Hypoxia, which is an important element in contributing to malignant transformation and cancer progression, as well as chemoresistance [147,148,149], induces the activity of HIF-1α, which positively regulates the HH signaling with malignant outcomes in different types of human cancers [150,151], including cholangiocarcinoma, where hypoxia-induced HIF-1α promotes stemness features and invasive behavior by modulating SHH, SMO, and GLI1 [121]. The gene discussed is SMO; the disease is cholangiocarcinoma.