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Chloride intracellular channels in oncology as potential novel biomarkers and personalized therapy targets: a systematic review

Bartosz Paweł Wojtera12, Kamila Ostrowska32, Mateusz Szewczyk1, Michał Masternak41, Wojciech Golusiński1

Abstract

Background: The chloride intracellular channels (CLICs) family includes six ion channels (CLIC1-CLIC6) expressed on the cellular level and secreted into interstitial fluid and blood. They are involved in the physiological functioning of multiple systems as well as the pathogenetic processes of cancer. CLICs play essential roles in the tumor microenvironment. The current systematic review aimed at identifying and summarizing the research of CLICs in oncology on clinical material to assess CLICs' potential as novel biomarkers and personalized therapy targets.

Materials and methods: The authors systematically searched the PubMed database for original articles concerning CLIC research on clinical material of all types of cancer — fluids and tissues.

Results: Fifty-three articles investigating in summary 3944 clinical samples were qualified for the current review. Studied material included 3438 tumor samples (87%), 437 blood samples (11%), and 69 interstitial fluid samples (2%). Studies investigated 21 cancer types, mostly hepatocellular carcinoma, colorectal, ovarian, and gastric cancer. Importantly, CLIC1, CLIC2, CLIC3, CLIC4, and CLIC5 were differently expressed in cancerous tissues and patients’ blood compared to healthy controls. Moreover, CLICs were found to be involved in several cancer-associated signaling pathways, such as PI3K/AKT, MAPK/ERK, and MAPK/p38.

Conclusion: CLIC family members may be candidates for potential novel cancer biomarkers due to the contrast in their expression between cancerous and healthy tissues and secretion to the interstitial fluid and blood. CLICs are investigated as potential therapeutic targets because of their involvement in cancer pathogenesis and tumor microenvironment.

