The half-life of endogenous ZNRF3 protein was dramatically extended in RSPO4-expressing cells compared with vector control in both LGR4+/LGR5- and LGR4-/LGR5+ cancer cells after CHX treatment (Fig. 5E), indicating that RSPO4 expression prevents the degradation of ZNRF3, which resulted in the accumulation or stabilization of ZNRF3. Here, ZNRF3 is linked to cancer.