Abstract
Cervical cancer is a significant gynecological cancer and causes cancer-related deaths worldwide. Human papillomavirus (HPV) is implicated in the etiology of cervical malignancy. However, much evidence indicates that HPV infection is a necessary but not sufficient cause in cervical carcinogenesis. Therefore, the cellular pathophysiology of cervical cancer is worthy of study. This review summarizes the recent findings concerning the ion transport processes involved in cell volume regulation and intracellular Ca2+ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment. For cell volume regulation, we focused on the volume-sensitive Cl− channels and K+-Cl− cotransporter (KCC) family, important regulators for ionic and osmotic homeostasis of epithelial cells. Regarding intracellular Ca2+ homeostasis, the Ca2+ store sensor STIM molecules and plasma membrane Ca2+ channel Orai proteins, the predominant Ca2+ entry mechanism in epithelial cells, are discussed. Furthermore, we evaluate the potential of these membrane ion transport systems as diagnostic biomarkers and pharmacological interventions and highlight the challenges.
Highlights
An Overview of the Epidemiology and Pathogenesis of Cervical CancerCervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women, with an estimated 604,000 new cases and 342,000 deaths worldwide in 2020 [1]
This review focuses on the membrane ion transport processes involved in cell volume regulation and intracellular Ca2+ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment
We focused on the volume-sensitive Cl− channels and K+ -Cl− cotransporter (KCC) family, important regulators for the ionic and osmotic homeostasis of epithelial cells
Summary
Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women, with an estimated 604,000 new cases and 342,000 deaths worldwide in 2020 [1]. Multiple genes involved in DNA repair, cell proliferation, growth factor activity, angiogenesis, and mitogenesis become highly expressed in CIN and cervical cancer [5] This genomic instability allows HPVinfected cells to progress towards invasive carcinoma. This review focuses on the membrane ion transport processes involved in cell volume regulation and intracellular Ca2+ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment. In response to the hypotonic stress, cells defend themselves by activating an efflux of cell osmolytes, including ions and specific organic molecules together with osmotically responsive water, to accomplish the process of regulatory volume decrease (RVD) [28,30].
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