Tescalcin ( TESC ) or calcineurin B homologous protein 3 (CHP3) is a protein-coding gene. TESC is an autosomal gene, and a key ortholog of this gene is CHP1. TESC was discovered in humans as a novel Na+/H+ exchanger (NHE) protein that might play several roles in the physiology of cells, for example by modulating cytoplasmic pH by encouraging optimal transport of NHE1 isoforms. Moreover, there are also a few research studies which have demonstrated that TESC is involved in gene expression, cell growth and differentiation. TESC, for instance, regulates the gene expression of the E26 transformation-specific (ETS) transcription factor, which is involved in megakaryocyte differentiation. The granulocyte- or macrophage-like lineage differentiation also depends on whether TESC is up- or down-regulated in HL-60 cells. TESC is differentially expressed in mammalian tissues: it is found most abundantly in embryonic gonads, adult mouse heart, brain, stomach and testis, and mouse and human primitive hematopoietic progenitor cells and cell lines.
TESC is one of the major modulators of polymorphisms in genes with extensive ramifications for the hippocampus and memory in neurobiology. TESC and the regulation of genetic polymorphisms is a much-debated scientific question. TESC acts on specific genes, including hippocampal structure and function genes, in very subtle ways. Experiments have demonstrated that TESC changes can induce pronounced gene-activity shifts that affect both the health of neurons and cognition. Because TESC and RELN have a biological association, it's likely that what we have is neurodevelopmentally-derived and deserving of mechanistic research.
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TESC Regulatory Gene Polymorphism
TESC is a regulation protein involved in some cell types (particularly in calcium signalling). This gene polymorphism can also impact its activity and so many other calcium-related biological functions such as cell growth, differentiation and death. Gene polymorphism typically means natural differences in the sequences of genes among individuals that may influence gene expression or protein activity in some manner, altering a person's body or proneness to disease. Polymorphisms for the TESC gene could correspond to a specific disease or physiology. These are TESC-related gene expression diseases:
Cholecystokinin
TESC RNA interference knockdown may stop the proliferation of tumours. According to RNA sequencing data, TESC silencing decreased FOXM1 activity and induced cell cycle arrest. We performed correlation analysis between the TESC cell count and FOXM1 in patients with cholangiocarcinoma. TESC is induced by TGF- through the EGFR-STAT3 system and controls TGF--induced growth of tumor cells. In vivo studies demonstrated that TESC knockdown reduced the size of the tumour cells markedly and is an ideal biomarker or target for cholangiocarcinoma.
Neurodegenerative Diseases
We have learned that TESC plays a crucial role in regulating neuronal function, and its abnormal levels are associated with various neurodegenerative disorders. In these disorders, an imbalance in intracellular calcium ions is believed to be one of the primary mechanisms contributing to neuronal damage and death. TESC could also regulate calcium signalling and intracellular calcium ion homeostasis to help neurons survive and function. TESC-overexpressing mice have hippocampal volume, which might be a good therapy.
Hepatocellular Carcinoma (HCC)
TESC expression is far higher in liver cancer than in normal liver tissue and correlates with lower survival. TESC alone predicts survival based on multivariate Cox regression. High TESC levels are associated with cancer stem cell pathways, cancer stem cell surface markers, stem cell transcription factors, epithelial-mesenchymal transition (EMT) factors, immune checkpoint proteins and other cancer-associated biological mechanisms in liver cancer. Moreover, TESC is also considered to increase cancer stem cell activities through EMT. TESC is a new stem cell-related gene that can act as a separate prognostic indicator for liver cancer. TESC could promote cancer stem cells through a boost in EMT. TESC as a biomarker or target for liver cancer patients needs to be investigated further.
Differentiated Thyroid Cancer (DTC)
TESC is greatly overexpressed in DTC tissues. The lack of TESC in both IHH-4 (BRAF V600E mutation) and TPC-1 (BRAF V600E wild-type) cells reduced cell proliferation, migration and invasion. Additionally, TESC knockdown also suppressed the phosphorylation of ERK1/2 and decreased NIS expression in DTC cells, while the uptake of iodine was increased.
