LGR5 and cancer: 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.