Interactive web portal details the extent of splicing events in non-coding sequences

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An online tool reveals the extent of gene restructuring events in non-coding sequences.

An interactive web portal developed by KAUST scientists provides a platform for cancer researchers to interrogate how RNA splicing in the non-coding parts of genes fuels the growth of different tumor types.

The new resource, named SpUR (short for Splicing in Untranslated Regions) and freely available online, details more than 1,000 splicing events commonly observed in cancers in non-coding regions of mRNA located just downstream of d stop coding for proteins. The sites and expression levels of these events are cataloged and visualized for almost 8,000 samples in 10 cancer types and the corresponding normal tissues.

With this tool, independent research teams can now dig deeper into the role of individual splicing events in cancer development and progression.

These events could become candidates for studying RNA dysregulations in cancer for academic researchers. Or they could serve as a primary source for the development of RNA-based cancer drugs.”


Xin Gao, Acting Associate Director of the Computational Bioscience Research Center and Deputy Director of the Smart Health Initiative at KAUST

Computer scientist Gao, along with postdoc Bin Zhang and research engineer Adil Salhi, created the SpUR database in collaboration with researchers from the Cancer Science Institute in Singapore.

Research has shown that splicing in sequences downstream of a gene (called 3′ untranslated regions or 3′ UTRs) is ubiquitous in cancers, particularly in genes linked to tumor aggression. Therefore, patients whose cancers harbor more of these genetic restructuring events tend to have poorer survival outcomes.

As a proof of principle, the researchers designed splicing switching agents known as antisense oligonucleotides (ASOs) that could block this splicing process in 3′ UTRs. When given to liver cancer cells, these drugs help suppress tumor growth. And since the same types of splicing events are “ubiquitously expressed in different types of cancer,” Gao notes, this type of therapeutic strategy “could be useful for developing broad-spectrum anti-cancer drugs.”

A potential target:CTNNB1, which is a gene that provides instructions for making a protein called beta-catenin. Pharmaceutical companies have long tried to target beta-catenin, given its central role in many cancer signaling pathways, but with limited success. The study by Gao et al. showed that splicing in the 3′ UTR ofCTNNB1is prevalent in cancers of the liver, breast, colon, kidney, lung, and other organs, and that a spliced ​​variant is the primary driver of tumor progression.

In a mouse model of liver cancer, blocking this splicing resulted in complete tumor regression. ASO therapy directed toCTNNB1splicing could therefore have broad utility in patients and, as Gao points out, it is probably not the only one.

Source:

KAUST – King Abdullah University of Science and Technology

Journal reference:

Chan, JJ, et al. (2022) Pan-cancer, pervasive upregulation of 3’UTR splicing drives tumorigenesis. Cell Biology Nature. doi.org/10.1038/s41556-022-00913-z.

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