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snoRNA is a well-conserved, abundant, short non-coding RNA molecule, with a length of 60-300 nucleotides, which localize to a specific compartment of the cell nucleus—the nucleolus. In vertebrates, most snoRNAs are encoded in introns of protein-coding or non-coding genes and are transcribed simultaneously by RNA Pol II. Most snoRNA host genes encode for proteins or transcripts necessary for ribosome biogenesis or function and often belong to the 5'-terminal oligopyrimidine (TOP) family that undergoes growth-dependent translation regulation. Although it is generally believed that snoRNAs have only cellular housekeeping functions, recent independent reports have converged in implicating snoRNAs in control of cell fate and oncogenesis. The deepening understanding of the role of snoRNAs in tumorigenesis would point towards the potential as novel tumor biomarkers and therapeutic targets.
Discoveries showed that the function of snoRNAs is not restricted to "house-keeping" genes are accumulation. They act as regulatory factors affecting the PI3K-AKT and K-Ras signaling pathway, which regulate the proliferation and apoptosis of cells during tumorigenesis. Recent studies have indicated that snoRD126 activates the PI3K-AKT pathway through the activation of fibroblast growth factor receptor (FGFR2), thereby promoting CRC cell growth. The activated AKT pathway is involved in the phosphorylation of several target enzymes, kinases and transcription factors through its various downstream aspects that in particular include the mTOR pathway. The mTOR pathway is related to the acceleration of cell growth. In addition, current evidence indicates that mTOR pseudouridylates the 28S rRNA where growth is favorable, which is symbolic as the function of snoRNAs, indicating that the mTOR pathway may promote cell proliferation by this method.
Figure 1. RNA related pathways. (Di Zhang J Z, et al. 2019)
The role of snoRNAs in cells is diverse, and the expression of cancer-specific snoRNAs should be developed for the development of cancer biomarkers. Studies have shown that snoRNAs are stable and measurable in peripheral blood plasma and serum samples. snoRNAs may become circulating biomarkers of cancer.
Increased levels of C/D box snoRNAs, SNORD33, SNORD66, and SNORD76, are detected not only in tumors but also in plasma, which have observed sensitivity and specificity in distinguishing non-small-cell-lung carcinoma (NSCLC) patients. Early detection of circulating plasma snoRNAs will serve as a potential noninvasive approach for the diagnosis of NSCLC. Increased expression of H/ACA snoRNA SNORA42 in tissues correlated the unfavorable outcome of the disease and can be used to predict the disease course. Recent observations further supported the development of snoRNAs as a potential biomarker. The three C/D box snoRNAs, SNORD43, SNORD44, and SNORD48, appear to be putative suppressors of breast cancer and head and neck squamous cell carcinomas (HNSCC). In conclusion, snoRNAs may serve as potential biomarkers for both diagnosis and prognosis of malignancies.
Table 1. Representative snoRNAs involved in cancer and their roles in tumorigenesis. (Thorenoor N, Slaby O. 2015)
|snoRNAs||Class||Changes||Proposed role||Cancer type|
|U50||C/D box||↓||Tumor suppressor||Breast and prostate cancer|
|h5sn2||H/ACA box||↓||Tumor suppressor||Meningioma|
|RNU43||C/D box||↓||Tumor suppressor||Breast cancer and HNSCC|
|RNU44||C/D box||↓||Tumor suppressor||Breast cancer and HNSCC|
|SNORD113-1||C/D box||↓||Tumor suppressor||Hepatocellular carcinoma|
|SNORD44||C/D box||↑||Oncogene||Breast cancer|