To further confirm this, we depleted the expression of LGR4 and LGR5 by siRNAs, and found that after the knockdown, RSPO4 lost its inhibitory effect on Wnt/β-catenin signaling in both LGR4+/LGR5- and LGR4-/LGR5+ tumor cell lines (Fig. 4F and 4G), and ZNRF3 protein was unable to accumulate in the presence of RSPO4 (lane 2 and lane 3, Fig. 4G). Here, ZNRF3 is linked to neoplasm.