You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Chloride Channels and Transporters in Cancers: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Jeong Hee Hong.

The canonical roles of chloride channels and chloride-associated transporters have been physiologically determined; these roles include the maintenance of membrane potential, pH balance, and volume regulation and subsequent cellular functions such as autophagy and cellular proliferative processes. Although complicated ion movements, crosstalk among channels/transporters through homeostatic electric regulation, difficulties with experimental implementation such as activity measurement of intracellular location were disturbed to verify the precise modulation of channels/transporters, recently defined cancerous function and communication with tumor microenvironment of chloride channels/transporters should be highlighted beyond classical homeostatic ion balance.

  • chloride channels
  • chloride-associated transporters

1. Chloride Transport

Electrolytes, such as charged anion chloride, drive cellular electrical shifting energy, which mediates various cellular processes. Intracellular chloride ions are abundant (5–40 mM) as are sodium ions [1]. The movement of chloride is considered to regulate cellular membrane potential, cellular volume, and electrostatic compensation as well as maintain the pH of cellular or intra-organelles such as lysosomes. In addition to its classical roles, chloride channels participate in modulation of the cellular fate and motility of cancer cells. Therefore, the finding that these channels function in malignant conditions beyond simply transporting chloride is meaningful.

2. Membrane-Associated Components of Chloride Movement

2.1. Transmembrane Member 16A

2. Membrane-Associated Components of Chloride Movement

2.1. Transmembrane Member 16A

Transmembrane member (TMEM) 16A (calcium-activated chloride channel; anoctamin 1, ANO1) transports chloride and bicarbonate and plays a role in the proliferation and development of malignant cell types. The expression of TMEM16A has been identified in a broad range of cancers. Cellular specific mechanism of TMEM16A is extensively reviewed and highlighted in various cancers [17,18][2][3]. Briefly, TMEM16A positively correlates with epidermal growth factor receptor (EGFR) expression in tumor development [2][4], and both TMEM16A and EGFR are found in NSCLC tissues. Tumor, node, metastasis (TNM) stage 3 + 4 primary NSCLC is positive for TMEM16A and EGFR [2][4]. Thus, TMEM16A is considered as a potential diagnostic marker for lung cancer. Treatment of TMEM16A inhibitor T16Ainh-A01 or knockdown of TMEM16A inhibits the cellular proliferation and invasion by attenuating EGFR phosphorylation in H1299 lung cancer cells [19][5]. Knocking down TMEM16A attenuates proliferation and migration by inhibiting phosphoinositide 3-kinase/protein kinase B (PI3K/PKB) and mitogen-activated protein kinase (MAPK) pathways in HCC, HepG2, and SMMC7721 cells [20][6]. Colorectal cancer (CRC) and HCT116 and DLD-1 cells also express abundant TMEM16A, which is a prognostic factor for patients with CRC [21][7].

2.2. TMEM206

An acidic milieu is involved in various diseases, such as ischemia, cancer development, and inflammation [32][8]. Acid-sensitive chloride channels (also known as proton-activated chloride channels, PAC; TMEM206) are expressed in normal and malignant tissues. Protein profiling has revealed that colorectal, breast, and hepatic cancer cells have increased amounts of TMEM206, which plays a key role in cellular responses to acidic conditions [32,33][8][9]. Consistent with this concept, silencing TMEM206 attenuates acid-mediated cell death and alleviates acidosis-associated pathologies such as ischemic stroke. The cytoplasmic expression of TMEM206 is associated with CRC development and proliferation. The CRC cell lines SW480 and HCT-116 overexpress TMEM206, which results in enhanced cellular migration, invasion, and proliferation via AKT/ERK phosphorylation [32][8]. Although the precise mechanism of action of TMEM206 in other cancerous tissues remains unknown, TMEM206 could be considered as a diagnostic marker for CRC.

2.3. Calcium-Activated Chloride Channel Regulators

Calcium-activated chloride channel regulators (CLCAs) modulate chloride in epithelia, play critical roles in transporting electrolytes including chloride, modulate function of TMEM16A and its adhesion molecules, and negatively regulate cancer development. Nasopharyngeal, breast, and colorectal cancers have low levels of CLCAs [34,35,36,37,38][10][11][12][13][14]. The CLCA1 protein is primarily expressed in the small intestine, colon, and appendix. The expressions of CLCA1 and CLCA4 are decreased in intestinal tissues from patients with CRC, the CRC cell lines SW620 and LOVO, and in hormone receptor-positive breast cancer cell line MCF7 cells [35,37,38][11][13][14]. CLCA1 is negatively involved in the differentiation of intestinal Caco-2 cells [38][14]. Low levels of CLCA2 mRNA and protein have been identified in nasopharyngeal carcinoma (NPC) S18 and 5-8F cells, whereas overexpressed CLCA2 inhibits FAK/ERK signaling in these cells [34][10].