Fig. 1 TESC knockdown leads to downregulation of EMT key gene expression and decreased cancer cell migration ability (Ye, P.; et al. 2024).
TESC is Expressed in Hippocampus
A brain region located in the medial temporal lobe called the hippocampus, so named because of its seahorse appearance. It's involved in memory and spatial perception, but especially in declarative memory, which is remembered facts and events. There are two haplogroups: the hippocampus and the dentate gyrus. And hippocampus neurons are remarkably plastic, and the more wired together you learn and accumulate, the more interconnected you get. This is because it's the hippocampus that encodes, holds and retrieves information. Damage or hippocampal disorders were associated with a multitude of neuropsychiatric conditions, from Alzheimer's to depression and post-traumatic stress disorder (PTSD). More generally, the hippocampus is a huge brain region that generates and stores memories, and directly connects to TESC.
TESC Overexpression Protects Hippocampal Volume
Learning and memory have one of the most important parts of the brain: the hippocampus. An under-estimation of its volume is frequently associated with neurodegenerative diseases and dementia. TESC is a protein that's distributed throughout the nervous system, and studies have recently shown that it can increase neuroprotection and maintain hippocampal volume by being overexpressed. TESC overexpression can increase nerve cell survival, reduce inflammatory factors, and induce nerve growth factors, which is all good for hippocampal neurons. This process could open the door to new drugs for Alzheimer's and depression.
TESC Overexpression Prevents Memory Decline
TESC is primarily expressed in the hippocampus and neurons. In cellular experiments, TESC overexpression was found to enhance the viability of HT22 cells and prevent cell death induced by Aβ. In animal studies, mice with TESC overexpression exhibited increased hippocampal volume, elevated levels of the anti-apoptotic protein Bcl2, and the antioxidant enzyme SOD1, along with decreased expression of the pro-apoptotic protein Caspase3. Additionally, these mice demonstrated enhanced long-term potentiation (LTP) in hippocampal slices. Notably, TESC overexpression mitigated Aβ-induced hippocampal atrophy and memory decline, upregulated the anti-apoptotic protein Bcl2, downregulated the pro-apoptotic protein Caspase3, and improved the attenuation of LTP caused by Aβ. This study not only confirmed the association between TESC and hippocampal volume identified in genome-wide association studies (GWAS) but also revealed the protective effects of TESC overexpression in both normal and AD mice.
Conclusion
TESC is a protein coding gene, and a prominent sister gene of TESC is CHP1. TESC relates to different physiological cell functions and influences gene expression, cell growth and differentiation. The diseases that have been linked to abnormal expression of TESC today are cholangiocarcinoma, neurodegenerative disorders (including Alzheimer's and Parkinson's), liver cell carcinoma, differentiated thyroid cancer and pituitary adenoma.
The main expression sites of TESC are the hippocampus and neurons. The hippocampus is involved in memory and spatial navigation, especially declarative memory (factual and event memory). TESC overexpression makes the mouse hippocampus bigger, and is a major regulator of memory impairment.
TESC research is incomplete, but as far as we can tell, it's involved in a wide range of physiological and pathological processes. More work will enable us to find out its mechanism and what it can offer as a therapeutic target.
References
- Zhuang, H.; et al. TESC mediates resistance to lenvatinib in hepatocellular carcinoma by regulating cell autophagy. Cancer Research. 2024, 84(6): 5866-5866.
- Hsieh, C.; et al. Tesc promotes tgf-α/egfr-foxm1-mediated tumor progression in cholangiocarcinoma. Cancers. 2020, 12(5): 1105.
- Ye, P.; et al. TESC associated with poor prognosis enhances cancer stemness and migratory properties in liver cancer. Clinical and Experimental Medicine. 2024, 24(1): 1-13.
- Guo, Y.; et al. TESC promotes differentiated thyroid cancer development by activating ERK and weakening NIS and radioiodine uptake. Endocrine. 2023, 81(3): 503-512.
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