High expression of the N6-methyladenosine (m6A) methyltransferase METTL3 promotes tumor growth and glycolysis in cholangiocarcinoma (CCA), found a new study published in the journal Cancer Cell International. It does so by modifying the AKR1B10 mRNA. This finding suggests that METTL3 could be a potential new therapeutic target in CCA.

It was already known that m6A RNA methylation plays an important role in tumor progression. To better understand the role of METTL3 in the case of CCA, a team of researchers from China first analyzed the expression of the enzyme in databases and tissue microarrays. They then conducted loss-of-function and gain-of-function experiments to better understand the role of METTL3 in CCA.

The results showed that the expression of METTL3 was upregulated in CCA and that higher expression was associated with poor prognosis. 


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Moreover, METTL3 overexpression facilitated the proliferation, migration, and invasion of CCA cells. It also facilitated lactate production and glucose uptake in these cells. 

On the contrary, when METTL3 was knocked down, these cellular events were inhibited as was CCA tumor growth in vivo

Using RNA sequencing, the researchers identified the m6A target of METTL3 as being AKR1B10. They also showed that METTL3 directly binds to AKR1B10 at an m6A modification site.

The researchers then analyzed the expression levels of AKR1B10 in CCA and found that this was also upregulated. When they silenced AKR1B10, the researchers saw that the malignant phenotype was suppressed.

“Elevated METTL3 expression promotes tumor growth and glycolysis in CCA through m6A modification of AKR1B10,” the researchers concluded. “Therefore, METTL3 may function as a novel therapeutic target for CCA.”

CCA is a heterogeneous group of rare malignant tumors that originate from cells of the biliary tree. The disease comprises around 15% of all primary liver tumors. It is the second most common primary malignancy of the liver after hepatocellular carcinoma and is responsible for around 3% of gastrointestinal tumors.

Reference

Cai J, Cui Z, Zhou J, et al. METTL3 promotes glycolysis and cholangiocarcinoma progression by mediating the m6A modification of AKR1B10. Cancer Cell Int. Published online December 7, 2022. doi:10.1186/s12935-022-02809-2