2.4. Chloride Intracellular Channels

Chloride intracellular channel 1 (CLIC1; also known as NCC27) belongs to the highly conserved CLIC family of chloride ion channels [39][15]. It can reside in the cytoplasm and temporarily in plasma and internal cell membranes [40][16]. CLIC1 participates in various cellular functions, including the maintenance of pH homeostasis, cell survival, cell cycle regulation, cell volume regulation, membrane potential modulation, and organelle acidification [40,41,42,43,44,45,46,47,48][16][17][18][19][20][21][22][23][24]. This channel is upregulated in various cancer type such as prostate [46][22], gallbladder (GBC) [48][24], colon cancer [47][23], gastric [49][25], clear cell renal cell carcinoma [50][26], and glioblastoma stem cells [51,52][27][28]. Overexpressed CLIC1 in patients with HCC [53][29] positively correlates with HCC proliferation and metastasis [54][30]. CLIC1 participates in hypoxia-induced colonic carcinoma metastasis via the MAPK/ERK pathway [45][21]. Moreover, CLIC1 is recruited to the plasma membrane in response to chemotaxis, such as directional treatment with epidermal growth factor (EGF) and mechanotaxis and its ectopic expression of CLIC1 enhances migratory apparatus such as lamellipodia and invadopodia [54][30]. Hypoxia-induced tumor cells possess irregular microvascular networks and blood flow [55][31] and can be transformed to promote cancer metastasis [56][32]. Mechanistically, limited blood perfusion or altered flow due to hypoxic conditions might contribute to the migration and invasion of cancer cells [57][33]. Upregulated CLIC1 expression correlates with lymph node metastasis and lymphatic invasion [49][25] as well as lung cancer migration and invasion [40][16]. Cell growth is promoted by CLIC1 via the MAPK/ERK pathway in prostate cancer [46][22] and CLIC1 is expressed in pancreatic ductal adenocarcinoma (PDAC) [58][34] where it plays an important role in promoting cancer cell survival, proliferation, and invasion [46,59][22][35]. In various regulatory processes involving CLIC1, small interfering (si)RNAs of CLIC1 induce the downregulation of cell proliferation, growth, and invasiveness of pancreatic cancer cell lines such as PANC-1 and MIAPaca-2 compared with control cells [58,60][34][36]. Furthermore, CLIC1 is associated with proteasome activator 28 β (PA28 β), and its specific siRNA downregulates CLIC1 in gastric cancer [61][37]. A regulatory volume decrease (RVD) is a critical process in cancer cell motility, such as migration and invasion [62][38].

2.5. Voltage-Gated Chloride Channels

Voltage-gated chloride channel 3 (CLC-3; also known as CLCN3) is expressed in cell membranes and intracellular vesicles where it exchanges chloride for hydrogen. CLC-3 protein is expressed in prostate carcinoma [70][39], nasopharyngeal [62][38], neuroendocrine [71][40], and brain cells [72][41] and is significantly overexpressed in HCC, compared with normal control tissues [73][42]. Moreover, upregulated CLC-3 is associated with HCC tumor size and prognosis [73][42]. Overexpressed CLC-3 protein participates in cell proliferation and migration. The regulation of cell volume by CLC-3 is involved in the development and metastasis of NPC and prostate cancer [62,70,74][38][39][43]. Signaling by Wnt/β-catenin contributes to metastasis and adhesion by regulating the EMT process in tumorigenesis [75,76][44][45]. The expression of CLC-3 is more abundant in tissues at the late stage of CRC and in the CRC LOVO and SW620 compared with that in normal cells. SiRNA-CLC-3 (siCLC-3) inhibits CRC cell viability, proliferation, and metastasis by inhibiting Wnt/β-catenin signaling, whereas the Wnt/β-catenin activator lithium chloride rescues the effect of siCLC-3 [77][46]. CLC-3 could be a prognostic marker for HCC, CRC, NPC, and prostate cancer. Patients with breast cancer are treated with tamoxifen, a non-steroidal anticancer agent [78][47] that inhibits the migration, chloride current, and volume regulatory mechanisms in HCC MHCC97H cells in vitro [79][48]. The activator of protein kinase C (PKC) phorbol-12-myristate-13 acetate (PMA) inhibits PKC expression in the presence of tamoxifen and reduces the migration of cells with CLC-3 knockdown, suggesting that CLC-3 is involved in the mechanism of anticancer drug and cellular volume regulation [80][49]. CLC-4 is expressed on the cell surface and intracellular endosomal membranes in the CRC cell lines RKO and LS174 [81][50]. The migration and invasion of CRC cells is reduced by CLC-4 siRNA or shRNA [82][51].

2.6. Cystic Fibrosis Transmembrane Conductance Regulator

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel that regulates the balance of electrolytes in the respiratory and endocrine systems, exocrine glands, and other tissues. Malfunctioning and/or abnormal expression of CFTR have been found in various types of cancer. The upregulated expression of CFTR is associated with an invasive phenotype in cervical and ovarian carcinomas [85,86][52][53]. Conversely, the mRNA and protein expression of CFTR are reduced in NPC 5-8F, 6-10B, and HNE-1, compared with normal cells, whereas CFTR knockdown increases NPC cell migration and invasion [87][54]. Enhanced CFTR protein expression in NPC 5-8F cells increases epithelial markers such as occludin and E-cadherin, and attenuates the mesenchymal marker smooth muscle actin [87][54]. In addition, protein expression of CFTR is decreased in CRC, compared with normal tissues [88][55]. However, CFTR mRNA overexpression decreases cell proliferation, migration, and invasion in the CRC cell lines HCT116 and CaCo-2 [88][55]. The results of studies on the roles of CFTR in cancer have been contradictory. Enhanced CFTR expression inhibits various cancerous processes such as EMT in breast carcinoma [89][56], lung cancer [90][57], NPC [87][54], endometrial carcinoma cells [91][58], prostate cancer [92][59], and intestinal carcinoma [93][60].

