Figure 6. The working model illustrating the molecular mechanisms underlying the chemotherapy-resisting effects of LIF in neoplastic cholangiocytes.

In CCA, LIFR is up-regulated by cholangiocytes under the influence of LIF released by both the neoplastic cholangiocytes (autocrine loop) and the tumor reactive stromal cells, including CAF and TAM (paracrine loop). When LIFR dimerizes with gp130, LIF signaling is transduced through PI3K/AKT rather than the conventional STAT3 or MAPK/ERK pathways to increase levels of the anti-apoptotic protein Mcl-1, which confers resistance to the cytotoxic effects of chemotherapeutic agents by reducing activation of caspases 3/7.