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References

  1. Moore DC, Guinigundo AS. Biomarker-Driven Oncology Clinical Trials: Novel Designs in the Era of Precision Medicine. J Adv Pract Oncol. 2023; 14(Suppl 1): 9–13.
  2. Kleszcz R. Advantages of the Combinatorial Molecular Targeted Therapy of Head and Neck Cancer-A Step before Anakoinosis-Based Personalized Treatment. Cancers (Basel). 2023; 15(17).
  3. Kolenda T, Przybyła W, Kapałczyńska M, et al. Tumor microenvironment - Unknown niche with powerful therapeutic potential. Rep Pract Oncol Radiother. 2018; 23(3): 143–153.
  4. Kozłowska-Masłoń J, Guglas K, Kolenda T, et al. miRNA in head and neck squamous cell carcinomas: promising but still distant future of personalized oncology. Rep Pract Oncol Radiother. 2023; 28(5): 681–697.
  5. Piwocka O, Musielak M, Piotrowski I, et al. Primary cancer-associated fibroblasts exhibit high heterogeneity among breast cancer subtypes. Rep Pract Oncol Radiother. 2023; 28(2): 159–171.
  6. Kaźmierska J, Bajon T, Winiecki T, et al. Significance of neutrophil to lymphocyte ratio as a predictor of outcome in head and neck cancer treated with definitive chemoradiation. Rep Pract Oncol Radiother. 2023; 28(3): 389–398.
  7. Gururaja Rao S, Ponnalagu D, Patel NJ, et al. Three Decades of Chloride Intracellular Channel Proteins: From Organelle to Organ Physiology. Curr Protoc Pharmacol. 2018; 80(1): 11.21.1–11.21.17.
  8. Argenzio E, Moolenaar WH. Emerging biological roles of Cl- intracellular channel proteins. J Cell Sci. 2016; 129(22): 4165–4174.
  9. Gururaja Rao S, Patel NJ, Singh H. Intracellular Chloride Channels: Novel Biomarkers in Diseases. Front Physiol. 2020; 11: 96.
  10. Huang Q, Lv Q, Tang W, et al. A comprehensively prognostic and immunological analysis of chloride intracellular channel protein 5 (CLIC5) in pan-cancer and identification in ovarian cancer. J Cancer Res Clin Oncol. 2023; 149(12): 10561–10583.
  11. Geng HY, Feng ZJ, Zhang JJ, et al. Exosomal CLIC1 released by CLL promotes HUVECs angiogenesis by regulating ITGβ1-MAPK/ERK axis. Kaohsiung J Med Sci. 2021; 37(3): 226–235.
  12. Sanchez VC, Yang HH, Craig-Lucas A, et al. Host CLIC4 expression in the tumor microenvironment is essential for breast cancer metastatic competence. PLoS Genet. 2022; 18(6): e1010271.
  13. Hernandez-Fernaud JR, Ruengeler E, Casazza A, et al. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity. Nat Commun. 2017; 8: 14206.
  14. Wojtera BP, Sobecka A, Szewczyk M, et al. CLIC1 plasma concentration is associated with lymph node metastases in oral squamous cell carcinoma. Adv Clin Exp Med. 2023; 32(3): 341–347.
  15. Chang YH, Wu CC, Chang KP, et al. Cell secretome analysis using hollow fiber culture system leads to the discovery of CLIC1 protein as a novel plasma marker for nasopharyngeal carcinoma. J Proteome Res. 2009; 8(12): 5465–5474.
  16. Tang HY, Beer LA, Tanyi JL, et al. Protein isoform-specific validation defines multiple chloride intracellular channel and tropomyosin isoforms as serological biomarkers of ovarian cancer. J Proteomics. 2013; 89: 165–178.
  17. Huang S, Huang Z, Chen P, et al. Aberrant Expression Is Associated With Adverse Outcome in Cytogenetically Normal Acute Myeloid Leukemia. Front Oncol. 2020; 10: 1648.
  18. Peng P, Zhang W, Cao D, et al. The proteomic comparison of peripheral circulation-derived exosomes from the epithelial ovarian carcinoma (EOC) patients and non-EOC subjects. Transl Cancer Res. 2019; 8(2): 452–465.
  19. Geng H, Feng C, Sun Z, et al. Chloride intracellular channel 1 promotes esophageal squamous cell carcinoma proliferation via mTOR signalling. Transl Oncol. 2023; 27: 101560.
  20. Barbieri F, Bosio AG, Pattarozzi A, et al. Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives. J Exp Clin Cancer Res. 2022; 41(1): 53.
  21. Ferician AM, Ferician OC, Nesiu A, et al. The Mutually Mediated Chloride Intracellular Channel Protein 1 (CLIC1) Relationship between Malignant Cells and Tumor Blood Vessel Endothelium Exhibits a Significant Impact on Tumor Angiogenesis, Progression, and Metastasis in Clear Cell Renal Cell Carcinoma (ccRCC). Cancers (Basel). 2022; 14(23).
  22. Wei X, Pan B, Yang M, et al. CLIC1 Drives Angiogenesis in Hepatocellular Carcinoma by Modulating VEGFA. Technol Cancer Res Treat. 2022; 21: 15330338221106820.
  23. Xia J, Wang Q, Ju F, et al. Chloride Intracellular Channel 1 is a Potential Biomarker for Breast Cancer. Breast Cancer (Dove Med Press). 2022; 14: 247–258.
  24. Yasuda Y, Nagano T, Jimbo N, et al. Chloride Intracellular Channel 1 Expression Is Associated With Poor Prognosis of Lung Adenocarcinoma. Anticancer Res. 2022; 42(1): 271–277.
  25. Qiu Y, Mao Yt, Zhu Jh, et al. CLIC1 knockout inhibits invasion and migration of gastric cancer by upregulating AMOT-p130 expression. Clin Transl Oncol. 2020; 23(3): 514–525.
  26. Raica M, Ceausu AR, Cimpean AM, et al. Chloride Intracellular Channel Protein 1 (CLIC1), E-cadherin and P-cadherin Define Distinct Subclasses of HER2, Luminal B and Triple-negative Breast Cancer. Anticancer Res. 2021; 41(2): 795–802.
  27. Wang W, Li X, Xu Ye, et al. Acetylation-stabilized chloride intracellular channel 1 exerts a tumor-promoting effect on cervical cancer cells by activating NF-κB. Cell Oncol (Dordr). 2021; 44(3): 557–568.
  28. Adelmann TG, Camerota TC, Ceausu AR, et al. Chloride Intracellular Channel Protein 1 (CLIC1) Ιs Over-expressed in Muscle Invasive Urinary Bladder Cancer. Anticancer Res. 2020; 40(12): 6879–6884.
