Both
mucin 1 (MUC1) and
galectin-3 are known to be overexpressed in various malignant
tumors and associated with a poor prognosis. It has been extensively reported that MUC1 is involved in potentiation of
growth factor-dependent signal transduction. Because some
carbohydrate moieties carried on MUC1 change to preferable ones for binding of
galectin-3 in
cancer cells, we speculated that MUC1-mediated signaling may occur through direct binding of
galectin-3. Immunochemical studies showed that the distribution of
galectin-3 coincided with that of MUC1 in various human
tumor tissues but not in human nonmalignant tissues, and the level of
galectin-3 retained on the surface of various
cancer cells paralleled that of MUC1. Treatment of MUC1-expressing cells with
galectin-3 induced phosphorylation of ERK1/2 and Akt following enhanced phosphorylation of MUC1 C-terminal domain, consistently promoting
tumor cell
malignancy. It is also noted that this enhanced phosphorylation occurred independently of
EGF receptor-mediated signaling in both
EGF receptor- and MUC1-expressing cells, and multivalency of
galectin-3 was important for initiation of MUC1-mediated signaling. Expectedly, both silencing of endogenous
galectin-3 and treatment with
galectin-3 antagonists down-regulated cell proliferation of MUC1-expressing cells. These results suggest that the binding of
galectin-3 to MUC1 plays a key role in MUC1-mediated signaling. Thus, constitutive activation of MUC1-mediated signaling in an autocrine/paracrine manner caused by
ligation of
galectin-3 promotes uncontrolled
tumor cell
malignancy. This signaling may be another MUC1-mediated pathway and function in parallel with a
growth factor-dependent MUC1-mediated signaling pathway.