2.7. Voltage-Dependent Anion Channels

The expression of voltage-dependent anion channels (VDACs) on the mitochondrial membrane of all eukaryotes, including mammals [96][61], is increased in various tumor tissues, such as carcinoma of the breast [97][62], colon [98][63], thyroid gland [99][64], lung [100][65], pancreas [101][66], and liver [102][67] compared with that in normal tissues. The VDAC1, 2, and 3 isotypes of these channels play different roles; VDAC1 and VDAC2 participate in pore formation within the mitochondrial membrane [96][61] and VDAC3 participates in the regulation of mitochondrial membrane potential [103][68]. The expression of VDAC is associated with neurodegenerative disorders and muscular and myocardial diseases including various types of cancers [104][69]. The progression of tumorigenesis is decreased in HeLa cells with depleted VDAC1 [105][70]. The expression of VDAC1 is more abundant in cancer, A549, and HeLa cells, than in normal WI-38 fibroblasts derived from lung tissue [106][71], HCC tissues, HepG2 and SMMC7721 cells, as well as lung adenocarcinoma tumors [107][72]. Small interfering RNA-VDAC1 and miR-7 downregulate cell growth, proliferation, migration, and invasion in HCC tissues [102][67], lung cancer A549 cells [100][65], and cervical cancer HeLa cells [105][70]. Furthermore, miR-490-3p is significantly associated with the carcinogenesis of various cancers [98][63], and it can regulate the growth and EMT of HCC cells [108][73] and the invasiveness of triple-negative breast cancer cells, MDA-MB-231, and MDA-MB-436 [109][74]. MiR-490-3p downregulates VDAC1 through the mammalian target of rapamycin (mTOR) pathway in CRC tissues and cell lines [98][63]. The expression of VDAC2 is upregulated in melanoma cells and HCC cell lines such as HepG2 [110][75] but downregulated in glioma stem cells [111][76] and it plays an anti-apoptotic role in primary cultured mouse embryonic fibroblasts. Although its different role of VDACs is defined, precise roles of VDAC family in different cancers remain unresolved and await identification in future studies.

2.8. Volume-Regulated Anion Channel

Volume regulation is critical function to maintain cellular fate. Volume-regulated anion channels (VRACs; also called volume-sensitive organic osmolyte anion channel or swelling-induced chloride current IClswell) are considered as regulatory channels of cellular volume [112][77]. VRAC is involved in the RVD and regulates proliferation of nasopharyngeal carcinoma cell [113,114[78][79][80],115], OSCC HST-1 cells [27][81], and gastric cancer [116][82]. Inhibited VRAC by 4-(2-Butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB) reduces proliferation, migration, and invasion of glioblastoma U251 and U87 cells [117][83]. Leucine-rich-repeat-containing 8A (LRRC8A, also called SWELL1) is component protein of VRAC. LRRC8A expresses in HCC tissues and induced cellular proliferation and migration in HCC SMMC-7721, Sk-hep-1, Huh7, and HCCLM3 cells [118][84]. Moreover, survival of cisplatin-resistant A549 cells or A2780 cells is modulated by the LRRC8A [119,120][85][86]. Although dual function of VRAC components LRRC8A and LRRC8D on drug resistance has been addressed [121][87], VRACs may be associated with chemo-resistant mechanism and are needed to verify its precise mechanism in various cancers.

2.9. Chloride-Bicarbonate Exchangers

Chloride-bicarbonate (CB) exchangers consist of solute carrier (SLC) families, including anion exchangers (AEs) and SLC26As. The CB exchangers mediate the electroneutral or electrogenic exchange of bicarbonate for chloride (respective stoichiometry of chloride: bicarbonate, 1:1 or 1:2) and are associated with the regulation of intracellular pH. The anion exchangers AE1, AE2, AE3, and AE4 [122,123,124,125][88][89][90][91] are expressed in various tissues and localize in the plasma membrane. Both AE1 and AE2 are involved in cancer whereas other AEs are unknown. Histologic findings have shown that AE1 is expressed in the cytoplasm of gastric cancer cells [126,127][92][93]. Knockdown of AE1 induces the release of p16INK4A and inhibits gastric cancer growth [126,128][92][94]. The expression of AE1 positively correlates with cancer size and metastasis [127][93]. Although the modulation of AE1 expression is poorly verified, miR-24-mediates AE1 attenuation in gastric cancer cells [129][95]. The expression of AE1 is associated with tumor progression through crosstalk with MAPK and hedgehog signaling pathways in esophageal carcinoma [130][96]. Although AE2 is expressed in most tissues, it has been addressed that the AE2 gene is highly expressed in HCC cells, gastric, and colorectal cancers [131,132,133,134,135][97][98][99][100][101].

