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Novel Insights Into Ion Channels in Cancer Stem Cells (Review)

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Novel Insights Into Ion Channels in Cancer Stem Cells (Review) INTERNATIONAL JOURNAL OF ONCOLOGY 53: 1435-1441, 2018 Novel insights into ion channels in cancer stem cells (Review) QIJIAO CHENG1*, ANHAI CHEN1*, QIAN DU1, QIUSHI LIAO1, ZHANGLI SHUAI1, CHANGMEI CHEN1, XINRONG YANG1, YAXIA HU1, JU ZHAO1, SONGPO LIU1, GUO RONG WEN1, JIAXIN AN1, HAI JING1, BIGUANG TUO1, RUI XIE1 and JINGYU XU1,2 1Department of Gastroenterology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China; 2Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany Received February 15, 2018; Accepted June 28, 2018 DOI: 10.3892/ijo.2018.4500 Abstract. Cancer stem cells (CSCs) are immortal cells in have proven efficaciousinseveral cases; however, few patients tumor tissues that have been proposed as the driving force of survive >5 years due to the high recurrence and metastasis of tumorigenesis and tumor invasion. Previously, ion channels tumor cells; CSCs are considered the root of tumor recurrence were revealed to contribute to cancer cell proliferation, migra- and metastasis (2,3). tion and apoptosis. Recent studies have demonstrated that ion CSCs have been identified and characterized in various channels are present in various CSCs; however, the functions of tumor types; in particular, CSCs exhibit self-renewal, multi- ion channels and their mechanisms in CSCs remain unknown. lineage differentiation and tumor initiation capacities, and The present review aimed to focus on the roles of ion channels proliferative potential (4). Targeting of CSCs or inhibition in the regulation of CSC behavior and the CSC-like proper- of important properties including self-renewal, differentia- ties of cancer cells. Evaluation of the relationship between ion tion and apoptosis resistance are novel therapeutic strategies channels and CSCs is critically important for understanding (Fig. 1). Several lines of evidence have indicated that CSCs malignancy. serve a key role in tumorigenesis, recurrence and metas- tasis (5-7). When tumors occur, CSCs are considered to be the origin of abnormal differentiation; uncontrolled self-renewal Contents of CSCs induces malignant transformation and rapid prolif- eration of cells. In advanced tumor stages, once activated, 1. Introduction CSCs can promote tumor development and metastasis by 2. Ion channels and CSCs regulating tumor angiogenesis (8). Notably, the current anti- 3. Ion channel blockers as a novel target for cancer tumor drugs mainly target rapidly proliferating mitotic cells; 4. Conclusion however, CSCs are usually dormant or quiescent, and can therefore exhibit immune escape and resist the suppressive effects of chemotherapy drugs, thereby becoming the root 1. Introduction of tumor recurrence (3). Therefore, CSCs are considered to be the key to tumor recurrence and metastasis of seed cells Cancer stem cells (CSCs). Cancer is a leading cause of and malignant tumors. Previous studies have suggested that mortality worldwide. In China, ~4 million new cases of there are three major sources of CSCs, as follows: i) Normal cancer were diagnosed in 2015, and 50% of all mortalities stem or progenitor cells are malignantly transformed into were associated with cancer (1). Surgery, chemotherapy CSCs due to gene mutations; ii) viral infection or formation of and/or radiotherapy are used to treat the majority of cancers CSCs through intercellular fusion (9,10); iii) mature end-stage and to improve survival of patients. These clinical measures tumor cells regain CSC-like properties induced by ionizing radiation, hypoxia or the tumor microenvironment (11,12). In addition, both inflammatory factors [interleukin (IL) 6, and transforming growth factor (TGF)-β], and cytokines [endothe- lial growth factor (EGF) and vascular (EGF)] regulate CSC Correspondence to: Dr Jingyu Xu or Dr Rui Xie, Department of growth and maintenance (Fig. 2). Gastroenterology, Affiliated Hospital to Zunyi Medical College, 201 Dalian Road, Zunyi, Guizhou 563003, P.R. China E-mail: [email protected] Ion channels and tumors. Previous studies have reported E-mail: [email protected] that ion channels serve an important role in cancer develop- ment (13,14). Numerous ion channels have been confirmed to *Contributed equally be highly expressed in various tumor types and are closely associated with tumor cell biological behaviors (15-17). Ion Key words: ion channels, cancer stem cells, tumorigenesis, invasion channels are specific hydrophilic microporous proteins that exhibit selective permeability for various ions; they are usually named according to the ions with the highest permeability, 1436 CHENG et al: EXPRESSION AND FUNCTION OF ION CHANNELS IN CANCER STEM CELLS including potassium (K+) channels, calcium (Ca2+) channels There are several known Ca2+ channels: Voltage-gated Ca2+ and chloride (Cl-) channels. These ion channels are distrib- channels (VGCCs), ligand-gated Ca2+ channels, store-operated uted in almost every cell membrane of the body and have an Ca2+ channels and transient receptor potential channels, and important role in the physiology and pathology of excitable Na+/Ca2+ channels. VGCCs belong to the CaV family and are cells with regards to the following aspects: i) Determination involved in Ca2+ influx; VGCCs are divided into L-type Ca2+ of cell excitability, conductivity, contractility and rhythmicity; channels, T-type Ca2+ channels, P-type Ca2+ channels, matrix in nerve, muscle and other excitable cells, Na+ and Ca2+ interaction molecule-1 (STIM1) and the Ca2+ release-activated channels mainly regulate depolarization, whereas K+ chan- Ca2+ channel protein-1 (Orai1). STIM1 and inositol trisphos- nels mainly regulate repolarization and maintain the resting phate receptor combine with membrane uncoupling and Orai1 potential (18,19); ii) regulation of vasomotor smoothing and to induce Ca2+ influx (37,38). contraction activities (20); iii) participation in synaptic trans- Lee et al revealed that Orai, a key calcium channel for mission (21); iv) maintenance of normal cell volume (22,23); store-operated Ca2+ entry, is highly expressed in CSC-enriched v) regulation of intracellular cAMP, cGMP, Ca2+ and other populations of human oral/oropharyngeal squamous cell carci- second messenger concentrations, in order to trigger muscle noma (OSCC). In addition, the activation of Orai1 promotes contraction, glandular secretion, protein kinase activation cancer self-renewal via nuclear factor of activated T-cells and gene expression regulation (24,25). The normal structure signaling. Overexpression of Orai1 promotes self-renewal and function of ion channels are the basis for cells to carry in OSCC and increases the expression of enhancer of zeste out their normal activities. Mutations in specific ion channel homolog 2, Hes1, zinc finger E-box-binding homeobox 2 and sites lead to abnormalities in their activation and inactivation, interleukin 4. Conversely, inhibition of Orai1 suppresses cancer causing cell dysfunction and the formation of various diseases, self-renewal in OSCC (39). Zhao et al detected overexpression including epilepsy and arrhythmia, and skeletal muscle of the Ca2+ channel α2δ1+ subunit in hepatocellular carcinoma dysfunction (26,27). Disorders associated with aberrant ion (HCC) CSCs. These HCC CSCs exhibit stem cell-like proper- channel functions are commonly known as ‘ion channel ties, such as increased self-renewal, increased invasiveness diseases’ (28,29). and expression of stem cell-associated genes (octamer-binding At present, few reports have focused on the association transcription factor 4, SRY-box 2, Nanog homeobox and BMI1 between ion channels and CSCs. Our recent work indi- proto-oncogene, polycomb ring finger) (40). cated that solute carrier family 8 member A1 and transient Liu et al demonstrated that silencing the expression of receptor potential cation channel subfamily C member 6 are transient receptor potential cation channel subfamily M expressed in cluster of differentiation (CD)133+ stem cells member 7 (TRPM7) in glioma stem cells was able to induce in Huh7 hepatic cancer cells, thus indicating that ion chan- the Notch and signal transducer and activator of transcrip- nels may be involved in the occurrence and development of tion 3 pathways, which were downregulated in glioma stem cancer (30). Furthermore, ion channel inhibitors can reduce cells. TRPM7 is a ubiquitous ion channel permeable to Ca2+ drug resistance of tumor cells via regulation of CSC func- and Mg2+. Activation of TRPM7 upregulates the CSC markers tion (31,32). The present review aimed to summarize the aldehyde dehydrogenase 1 (ALDH1) and CD133; TRPM7 roles of ion channels, and describe their expression and func- activates ALDH1 activity to promote proliferation, migra- tion in CSCs. Further evaluation of the association between tion and invasion of glioma cells (41). In addition, Morelli ion channels and CSCs is critically important to understand et al evaluated the abnormal expression of transient receptor malignancy. potential cation channel subfamily V member 2 (TRPV2) in glioblastoma (GBM) CSCs. TRPV2 was revealed to promote 2. Ion channels and CSCs in vitro and in vivo GBM CSC differentiation and inhibit their 2+ + proliferation (42). Ca -activated K -channels (BKCa) are asso- Association between Ca2+ channels and CSCs. Cytosolic ciated with a poor cancer prognosis, and are highly expressed 2+ 2+ + Ca ([Ca ]cyt) has an important role in intracellular signal in CD133 SH-SY5Y neuroblastoma cells and human GBM transduction, and participates in
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