Hepatocellular carcinoma (HCC) is a type of liver cancer with a poor prognosis for survival given the complications it bears on the patient. Though damages to the liver are acknowledged prodromic factors, the precise molecular aetiology remains ill-defined. However, many genes coding for proteins involved in calcium (Ca²⁺) homeostasis emerge as either mutated or deregulated. Ca²⁺ is a versatile signalling messenger that regulates functions that prime and drive oncogenesis, favouring metabolic reprogramming and gene expression. Ca²⁺ is present in cell compartments, between which it is trafficked through a network of transporters and exchangers, known as the Ca²⁺ transportome. The latter regulates and controls Ca²⁺ dynamics and tonicity. In HCC, the deregulation of the Ca²⁺ transportome contributes to tumorigenesis, the formation of metastasizing cells, and evasion of cell death. In this review, we reflect on these aspects by summarizing the current knowledge of the Ca²⁺ transportome and overviewing its composition in the plasma membrane, endoplasmic reticulum, and the mitochondria.

• Calcium/metabolism
• Carcinogenesis/metabolism
• Carcinoma, Hepatocellular/pathology
• Endoplasmic Reticulum/metabolism
• Humans
• Liver Neoplasms/pathology

Neuropathic pain is mainly triggered after nerve injury and associated with plasticity of the nociceptive pathway in primary sensory neurons. Currently, the treatment remains a challenge. In order to identify specific therapeutic targets, it is necessary to clarify the underlying mechanisms of neuropathic pain. It is well established that primary sensory neuron sensitization (peripheral sensitization) is one of the main components of neuropathic pain. Calcium channels act as key mediators in peripheral sensitization. As the target of gabapentin, the calcium channel subunit α2δ1 (Cavα2δ1) is a potential entry point in neuropathic pain research. Numerous studies have demonstrated that the upstream and downstream targets of Cavα2δ1 of the peripheral primary neurons, including thrombospondins, N-methyl-D-aspartate receptors, transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid family 1 (TRPV1), and protein kinase C (PKC), are involved in neuropathic pain. Thus, we reviewed and discussed the role of Cavα2δ1 and the associated signaling axis in neuropathic pain conditions.

• Cavα2δ1
• molecular target
• neuropathic pain
• peripheral sensitization
• primary sensory neuron

• Acute ischemic stroke
• Cerebrospinal fluid
• Neuroinflammation
• Voltage-gated calcium channel
• α2δ-1 subunit

Liver cancer (hepatocellular carcinoma) is a significant health burden worldwide. It is often not detected until at an advanced stage when there are few treatment options available. Changes in calcium concentrations within liver cancer cells are essential for regulating their growth, death, and migration (metastasis). Our aim was to review published papers which have identified proteins involved in calcium signaling as potential drug targets for the treatment of liver cancer. About twenty calcium signaling proteins were identified, including those involved in regulating calcium concentrations in the cytoplasm, endoplasmic reticulum and mitochondria. A few of these have turned out to be sites of action of natural products previously known to inhibit liver cancer. More systematic studies are now needed to determine which calcium signaling proteins might be used clinically for treatment of liver cancer, especially advanced stage cancers and those resistant to inhibition by current drugs.

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 non-alcoholic 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.

• Ca2+, hepatocellular carcinoma
• STIM1
• TRP channels
• cancer stem cells
• liver
• mitochondria
• reactive oxygen species

Cancer, the second cause of death worldwide, is characterized by several common criteria, known as the “cancer hallmarks” such as unrestrained cell proliferation, cell death resistance, angiogenesis, invasion and metastasis. Calcium permeable channels are proteins present in external and internal biological membranes, diffusing Ca²⁺ ions down their electrochemical gradient. Numerous physiological functions are mediated by calcium channels, ranging from intracellular calcium homeostasis to sensory transduction. Consequently, calcium channels play important roles in human physiology and it is not a surprise the increasing number of evidences connecting calcium channels disorders with tumor cells growth, survival and migration. Multiple studies suggest that calcium signals are augmented in various cancer cell types, contributing to cancer hallmarks. This review focuses in the role of calcium permeable channels signaling in cancer with special attention to the mechanisms behind the remodeling of the calcium signals. Transient Receptor Potential (TRP) channels and Store Operated Channels (SOC) are the main extracellular Ca²⁺ source in the plasma membrane of non-excitable cells, while inositol trisphosphate receptors (IP₃R) are the main channels releasing Ca²⁺ from the endoplasmic reticulum (ER). Alterations in the function and/or expression of these calcium channels, as wells as, the calcium buffering by mitochondria affect intracellular calcium homeostasis and signaling, contributing to the transformation of normal cells into their tumor counterparts. Several compounds reported to counteract several cancer hallmarks also modulate the activity and/or the expression of these channels including non-steroidal anti-inflammatory drugs (NSAIDs) like sulindac and aspirin, and inhibitors of polyamine biosynthesis, like difluoromethylornithine (DFMO). The possible role of the calcium permeable channels targeted by these compounds in cancer and their action mechanism will be discussed also in the review.

• Ca2+ channels
• TRP channels
• calcium channel modulators in cancer
• cancer hallmarks
• store-operated Ca2+ entry

• EC
• lymph node metastasis
• serum calcium level
• stratification analysis

Hepatocellular carcinoma (HCC) is the 5^th most frequently diagnosed cancer in the world, according to the World Health Organization. The incidence of HCC is between 3/100000 and 78.1/100000, with a high incidence reported in areas with viral hepatitis B and hepatitis C, thus affecting Asia and Africa predominantly. Several international clinical guidelines address HCC diagnosis and are structured according to the geographical area involved. All of these clinical guidelines, however, share a foundation of diagnosis by ultrasound surveillance and contrast imaging techniques, particularly computed tomography, magnetic resonance imaging, and sometimes contrast-enhanced ultrasound. The primary objective of this review was to systematically summarize the recent published studies on the clinical utility of serum biomarkers in the early diagnosis of HCC and for the prognosis of this disease.

• Hepatocellular carcinoma
• Biomarkers
• Imaging
• Ultrasonography
• Computed tomography
• Magnetic resonance imaging

• Auxiliary subunit
• Calcium channel
• Cancer
• Chloride channel
• Potassium channel
• Sodium channel

• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Ion Channels/genetics
• Ion Channels/metabolism
• Neoplasms/metabolism
• Oncogenes/genetics
• Protein Subunits/genetics
• Protein Subunits/metabolism
• Signal Transduction
• Tumor Suppressor Proteins/genetics

• BB/M011151/1 Biotechnology and Biological Sciences Research Council

• Ca(2+)channel
• Cancer stem cell
• Chemotherapy resistance
• Endoplasmic reticulum
• Glioma
• Intracellular Ca(2+)signaling
• Leukemia
• Melanoma
• Metastasis
• Proliferation
• Stem cell
• Store-operated channel
• Transient receptor potential channel
• Tumor relapse
• Voltage-gated channel