References

  1. Stauber, T.; Jentsch, T.J. Chloride in vesicular trafficking and function. Annu. Rev. Physiol. 2013, 75, 453–477.
  2. Wang, H.; Zou, L.; Ma, K.; Yu, J.; Wu, H.; Wei, M.; Xiao, Q. Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer. Mol. Cancer 2017, 16, 152.
  3. Kunzelmann, K.; Ousingsawat, J.; Benedetto, R.; Cabrita, I.; Schreiber, R. Contribution of anoctamins to cell survival and cell death. Cancers 2019, 11, 382.
  4. He, Y.; Li, H.; Chen, Y.; Li, P.; Gao, L.; Zheng, Y.; Sun, Y.; Chen, J.; Qian, X. Expression of anoctamin 1 is associated with advanced tumor stage in patients with non-small cell lung cancer and predicts recurrence after surgery. Clin. Transl. Oncol. 2017, 19, 1091–1098.
  5. Hu, C.; Zhang, R.G.; Jiang, D.P. TMEM16A as a potential biomarker in the diagnosis and prognosis of lung cancer. Arch. Iran. Med. 2019, 22, 32–38.
  6. Zhang, C.T.; Liu, J.X.; Han, Z.Y.; Cui, X.; Peng, D.T.; Xing, Y.F. Inhibition of TMEM16A suppresses growth and induces apoptosis in hepatocellular carcinoma. Int. J. Clin. Oncol. 2020, 25, 1145–1154.
  7. Mokutani, Y.; Uemura, M.; Munakata, K.; Okuzaki, D.; Haraguchi, N.; Takahashi, H.; Nishimura, J.; Hata, T.; Murata, K.; Takemasa, I.; et al. Down-regulation of microRNA-132 is associated with poor prognosis of colorectal cancer. Ann. Surg. Oncol. 2016, 23, S599–S608.
  8. Zhao, J.B.; Zhu, D.H.; Zhang, X.P.; Zhang, Y.; Zhou, J.P.; Dong, M. TMEM206 promotes the malignancy of colorectal cancer cells by interacting with AKT and extracellular signal-regulated kinase signaling pathways. J. Cell. Physiol. 2019, 234, 10888–10898.
  9. Zhang, L.; Liu, S.Y.; Yang, X.; Wang, Y.Q.; Cheng, Y.X. TMEM206 is a potential prognostic marker of hepatocellular carcinoma. Oncol. Lett. 2020, 20, 174.
  10. Qiang, Y.Y.; Li, C.Z.; Sun, R.; Zheng, L.S.; Peng, L.X.; Yang, J.P.; Meng, D.F.; Lang, Y.H.; Mei, Y.; Xie, P.; et al. Along with its favorable prognostic role, CLCA2 inhibits growth and metastasis of nasopharyngeal carcinoma cells via inhibition of FAK/ERK signaling. J. Exp. Clin. Cancer Res. 2018, 37, 34.
  11. Chen, H.; Liu, Y.; Jiang, C.D.; Chen, Y.M.; Li, H.; Liu, Q.A. Calcium-activated chloride channel A4 (CLCA4) plays inhibitory roles in invasion and migration through suppressing epithelial-mesenchymal transition via PI3K/AKT signaling in colorectal cancer. Med. Sci. Monit. 2019, 25, 4176–4185.
  12. Walia, V.; Ding, M.; Kumar, S.; Nie, D.; Premkumar, L.S.; Elble, R.C. hCLCA2 is a p53-inducible inhibitor of breast cancer cell proliferation. Cancer Res. 2009, 69, 6624–6632.
  13. Yu, Y.; Walia, V.; Elble, R.C. Loss of CLCA4 promotes epithelial-to-mesenchymal transition in breast cancer cells. PLoS ONE 2013, 8, e83943.
  14. Yang, B.; Cao, L.; Liu, B.; McCaig, C.D.; Pu, J. The transition from proliferation to differentiation in colorectal cancer is regulated by the calcium activated chloride channel A1. PLoS ONE 2013, 8, e60861.
  15. Wang, W.; Wan, M.H.; Liao, D.J.; Peng, G.L.; Xu, X.; Yin, W.Q.; Guo, G.X.; Jiang, F.N.; Zhong, W.D.; He, J.X. Identification of potent chloride intracellular channel protein 1 inhibitors from traditional chinese medicine through structure-based virtual screening and molecular dynamics analysis. Biomed. Res. Int. 2017, 2017, 4751780.
  16. Wang, W.; Xu, X.; Wang, W.J.; Shao, W.L.; Li, L.P.; Yin, W.Q.; Xiu, L.C.; Mo, M.C.; Zhao, J.; He, Q.Y.; et al. The expression and clinical significance of CLIC1 and HSP27 in lung adenocarcinoma. Tumor Biol. 2011, 32, 1199–1208.
  17. Schlesinger, P.H.; Blair, H.C.; Teitelbaum, S.L.; Edwards, J.C. Characterization of the osteoclast ruffled border chloride channel and its role in bone resorption. J. Biol. Chem. 1997, 272, 18636–18643.
  18. Valenzuela, S.M.; Mazzanti, M.; Tonini, R.; Qiu, M.R.; Warton, K.; Musgrove, E.A.; Campbell, T.J.; Breit, S.N. The nuclear chloride ion channel NCC27 is involved in regulation of the cell cycle. J. Physiol. 2000, 529, 541–552.
  19. Shi, Z.H.; Zhao, C.; Wu, H.; Wang, W.; Liu, X.M. CLIC1 protein A candidate prognostic biomarker for malignant-transformed hydatidiform Moles. Int. J. Gynecol. Cancer 2011, 21, 153–160.
  20. Ma, P.F.; Chen, J.Q.; Wang, Z.; Liu, J.L.; Li, B.P. Function of chloride intracellular channel 1 in gastric cancer cells. World J. Gastroenterol. 2012, 18, 3070–3080.
  21. Wang, P.; Zhang, C.; Yu, P.W.; Tang, B.; Liu, T.; Cui, H.; Xu, J.H. Regulation of colon cancer cell migration and invasion by CLIC1-mediated RVD. Mol. Cell. Biochem. 2012, 365, 313–321.
