remained unclear.

Recently, the research team led by Professor Gao Shan from the School of Life Science and Technology at Southeast University published a research paper titled "ICAM1 mRNA entraps ILF2/ILF3 to inhibit transcription of EIF4E and global protein synthesis" in the journal Molecular Cell. This study breaks through the traditional notion that "mRNA solely serves as a template for protein translation," and for the first time proposes and systematically elucidates a novel mechanism where mRNA directly participates in tumor regulation as a functional molecule by forming endogenous double-stranded RNA.

Researchers found in experiments that complete knockout of the ICAM1 protein using CRISPR–Cas9 technology significantly inhibited tumor cell proliferation, whereas downregulating ICAM1 mRNA expression via shRNA surprisingly promoted cell growth. Notably, the loss of ICAM1 protein and the reduction of ICAM1 mRNA led to diametrically opposite tumor phenotypes, suggesting that ICAM1 mRNA might possess biological functions independent of its encoded protein. Subsequent functional experiments directly confirmed the non-coding tumor-suppressive role of ICAM1 mRNA itself.

Mechanistic studies revealed that ICAM1 mRNA can form a stable endogenous long double-stranded RNA (dsRNA) with its cis-antisense transcript ICAM1-AS within the nucleus, and bind in a length-dependent manner to the transcription regulatory complex ILF2/ILF3, which possesses dsRNA-binding capability. This dsRNA structure acts as a "molecular trap," preventing ILF2/ILF3 from interacting with chromatin DNA.

When ICAM1 mRNA or ICAM1-AS is knocked down, ILF2/ILF3 more readily binds to the promoter region of EIF4E, a key factor for translation initiation, significantly enhancing its transcriptional activity and thereby increasing overall cellular protein synthesis levels. Multiple experimental results showed that depletion of ICAM1 mRNA leads to elevated global translation efficiency accompanied by upregulation of various oncogenic proteins such as c-MYC and CDK2. Conversely, maintaining the dsRNA structure formed by ICAM1/ICAM1-AS can suppress the EIF4E-mediated translation program, thereby restricting tumor cell proliferation.

In clinical lung cancer tissue samples, the research team observed that ICAM1 protein is generally highly expressed, while ICAM1 mRNA and ICAM1-AS are coordinately downregulated, showing a significant RNA–protein expression discordance. This phenomenon suggests that tumor cells may gain a growth advantage by weakening the tumor-suppressive non-coding function of ICAM1 mRNA while retaining or even enhancing the pro-tumor role of the ICAM1 protein. Furthermore, low expression of ICAM1-AS is closely associated with the therapeutic sensitivity of ICAM1-targeting antibody-drug conjugates (ADCs).

In summary, this study is the first to propose and systematically elucidate a novel "mRNA–antisense RNA–transcription regulator–protein translation" regulatory axis. It reveals that mRNA can directly regulate transcription factor activity and global protein synthesis by forming endogenous double-stranded RNA, thereby participating in tumorigenesis and development independently of its encoded protein. The research further points out that while the ICAM1 protein acts as an oncoprotein, ICAM1 mRNA exhibits tumor suppressor gene functions. This discovery challenges the traditional definition of oncogenes and also suggests that shRNA/siRNA-mediated RNA degradation strategies cannot be simply equated with protein loss-of-function. This work provides a new paradigm for understanding the non-coding functions of mRNA and offers an important supplement and extension to the classic central dogma.

Schematic model of ICAM1 mRNA, as a functional RNA, regulating the ILF3-EIF4E signaling pathway

The first author of this paper is Associate Professor Jiang Siyuan from the School of Medicine, Southeast University. The corresponding author is Professor Gao Shan from the School of Life Science and Technology, Southeast University. (School of Life Sciences)

Link to the paper: https://www.cell.com/molecular-cell/abstract/S1097-2765(25)01016-0