Fig. 8

Molecular mechanism of Cetuximab resistance mediated by circHIF1A. The low expression of circHIF1A in CRC cells will release a large amount of free miR-361-5p, which negatively regulates the expression of HIF1A, leading to the decline of downstream GLUT1 and LDHA levels, the reduction of aerobic metabolism and glycolysis, as well as cell proliferation. Therefore, the response to Cetuximab treatment is increased (Cetuximab-sensitive). On the contrary, overexpression of circHIF1A in CRC cells competitively binds to miR-361-5p, resulting in a significant increase in HIF1A mRNA and HIF1α levels, promoting the expression of GLUT1 and LDHA. Then, the aerobic metabolism and glycolysis are enhanced, leading to increased proliferation and decreased response to Cetuximab treatment (Cetuximab-resistant)