  22. Tian, Y.D.; Guan, Y.B.; Jia, Y.Y.; Meng, Q.J.; Yang, J.J. Chloride intracellular channel 1 regulates prostate cancer cell proliferation and migration through the MAPK/ERK pathway. Cancer Biother. Radiopharm. 2014, 29, 339–344.
  23. Wang, P.; Zeng, Y.; Liu, T.; Zhang, C.; Yu, P.W.; Hao, Y.X.; Luo, H.X.; Liu, G. Chloride intracellular channel 1 regulates colon cancer cell migration and invasion through ROS/ERK pathway. World J. Gastroenterol. 2014, 20, 2071–2078.
  24. Ding, Q.C.; Li, M.L.; Wu, X.S.; Zhang, L.; Wu, W.G.; Ding, Q.; Weng, H.; Wang, X.A.; Liu, Y.B. CLIC1 overexpression is associated with poor prognosis in gallbladder cancer. Tumor Biol. 2015, 36, 193–198.
  25. Chen, C.D.; Wang, C.S.; Huang, Y.H.; Chien, K.Y.; Liang, Y.; Chen, W.J.; Lin, K.H. Overexpression of CLIC1 in human gastric carcinoma and its clinicopathological significance. Proteomics 2007, 7, 155–167.
  26. Nesiu, A.; Cimpean, A.M.; Ceausu, R.A.; Adile, A.; Ioiart, I.; Porta, C.; Mazzanti, M.; Camerota, T.C.; Raica, M. Intracellular chloride ion channel protein-1 expression in clear cell renal cell carcinoma. Cancer Genomics Proteomics 2019, 16, 299–307.
  27. Setti, M.; Savalli, N.; Osti, D.; Richichi, C.; Angelini, M.; Brescia, P.; Fornasari, L.; Carro, M.S.; Mazzanti, M.; Pelicci, G. Functional role of CLIC1 ion channel in glioblastoma-derived stem/progenitor cells. J. Natl. Cancer Inst. 2013, 105, 1644–1655.
  28. Peretti, M.; Raciti, F.M.; Carlini, V.; Verduci, I.; Sertic, S.; Barozzi, S.; Garre, M.; Pattarozzi, A.; Daga, A.; Barbieri, F.; et al. Mutual influence of ROS, pH, and CLIC1 membrane protein in the regulation of G1-S phase progression in human glioblastoma stem cells. Mol. Cancer Ther. 2018, 17, 2451–2461.
  29. Huang, J.S.; Chao, C.C.; Su, T.L.; Yeh, S.H.; Chen, D.S.; Chen, C.T.; Chen, P.J.; Jou, Y.S. Diverse cellular transformation capability of overexpressed genes in human hepatocellular carcinoma. Biochem. Biophys. Res. Commun. 2004, 315, 950–958.
  30. Peng, J.M.; Lin, S.H.; Yu, M.C.; Hsieh, S.Y. CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis. J. Clin. Investig. 2021, 131.
  31. Joyce, J.A.; Pollard, J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 2009, 9, 239–252.
  32. Law, A.Y.; Wong, C.K. Stanniocalcin-2 promotes epithelial-mesenchymal transition and invasiveness in hypoxic human ovarian cancer cells. Exp. Cell Res. 2010, 316, 3425–3434.
  33. Kokura, S.; Yoshida, N.; Imamoto, E.; Ueda, M.; Ishikawa, T.; Uchiyama, K.; Kuchide, M.; Naito, Y.; Okanoue, T.; Yoshikawa, T. Anoxia/reoxygenation down-regulates the expression of E-cadherin in human colon cancer cell lines. Cancer Lett. 2004, 211, 79–87.
  34. Jia, N.N.; Dong, S.L.; Zhao, G.; Gao, H.; Li, X.Q.; Zhang, H.H. CLIC1 overexpression is associated with poor prognosis in pancreatic ductal adenocarcinomas. J. Cancer Res. Ther. 2016, 12, 892–896.
  35. Zhang, S.; Wang, X.M.; Yin, Z.Y.; Zhao, W.X.; Zhou, J.Y.; Zhao, B.X.; Liu, P.G. Chloride intracellular channel 1 is overexpression in hepatic tumor and correlates with a poor prognosis. APMIS 2013, 121, 1047–1053.
  36. Lu, J.H.; Dong, Q.; Zhang, B.T.; Wang, X.F.; Ye, B.; Zhang, F.; Song, X.L.; Gao, G.F.; Mu, J.S.; Wang, Z.; et al. Chloride intracellular channel 1 (CLIC1) is activated and functions as an oncogene in pancreatic cancer. Med. Oncol. 2015, 32, 171.
  37. Zheng, D.L.; Huang, Q.L.; Zhou, F.; Huang, Q.J.; Lin, J.Y.; Lin, X. PA28 ss regulates cell invasion of gastric cancer via modulating the expression of chloride intracellular channel 1. J. Cell Biochem. 2012, 113, 1537–1546.
  38. Mao, J.W.; Chen, L.X.; Xu, B.; Lijing, W.J.; Li, H.Z.; Guo, J.; Li, W.D.; Nie, S.H.; Jacob, T.J.C.; Wang, L.W. Suppression of ClC-3 channel expression reduces migration of nasopharyngeal carcinoma cells. Biochem. Pharmacol. 2008, 75, 1706–1716.
  39. Lemonnier, L.; Shuba, Y.; Crepin, A.; Roudbaraki, M.; Slomianny, C.; Mauroy, B.; Nilius, B.; Prevarskaya, N.; Skryma, R. Bcl-2-dependent modulation of swelling-activated Cl- current and ClC-3 expression in human prostate cancer epithelial cells. Cancer Res. 2004, 64, 4841–4848.
  40. Weylandt, K.H.; Nebrig, M.; Jansen-Rosseck, N.; Amey, J.S.; Carmena, D.; Wiedenmann, B.; Higgins, C.F.; Sardini, A. CIC-3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment. Mol. Cancer Ther. 2008, 7, 2261.
  41. Sontheimer, H. An unexpected role for ion channels in brain tumor metastasis. Exp. Biol. Med. 2008, 233, 779–791.
  42. Cheng, W.; Zheng, S.T.; Li, L.; Zhou, Q.; Zhu, H.P.; Hu, J.; Luo, H.B. Chloride channel 3 (CIC-3) predicts the tumor size in hepatocarcinoma. Acta Histochem. 2019, 121, 284–288.
