In this study, we hypothesized that the HB-EGF-EGFR axis and proteases that control the shedding of HB-EGF regulate the balance between the tumor-suppressor miR-126 and the proinflammatory miR-221 in cancer cells during CRC and a murine model of CAC—the so-called Azoxymethane (AOM) Dextran Sodium Sulfate (DSS) model. Here, EGF is linked to cancer.