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Progress in Cellular Physiological Researches on Esophageal Cancer

Ion and water transporters have recently been examined in cancer cells, and different forms of transporters have been discovered in esophageal cancer. This article intends to provide a thorough assessment of what is currently known about the expression and function of cellular physiological variables in esophageal cancer. Ion transporters include voltage-gated K+ channels, Cl- transporters, and Ca2+ transporters. The presentation of and transient receptor potential channels in esophageal cancer cells and tissues and their ability to control cancer progression have been discovered. Aquaporin 3 and aquaporin 5 are water channels that play a crucial role in esophageal cancer progression. 

Controls of intracellular pH, like anion exchanger, sodium hydrogen exchanger, vacuolar H+ -ATPases, and carbonic anhydrases, also included cellular management of esophageal cancer. Their pharmacological interference and gene silencing induced tumorigenesis, submitting their potentiality as therapeutic purposes for esophageal cancer.

A more profound understanding of molecular mechanisms may guide discovering these cellular physiological procedures as a unique therapeutic method for esophageal cancer.


Esophageal cancer is highly aggressive neoplasia that accounts for a significant portion of worldwide cancer-related fatalities. The prognosis of esophageal squamous cell carcinoma (ESCC) has recently improved with surgical procedures, adjuvant therapy, and chemoradiotherapy, and perioperative management. However, even in patients with advanced disease, recurrence is common, and their prophecy remains inadequate. For the execution of repetitive or metastatic esophageal cancer to improve, it is essential to understand the molecular mechanisms controlling the tumorigenesis and the progress of the disease. 

Over the past ten years, many reports have exposed that ion and water transporters play essential roles in fundamental cellular functions. Adjustment in the process of these transporters has been reported in various human pathologies. Recently, the parts of ion and water transporters have been investigated in cancer cells, and different types of transporters have been observed in gastrointestinal cancers.

Esophageal Cancer

Ion channels and transporters in esophageal cancer 

Distinct subtypes of K+ channels are shown in human esophageal cancer cells and are linked to prognosis in recent research. In esophageal cancer, altered expression of many voltage-gated K+ channels (Kv) has been identified. The prototypic member of the ether a go-go family of Kv is Eag1 (Kv10.1). One of the elements of postponed rectifier K+ currents is encoded by the human ether-a-go-go-related gene (HERG). Overexpression of hERG1 has been seen in resected ESCC and has been linked to a poor prognosis after surgery. According to the findings of certain investigations, hERG1 expresses from an early stage of esophageal cancer progression through dysplasia.

There’s also evidence that Cl- transporters have a role in esophageal cancer. Na+/K+/2Cl- cotransporter 1 (NKCC1) expression was reported to be associated with the degree of histological differentiation in ESCC. Furosemide, an NKCC1 inhibitor, inhibited ESCC cell proliferation by disrupting the G2/M checkpoint because NKCC is one of the significant transporters controlling [Cl- I via Cl- absorption into the intracellular compartment, furosemide lowers [Cl- ]i.

The role of K+ -Cl cotransporter 3 (KCC3) in the regulation of cellular invasion, as well as the clinicopathological importance of its expression in ESCC, has also been investigated. KCC3 expression at the invasive front of ESCC was associated with a more inferior survival rate than in those without it, and multivariate analysis revealed that it was one of the most important independent prognostic factors. Furthermore, siRNA-mediated knockdown of KCC3 reduced cell migration and invasion in human ESCC cell lines.

Ca2+ channels, which regulate intracellular Ca2+ concentration ([Ca2+]i), play an essential role in cancer growth as well.

Water channels in esophageal cancer

Under physiological and pathological settings, aquaporins (AQPs), transmembrane proteins that allow water transport, are critical for cell volume management and electrolyte balance. In humans, 13 AQP subtypes and their vital roles have been identified thus far. A study in ESCC found that AQP3 is overexpressed in tumor regions of human ESCC and may play a key role in cell growth.

In ESCC cells, siRNA suppression of AQP5 decreased cell proliferation and progression through the G1-S phase, as well as causing apoptosis. Although AQP5 and p21 protein expression patterns were starkly different, AQP5 and CCND1 protein expression in ESCC tissue followed a similar pattern. AQP5 expression is linked to tumor size, histological type, and tumor recurrence in ESCC patients, according to immunohistochemical labeling.

pH regulators in esophageal cancer

Anion exchanger (AE) proteins help control intracellular pH by facilitating the electroneutral replacement of Cl- for HCO3 – beyond the plasma membrane of mammalian cells. According to a study, acid boosted MAPK-mediated proliferation in Barrett’s esophageal adenocarcinoma cells via intracellular acidification via AE.

The sodium-hydrogen exchanger (NHE) contributes to intracellular pH regulation by mediating a paired counter-transport of one H+ ion exchange for one Na+ ion. NHE1 was shown to be significantly expressed in esophageal adenocarcinoma tissues, and knocking it down in esophageal cancer cells decreased viability and promoted apoptosis. The cell’s particular proton pump, vacuolar H+ -ATPases (V-ATPases), is critical for maintaining internal pH.

The carbonic anhydrases (CAs) classifies zinc metalloenzymes that contribute to pH regulation in various physiological processes.

In mammals, 15 active isoforms of CAs have been discovered, 12 of which are catalytically active. CA IX expression in esophageal cancer is connected to poor prognosis and malignant phenotype in adenocarcinoma and squamous cell carcinoma (SCC).

Regulation of osmolality 

Some previous studies have shown the cytocidal effects of hypotonic pressure on cancer cells and the ability of peritoneal lavage with distilled water (DW) while surgery. Lately, changes in the cellular morphology have been analyzed and the volume of esophageal cancer cells presented to hypotonic stress using several novel methods and equipment. Video recordings by the high-speed digital camera have confirmed that hypotonic stress with DW produces cell swelling followed by cell rupture, and measures of cell volume differences using a high-resolution flow cytometer show that severe hypotonicity with DW develops broken fragments of esophageal cancer cells inside 5 min. Additionally, we attended the esophageal cancer cells with a Cl- channel blocker, 5-nitro-2-3- phenyl propyl amino)-benzoic acid (NPPB), improve the cytocidal effects by boosting cell volume during the hypotonic stress through the inhibition of regulatory volume reduction (RVD). After hypotonicity-induced cell inflammation, RVD occurs by beginning ion channels and transporters, producing effluxes of K+, Cl-, and H2O, causing cell shrinkage. In the TE5, TE9, and KYSE170 cells, therapy with NPPB increases cell volume by repressing RVD and enhancing the hypotonic solutions’ cytocidal results. Similar phenomena have also been demonstrated in gastric cancer cells, colorectal cancer cells, and pancreatic cancer cells.


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