  43. Xu, B.; Mao, J.W.; Wang, L.W.; Zhu, L.Y.; Li, H.Z.; Wang, W.Z.; Jin, X.B.; Zhu, J.Y.; Chen, L.X. ClC-3 chloride channels are essential for cell proliferation and cell cycle progression in nasopharyngeal carcinoma cells. Acta Biochim. Biophys. Sin. 2010, 42, 370–380.
  44. Fodde, R.; Brabletz, T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr. Opin. Cell Biol. 2007, 19, 150–158.
  45. Cai, J.C.; Guan, H.Y.; Fang, L.S.; Yang, Y.; Zhu, X.; Yuan, J.; Wu, J.H.; Li, M.F. MicroRNA-374a activates Wnt/beta-catenin signaling to promote breast cancer metastasis. J. Clin. Investig. 2013, 123, 566–579.
  46. Mu, H.L.; Mu, L.J.; Gao, J.F. Suppression of CLC-3 reduces the proliferation, invasion and migration of colorectal cancer through Wnt/beta-catenin signaling pathway. Biochem. Biophys. Res. Commun. 2020, 533, 1240–1246.
  47. Hughes-Davies, L.; Caldas, C.; Wishart, G.C. Tamoxifen: The drug that came in from the cold. Br. J. Cancer 2009, 101, 875–878.
  48. Mao, J.W.; Xu, B.; Li, H.Z.; Chen, L.X.; Jin, X.B.; Zhu, J.Y.; Wang, W.Z.; Zhu, L.Y.; Zuo, W.H.; Chen, W.Q.; et al. Lack of association between stretch-activated and volume-activated Cl− currents in hepatocellular carcinoma cells. J. Cell. Physiol. 2011, 226, 1176–1185.
  49. Mao, J.W.; Yuan, J.; Wang, L.W.; Zhang, H.F.; Jin, X.B.; Zhu, J.Y.; Li, H.Z.; Xu, B.; Chen, L.X. Tamoxifen inhibits migration of estrogen receptor-negative hepatocellular carcinoma cells by blocking the swelling-activated chloride current. J. Cell. Physiol. 2013, 228, 991–1001.
  50. Mohammad-Panah, R.; Ackerley, C.; Rommens, J.; Choudhury, M.; Wang, Y.C.; Bear, C.E. The chloride channel ClC-4 co-localizes with cystic fibrosis transmembrane conductance regulator and may mediate chloride flux across the apical membrane of intestinal epithelia. J. Biol. Chem. 2002, 277, 566–574.
  51. Ishiguro, T.; Avila, H.; Lin, S.Y.; Nakamura, T.; Yamamoto, M.; Boyd, D.D. Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases. Br. J. Cancer 2010, 102, 774–782.
  52. Xu, J.; Lin, L.B.; Yong, M.; Dong, X.J.; Yu, T.H.; Hu, L.N. Adenovirus-mediated overexpression of cystic fibrosis transmembrane conductance regulator enhances invasiveness and motility of serous ovarian cancer cells. Mol. Med. Rep. 2016, 13, 265–272.
  53. Peng, X.; Wu, Z.; Yu, L.; Li, J.K.; Xu, W.M.; Chan, H.C.; Zhang, Y.; Hu, L.N. Overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) is associated with human cervical cancer malignancy, progression and prognosis. Gynecol. Oncol. 2012, 125, 470–476.
  54. Tu, Z.W.; Chen, Q.; Zhang, J.T.; Jiang, X.H.; Xia, Y.F.; Chan, H.C. CFTR is a potential marker for nasopharyngeal carcinoma prognosis and metastasis. Oncotarget 2016, 7, 76955–76965.
  55. Liu, C.; Song, C.; Li, J.X.; Sun, Q. CFTR functions as a tumor suppressor and is regulated by DNA methylation in colorectal cancer. Cancer Manag. Res. 2020, 12, 4261–4270.
  56. Zhang, J.T.; Jiang, X.H.; Xie, C.; Cheng, H.; Dong, J.D.; Wang, Y.; Fok, K.L.; Zhang, X.H.; Sun, T.T.; Tsang, L.L.; et al. Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. BBA Mol. Cell Res. 2013, 1833, 2961–2969.
  57. Li, J.; Zhang, J.T.; Jiang, X.H.; Shi, X.S.; Shen, J.F.; Feng, F.L.; Chen, J.Y.; Liu, G.H.; He, P.; Jiang, J.H.; et al. The cystic fibrosis transmembrane conductance regulator as a biomarker in non-small cell lung cancer. Int. J. Oncol. 2015, 46, 2107–2115.
  58. Xia, X.; Wang, J.; Liu, Y.; Yue, M. Lower cystic fibrosis transmembrane conductance regulator (CFTR) promotes the proliferation and migration of endometrial carcinoma. Med. Sci. Monit. 2017, 23, 966–974.
  59. Xie, C.; Jiang, X.H.; Zhang, J.T.; Sun, T.T.; Dong, J.D.; Sanders, A.J.; Diao, R.Y.; Wang, Y.; Fok, K.L.; Tsang, L.L.; et al. CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer. Oncogene 2013, 32, 2282–2291.
  60. Than, B.L.N.; Linnekamp, J.F.; Starr, T.K.; Largaespada, D.A.; Rod, A.; Zhang, Y.; Bruner, V.; Abrahante, J.; Schumann, A.; Luczak, T.; et al. CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene 2016, 35, 4191–4199.
  61. Jozwiak, P.; Ciesielski, P.; Forma, E.; Kozal, K.; Wojcik-Krowiranda, K.; Cwonda, L.; Bienkiewicz, A.; Brys, M.; Krzeslak, A. Expression of voltage-dependent anion channels in endometrial cancer and its potential prognostic significance. Tumour Biol. 2020, 42, 1010428320951057.
  62. Yang, G.; Zhou, D.; Li, J.; Wang, W.; Zhong, W.; Fan, W.; Yu, M.; Cheng, H. VDAC1 is regulated by BRD4 and contributes to JQ1 resistance in breast cancer. Oncol. Lett. 2019, 18, 2340–2347.
