Calcium Regulates HCC Proliferation as well as EGFR Recycling/Degradation and Could Be a New Therapeutic Target in HCC

Calciumis the most abundant element in the human body. Its role is essential in physiological and biochemical processes such as signal transduction from outside to inside the cell between the cells of an organ, as well as the release of neurotransmitters from neurons, muscle contraction, fertilization, bone building, and blood clotting. As a result, intra- and extracellular calciumlevels are tightly regulated by the body. The liver is the most specialized organ of the body, as its functions, carried out by hepatocytes, are strongly governed by calciumions. In this work, we analyze the role of calciumin human hepatoma (HCC) cell lines harboring a wild type form of the Epidermal Growth FactorReceptor (EGFR), particularly its role in proliferation and in EGFR downmodulation. Our results highlight that calciumis involved in the proliferative capability of HCC cells, as its subtraction is responsible for EGFR degradation by proteasome machinery and, as a consequence, for EGFR intracellular signaling downregulation. However, calcium-regulated EGFR signaling is cell line-dependent. In cells responding weakly to the epidermal growth factor(EGF), calciumseems to have an opposite effect on EGFR internalization/degradation mechanisms. These results suggest that besides EGFR, calciumcould be a new therapeutic target in HCC.