The Regulation of Ion Channel Expression in Cancer

Posted by beauty33 on January 14th, 2022

Although more and more ion channels have been discovered in cancer cells in vitro and in vivo, and have shown their contribution to different aspects and stages of the cancer process, little is known about the mechanisms that control their expression. Voltage-gated Na+ channels (VGSC) are up-regulated in many types of cancer, where their activity enhances cellular behavior that is integral to the metastatic cascade.

The regulation of VGSC occurs in the hierarchical structure from transcription to translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play an important role in regulation. In general, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative correlation between genomic steroid hormone sensitivity and functional VGSC expression. Activity-dependent regulation through positive feedback has been confirmed in strongly metastatic cells, where VGSC is self-sustaining, and its activity promotes further functional channel expression. This kind of automatic regulation is different from normal cells. In normal cells, activity-dependent regulation mainly occurs through negative feedback.

The expression and/or activity of VGIC can be regulated from transcription to post-translation. These include specific post-transcriptional/pre-translational mechanisms, such as miRNA and post-translational, such as intracellular transport. The main regulators include hormones (mainly steroids and peptides) and growth factors, in fact, they are closely related to all aspects and stages of the cancer process. In addition, some drugs used in cancer treatment may affect VGIC.

Several separate Nav isoforms are known to be functionally expressed in different human cancers. These include sodium channels in breast and colon cancer; Nav1.6 in cervical cancer; and Nav1.7 in breast, prostate and non-small cell lung cancer. In addition, in research (especially for Nav1.5 and Nav1.7), it has been found that alternative splice variants of the isotype have sequence differences, the most significant being between the 3rd and 4th segments of domain I In the extracellular ring. At present, the basic principle of this phenomenon in cancer is not clear, but it is consistent with channel expression is (i) epigenetic and (ii) carcinogenesis. The mechanisms controlling alternative splicing have not been well characterized, but may involve cAMP and activity dependence.

It is well known that the development and/or progression of many cancers is hormone-dependent; hormone independence may appear during treatment, so the cancer may become more aggressive. Due to the inherent nature of natural tissues, some cancers exhibit particularly strong hormone sensitivity, such as BCa and prostate cancer (PCa). Estrogen and androgen are the key steroid hormones respectively. Therefore, such cancers are usually treated with hormone-based drugs.

It is well known that growth factors (GF) are involved in the occurrence and progression of cancer. Therefore, GF receptors and their related signaling mechanisms are the main targets of cancer treatment. Generally speaking, GF signals through its respective receptor tyrosine kinase (RTK), which in humans contains approximately 20 subfamilies. The binding of GF activates RTK by inducing receptor dimerization, but some may form oligomers without activating ligands. Dimerization leads to the activation of the tyrosine kinase domain in the cell, which in turn triggers signaling pathways, including JAK/STAT, MAP kinase, and PI3 kinase.

Activity-dependent regulation of ion channel function occurs in the central nervous system and is essential for correct neuron development, wiring, and plasticity. In particular, the expression of neuronal VGSCα is usually regulated by negative feedback. Therefore, patterned activities or long-term treatment with VGSC openers will result in a decrease in mRNA/protein expression and changes in intracellular transport balance, which is conducive to channel internalization. On the contrary, use VGSC Blocker treatment increases the expression of functional proteins on the plasma membrane. Therefore, steady-state VGSC expression is usually tightly regulated to optimize activity and avoid excessive excitement.

The idea that VGSCs are expressed during cancer progression and that VGSC activity enhances cell behaviors (such as movement, invasion, and adhesion) associated with metastasis has now been established. More and more evidence shows that this VGSC expression is controlled by the \"mainstream\" cancer mechanisms, mainly hormones and growth factors, so VGSC has become a key regulator of cancer progression. However, other messenger molecules, including immunomodulators, can also affect channel expression/activity. Although the regulation of VGSC in cancer obviously occurs in the hierarchical structure from transcription to translation, there is still a lot of work to determine the precise mechanisms involved. For the former, developmentally regulated transcription factors, such as REST (\"neuron-specific silencing factor\"), are also known to affect cancer processes and channel expression.

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