  63. Liu, X.; He, B.; Xu, T.; Pan, Y.; Hu, X.; Chen, X.; Wang, S. MiR-490-3p functions as a tumor suppressor by inhibiting oncogene VDAC1 expression in colorectal cancer. J. Cancer 2018, 9, 1218–1230.
  64. Ko, J.H.; Gu, W.; Lim, I.; Zhou, T.; Bang, H. Expression profiling of mitochondrial voltage-dependent anion channel-1 associated genes predicts recurrence-free survival in human carcinomas. PLoS ONE 2014, 9, e110094.
  65. Arif, T.; Vasilkovsky, L.; Refaely, Y.; Konson, A.; Shoshan-Barmatz, V. Silencing VDAC1 expression by siRNA inhibits cancer cell proliferation and tumor growth in vivo. Mol. Ther. Nucleic Acids 2014, 3, e159.
  66. Wang, W.; Zhang, T.; Zhao, W.; Xu, L.; Yang, Y.; Liao, Q.; Zhao, Y. A single talent immunogenic membrane antigen and novel prognostic predictor: Voltage-dependent anion channel 1 (VDAC1) in pancreatic cancer. Sci. Rep. 2016, 6, 33648.
  67. Wang, F.R.; Qiang, Y.; Zhu, L.R.; Jiang, Y.S.; Wang, Y.D.; Shao, X.; Yin, L.; Chen, J.H.; Chen, Z. MicroRNA-7 downregulates the oncogene VDAC1 to influence hepatocellular carcinoma proliferation and metastasis. Tumor Biol. 2016, 37, 10235–10246.
  68. Maldonado, E.N.; Lemasters, J.J. Warburg revisited: Regulation of mitochondrial metabolism by voltage-dependent anion channels in cancer cells. J. Pharmacol. Exp. Ther. 2012, 342, 637–641.
  69. Shoshan-Barmatz, V.; De Pinto, V.; Zweckstetter, M.; Raviv, Z.; Keinan, N.; Arbel, N. VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol. Asp. Med. 2010, 31, 227–285.
  70. Koren, I.; Raviv, Z.; Shoshan-Barmatz, V. Downregulation of voltage-dependent anion channel-1 expression by RNA interference prevents cancer cell growth in vivo. Cancer Biol. Ther. 2010, 9, 1046–1052.
  71. Simamura, E.; Hirai, K.; Shimada, H.; Koyama, J.; Niwa, Y.; Shimizu, S. Furanonaphthoquinones cause apoptosis of cancer cells by inducing the production of reactive oxygen species by the mitochondrial voltage-dependent anion channel. Cancer Biol. Ther. 2006, 5, 1523–1529.
  72. Pernemalm, M.; De Petris, L.; Branca, R.M.; Forshed, J.; Kanter, L.; Soria, J.C.; Girard, P.; Validire, P.; Pawitan, Y.; van den Oord, J.; et al. Quantitative proteomics profiling of primary lung adenocarcinoma tumors reveals functional perturbations in tumor metabolism. J. Proteome Res. 2013, 12, 3934–3943.
  73. Zhang, L.Y.; Liu, M.; Li, X.; Tang, H. miR-490-3p modulates cell growth and epithelial to mesenchymal transition of hepatocellular carcinoma cells by targeting endoplasmic reticulum-Golgi intermediate compartment protein 3 (ERGIC3). J. Biol. Chem. 2013, 288, 4035–4047.
  74. Jia, Z.; Liu, Y.; Gao, Q.; Han, Y.; Zhang, G.; Xu, S.; Cheng, K.; Zou, W. miR-490-3p inhibits the growth and invasiveness in triple-negative breast cancer by repressing the expression of TNKS2. Gene 2016, 593, 41–47.
  75. Maldonado, E.N.; Sheldon, K.L.; DeHart, D.N.; Patnaik, J.; Manevich, Y.; Townsend, D.M.; Bezrukov, S.M.; Rostovtseva, T.K.; Lemasters, J.J. Voltage-dependent anion channels modulate mitochondrial metabolism in cancer cells: Regulation by free tubulin and erastin. J. Biol. Chem. 2013, 288, 11920–11929.
  76. Zhou, K.; Yao, Y.L.; He, Z.C.; Chen, C.; Zhang, X.N.; Yang, K.D.; Liu, Y.Q.; Liu, Q.; Fu, W.J.; Chen, Y.P.; et al. VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells. Cell Death Dis. 2018, 9, 988.
  77. Verkman, A.S.; Galietta, L.J.V. Chloride transport modulators as drug candidates. Am. J. Physiol. Cell Physiol. 2021, 321, C932–C946.
  78. Chen, L.; Wang, L.; Zhu, L.; Nie, S.; Zhang, J.; Zhong, P.; Cai, B.; Luo, H.; Jacob, T.J. Cell cycle-dependent expression of volume-activated chloride currents in nasopharyngeal carcinoma cells. Am. J. Physiol. Cell Physiol. 2002, 283, C1313–C1323.
  79. Wang, L.W.; Chen, L.X.; Zhu, L.Y.; Rawle, M.; Nie, S.H.; Zhang, J.; Ping, Z.; Cai, K.R.; Jacob, T.J.C. Regulatory volume decrease is actively modulated during the cell cycle. J. Cell. Physiol. 2002, 193, 110–119.
  80. Chen, L.X.; Zhu, L.Y.; Jacob, T.J.; Wang, L.W. Roles of volume-activated Cl- currents and regulatory volume decrease in the cell cycle and proliferation in nasopharyngeal carcinoma cells. Cell Prolif. 2007, 40, 253–267.
  81. Yoshimoto, S.; Matsuda, M.; Kato, K.; Jimi, E.; Takeuchi, H.; Nakano, S.; Kajioka, S.; Matsuzaki, E.; Hirofuji, T.; Inoue, R.; et al. Volume-regulated chloride channel regulates cell proliferation and is involved in the possible interaction between TMEM16A and LRRC8A in human metastatic oral squamous cell carcinoma cells. Eur. J. Pharmacol. 2021, 895, 173881.
