Fig. 2

Roles of EpCAM in cancer development and progression. a EpCAM on CSCs membrane surface was cleaved by ADAM17 and γ-secretase, generating EpICD. Most of the EpICD is degraded by proteasome, while the remaining EpICD can bind with FHL2, β-catenin and Lef-1, forming the trans-nuclear complex to activate proliferation and pluripotency related genes. b EpEX/EGFR pathway and EpICD trans-nuclear complex can promote cell proliferation. EGF and TGF-β pathway can regulate EMT markers and EpCAM expression. c In hypoxic condition, EpCAM is upregulated in ATP-high state, whereas in ATP-low situation, HIF-1α is upregulated. CAIX is overexpressed mediated by HIF-1α. CAIX⁺, together with higher EpCAM and K19 expression HCC subgroup exhibited with high resistance to chemoembolization. Additionally, N-glycosylated EpCAM can regulate HIF-1α and promote EMT and stemness related properties. d MHC-I/TCR interaction serves as T cell activation signals. While activated EpEX/EGFR/ERK pathway results in reduction of PD-L1 ubiquitination degradation. PD-L1 on tumor surface hampers activation of CD8⁺ T cells and leading to immune escape. CAIX carbonic anhydrase-IX, ECM extracellular matrix, FHL2 four and a half LIM domain protein 2, HIF-1α hypoxia inducible factor 1α, K19 keratin 19, Lef-1 lymphoid enhancer factor 1