Targeting ca²⁺ signaling in the initiation, promotion and progression of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a considerable health burden worldwide and a major contributor to cancer-related deaths. HCC is often not noticed until at an advanced stage where treatment options are limited and current systemic drugs can usually only prolong survival for a short time. Understanding the biology and pathology of HCC is a challenge, due to the cellular and anatomic complexities of the liver. While not yet fully understood, liver cancer stem cells play a central role in the initiation and progression of HCC and in resistance to drugs. There are approximately twenty Ca²⁺-signaling proteins identified as potential targets for therapeutic treatment at different stages of HCC. These potential targets include inhibition of the self-renewal properties of liver cancer stem cells; HCC initiation and promotion by hepatitis B and C and nonalcoholic fatty liver disease (principally involving reduction of reactive oxygen species); and cell proliferation, tumor growth, migration and metastasis. A few of these Ca²⁺-signaling pathways have been identified as targets for natural products previously known to reduce HCC. Promising Ca²⁺-signaling targets include voltage-operated Ca²⁺ channel proteins (liver cancer stem cells), inositol trisphosphate receptors, store-operated Ca²⁺ entry, TRP channels, sarco/endoplasmic reticulum (Ca²⁺+Mg²⁺) ATP-ase and Ca²⁺/calmodulin-dependent protein kinases. However, none of these Ca²⁺-signaling targets has been seriously studied any further than laboratory research experiments. The future application of more systematic studies, including genomics, gene expression (RNA-seq), and improved knowledge of the fundamental biology and pathology of HCC will likely reveal new Ca²⁺-signaling protein targets and consolidate priorities for those already identified.