  82. Kurashima, K.; Shiozaki, A.; Kudou, M.; Shimizu, H.; Arita, T.; Kosuga, T.; Konishi, H.; Komatsu, S.; Kubota, T.; Fujiwara, H.; et al. LRRC8A influences the growth of gastric cancer cells via the p53 signaling pathway. Gastric Cancer 2021, 24, 1063–1075.
  83. Wong, R.; Chen, W.; Zhong, X.; Rutka, J.T.; Feng, Z.P.; Sun, H.S. Swelling-induced chloride current in glioblastoma proliferation, migration, and invasion. J. Cell. Physiol. 2018, 233, 363–370.
  84. Lu, P.; Ding, Q.; Li, X.; Ji, X.; Li, L.; Fan, Y.; Xia, Y.; Tian, D.; Liu, M. SWELL1 promotes cell growth and metastasis of hepatocellular carcinoma in vitro and in vivo. EBioMedicine 2019, 48, 100–116.
  85. Min, X.J.; Li, H.; Hou, S.C.; He, W.; Liu, J.; Hu, B.; Wang, J. Dysfunction of volume-sensitive chloride channels contributes to cisplatin resistance in human lung adenocarcinoma cells. Exp. Biol. Med. 2011, 236, 483–491.
  86. Sorensen, B.H.; Dam, C.S.; Sturup, S.; Lambert, I.H. Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells. J. Inorg. Biochem. 2016, 160, 287–295.
  87. Planells-Cases, R.; Lutter, D.; Guyader, C.; Gerhards, N.M.; Ullrich, F.; Elger, D.A.; Kucukosmanoglu, A.; Xu, G.; Voss, F.K.; Reincke, S.M.; et al. Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. EMBO J. 2015, 34, 2993–3008.
  88. Mueller, T.J.; Morrison, M. Detection of a variant of protein 3, the major transmembrane protein of the human erythrocyte. J. Biol. Chem. 1977, 252, 6573–6576.
  89. Demuth, D.R.; Showe, L.C.; Ballantine, M.; Palumbo, A.; Fraser, P.J.; Cioe, L.; Rovera, G.; Curtis, P.J. Cloning and structural characterization of a human non-erythroid band 3-like protein. EMBO J. 1986, 5, 1205–1214.
  90. Kopito, R.R.; Lee, B.S.; Simmons, D.M.; Lindsey, A.E.; Morgans, C.W.; Schneider, K. Regulation of intracellular pH by a neuronal homolog of the erythrocyte anion exchanger. Cell 1989, 59, 927–937.
  91. Tsuganezawa, H.; Kobayashi, K.; Iyori, M.; Araki, T.; Koizumi, A.; Watanabe, S.I.; Kaneko, A.; Fukao, T.; Monkawa, T.; Yoshida, T.; et al. A new member of the HCO 3-transporter superfamily is an apical anion exchanger of beta-intercalated cells in the kidney. J. Biol. Chem. 2001, 276, 8180–8189.
  92. Shen, W.W.; Wu, J.; Cai, L.; Liu, B.Y.; Gao, Y.; Chen, G.Q.; Fu, G.H. Expression of anion exchanger 1 sequestrates p16 in the cytoplasm in gastric and colonic adenocarcinoma. Neoplasia 2007, 9, 812–819.
  93. Xu, W.Q.; Song, L.J.; Liu, Q.; Zhao, L.; Zheng, L.; Yan, Z.W.; Fu, G.H. Expression of anion exchanger 1 is associated with tumor progress in human gastric cancer. J. Cancer Res. Clin. 2009, 135, 1323–1330.
  94. Suo, W.H.; Zhang, N.; Wu, P.P.; Zhao, L.; Song, L.J.; Shen, W.W.; Zheng, L.; Tao, J.; Long, X.D.; Fu, G.H. Anti-tumour effects of small interfering RNA targeting anion exchanger 1 in experimental gastric cancer. Br. J. Pharmacol. 2012, 165, 135–147.
  95. Wu, J.; Zhang, Y.C.; Suo, W.H.; Liu, X.B.; Shen, W.W.; Tian, H.; Fu, G.H. Induction of anion exchanger-1 translation and its opposite roles in the carcinogenesis of gastric cancer cells and differentiation of K562 cells. Oncogene 2010, 29, 1987–1996.
  96. Shiozaki, A.; Kudou, M.; Ichikawa, D.; Shimizu, H.; Arita, T.; Kosuga, T.; Konishi, H.; Komatsu, S.; Fujiwara, H.; Okamoto, K.; et al. Expression and role of anion exchanger 1 in esophageal squamous cell carcinoma. Oncotarget 2017, 8, 17921–17935.
  97. Wu, T.T.; Hsieh, Y.H.; Wu, C.C.; Tsai, J.H.; Hsieh, Y.S.; Huang, C.Y.; Liu, J.Y. Overexpression of anion exchanger 2 in human hepatocellular carcinoma. Chin. J. Physiol. 2006, 49, 192–198.
  98. Song, L.J.; Liu, R.J.; Zeng, Z.; Alper, S.L.; Cui, H.J.; Lu, Y.; Zheng, L.; Yan, Z.W.; Fu, G.H. Gastrin inhibits a novel, pathological colon cancer signaling pathway involving EGR1, AE2, and P-ERK. J. Mol. Med. 2012, 90, 707–718.
  99. Wang, T.; Zhao, L.; Yang, Y.; Tian, H.; Suo, W.H.; Yan, M.; Fu, G.H. EGR1 is critical for gastrin-dependent upregulation of anion exchanger 2 in gastric cancer cells. FEBS J. 2013, 280, 174–183.
  100. Yang, Y.; Wu, P.P.; Wu, J.; Shen, W.W.; Wu, Y.L.; Fu, A.F.; Zheng, L.; Jin, X.L.; Fu, G.H. Expression of anion exchanger 2 in human gastric cancer. Exp. Oncol. 2008, 30, 81–87.
  101. Hwang, J.M.; Kao, S.H.; Hsieh, Y.H.; Li, K.L.; Wang, P.H.; Hsu, L.S.; Liu, J.Y. Reduction of anion exchanger 2 expression induces apoptosis of human hepatocellular carcinoma cells. Mol. Cell. Biochem. 2009, 327, 135–144.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Academic Video Service
Feedback