Editors' ChoiceCancer

RNase moonlights as a cancer instigator

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Science Translational Medicine  11 Apr 2018:
Vol. 10, Issue 436, eaat3892
DOI: 10.1126/scitranslmed.aat3892


RNase 5 is a bona fide EGFR ligand that promotes oncogenic transformation in pancreatic cancer.

Epidermal growth factor receptor (EGFR) inhibitors have been widely used for effective targeted therapies in a variety of cancer types. Specific EGFR mutations in certain tumor types (for example, lung cancer) can be predictive of patient responsiveness toward these inhibitor treatments. It is, however, imperative to identify reliable biomarkers for EGFR inhibitor treatments in other cancer types that do not carry frequent EGFR mutations, such as pancreatic cancer.

Ribonuclease (RNase) normally catalyzes the degradation of RNA. By serendipity, Wang et al. found that a bovine version of RNase can activate oncogenic signaling in variety of cancer cell lines. To understand how the RNase does this, they performed an antibody array and found that RNase can promote EGFR phosphorylation. RNase 5 (aka angiogenin), a human counterpart of bovine RNase, was also shown to induce EGFR phosphorylation by acting as a bona fide ligand. Interestingly, this activity seemed to be independent of the enzymatic activity of RNase 5. High concentrations of serum RNase 5 were found in both patient tumors and mouse models of pancreatic cancer, with high expression of the enzyme predicting worse prognosis. Further experiments showed that RNase 5 promoted pancreatic carcinogenesis by activating EGFR hyper-phosphorylation, the effect ameliorated by the EGFR inhibitor erlotinib treatment. By depleting RNase 5 in pancreatic cancer cell lines and syngeneic pancreatic cancer mouse models, tumors became less sensitive to erlotinib. Lastly, in a cohort of pancreatic cancer patients, high concentrations of plasma RNase 5 associated with better sensitivity toward erlotinib treatment. Collectively, this study shows that RNase 5 is an EGFR ligand and may show promise as a biomarker for selecting pancreatic cancer patients responsive to EGFR inhibitor treatment.

Further investigation should be carried out to understand the regulatory pathway of RNase 5 secretion in the pancreatic cancer microenvironment. In addition, it will be important to know whether RNase 5 can be used as a general serum marker for EGFR inhibitor responsiveness in other cancers beside pancreatic cancer. Overall, this unexpected RNase function may turn out to be important for deciding among cancer patient treatment options.

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