  29. Jiang X, Liu Y, Wang G, et al. Up-regulation of CLIC1 activates MYC signaling and forms a positive feedback regulatory loop with MYC in Hepatocellular carcinoma. Am J Cancer Res. 2020; 10(8): 2355–2370.
  30. Nesiu A, Cimpean AM, Ceausu RA, et al. Intracellular Chloride Ion Channel Protein-1 Expression in Clear Cell Renal Cell Carcinoma. Cancer Genomics Proteomics. 2019; 16(4): 299–307.
  31. Li BP, Mao YT, Wang Z, et al. CLIC1 Promotes the Progression of Gastric Cancer by Regulating the MAPK/AKT Pathways. Cell Physiol Biochem. 2018; 46(3): 907–924.
  32. Yu W, Cui R, Qu H, et al. Expression and prognostic value of CLIC1 in epithelial ovarian cancer. Exp Ther Med. 2018; 15(6): 4943–4949.
  33. Zhou N, Cheng W, Peng C, et al. Decreased expression of hsa‑miR‑372 predicts poor prognosis in patients with gallbladder cancer by affecting chloride intracellular channel 1. Mol Med Rep. 2017; 16(5): 7848–7854.
  34. Jia N, Dong S, Zhao Ge, et al. CLIC1 overexpression is associated with poor prognosis in pancreatic ductal adenocarcinomas. J Cancer Res Ther. 2016; 12(2): 892–896.
  35. Ding Q, Li M, Wu X, et al. CLIC1 overexpression is associated with poor prognosis in gallbladder cancer. Tumour Biol. 2015; 36(1): 193–198.
  36. Lu J, Dong Q, Zhang B, et al. Chloride intracellular channel 1 (CLIC1) is activated and functions as an oncogene in pancreatic cancer. Med Oncol. 2015; 32(6): 616.
  37. Wei X, Li J, Xie H, et al. Chloride intracellular channel 1 participates in migration and invasion of hepatocellular carcinoma by targeting maspin. J Gastroenterol Hepatol. 2015; 30(1): 208–216.
  38. Ye Y, Yin M, Huang B, et al. CLIC1 a novel biomarker of intraperitoneal metastasis in serous epithelial ovarian cancer. Tumour Biol. 2015; 36(6): 4175–4179.
  39. Cristofaro MG, Scumaci D, Fiumara CV, et al. Identification of prognosis-related proteins in gingival squamous cell carcinoma by twodimensional gel electrophoresis and mass spectrometry-based proteomics. Ann Ital Chir. 2014; 85(6): 518–524.
  40. Megger DA, Bracht T, Kohl M, et al. Proteomic differences between hepatocellular carcinoma and nontumorous liver tissue investigated by a combined gel-based and label-free quantitative proteomics study. Mol Cell Proteomics. 2013; 12(7): 2006–2020.
  41. Zhang S, Wang XM, Yin ZY, et al. Chloride intracellular channel 1 is overexpression in hepatic tumor and correlates with a poor prognosis. APMIS. 2013; 121(11): 1047–1053.
  42. Wang L, He S, Tu Y, et al. Elevated expression of chloride intracellular channel 1 is correlated with poor prognosis in human gliomas. J Exp Clin Cancer Res. 2012; 31(1): 44.
  43. Wang W, Xu X, Wang W, et al. The expression and clinical significance of CLIC1 and HSP27 in lung adenocarcinoma. Tumour Biol. 2011; 32(6): 1199–1208.
  44. Zheng DL, Huang QL, Zhou F, et al. PA28β regulates cell invasion of gastric cancer via modulating the expression of chloride intracellular channel 1. J Cell Biochem. 2012; 113(5): 1537–1546.
  45. Petrova DT, Asif AR, Armstrong VW, et al. Expression of chloride intracellular channel protein 1 (CLIC1) and tumor protein D52 (TPD52) as potential biomarkers for colorectal cancer. Clin Biochem. 2008; 41(14-15): 1224–1236.
  46. Chen CD, Wang CS, Huang YH, et al. Overexpression of CLIC1 in human gastric carcinoma and its clinicopathological significance. Proteomics. 2007; 7(1): 155–167.
  47. Blanc JF, Lalanne C, Plomion C, et al. Proteomic analysis of differentially expressed proteins in hepatocellular carcinoma developed in patients with chronic viral hepatitis C. Proteomics. 2005; 5(14): 3778–3789.
  48. Baek HY, Lim JW, Kim H, et al. Oxidative-stress-related proteome changes in Helicobacter pylori-infected human gastric mucosa. Biochem J. 2004; 379(Pt 2): 291–299.
  49. Tomonaga T, Matsushita K, Yamaguchi S, et al. Identification of altered protein expression and post-translational modifications in primary colorectal cancer by using agarose two-dimensional gel electrophoresis. Clin Cancer Res. 2004; 10(6): 2007–2014.
  50. Ueno Y, Ozaki S, Umakoshi A, et al. Chloride intracellular channel protein 2 in cancer and non-cancer human tissues: relationship with tight junctions. Tissue Barriers. 2019; 7(1): 1593775.
  51. Ozaki S, Umakoshi A, Yano H, et al. Chloride intracellular channel protein 2 is secreted and inhibits MMP14 activity, while preventing tumor cell invasion and metastasis. Neoplasia. 2021; 23(8): 754–765.
  52. Chen M, Zhang S, Wen X, et al. Prognostic value of CLIC3 mRNA overexpression in bladder cancer. PeerJ. 2020; 8: e8348.
  53. Wang Z, Ling S, Rettig E, et al. Epigenetic screening of salivary gland mucoepidermoid carcinoma identifies hypomethylation of CLIC3 as a common alteration. Oral Oncol. 2015; 51(12): 1120–1125.
  54. Yokoyama R, Kubota A, Kojima H, et al. Detection of Cells Displaying High Expression of CLIC4 in Tumor Tissue of Patients With Colorectal Cancer. In Vivo. 2021; 35(6): 3165–3173.
  55. Lima FJ, Lopes ML, Barros CC, et al. Modification in CLIC4 Expression is Associated with P53, TGF-β, TNF-α and Myofibroblasts in Lip Carcinogenesis. Braz Dent J. 2020; 31(3): 290–297.
  56. Zou Q, Yang Z, Li D, et al. Association of chloride intracellular channel 4 and Indian hedgehog proteins with survival of patients with pancreatic ductal adenocarcinoma. Int J Exp Pathol. 2016; 97(6): 422–429.
  57. Deng YJ, Tang Na, Liu C, et al. CLIC4, ERp29, and Smac/DIABLO derived from metastatic cancer stem-like cells stratify prognostic risks of colorectal cancer. Clin Cancer Res. 2014; 20(14): 3809–3817.
  58. Okudela K, Katayama A, Woo T, et al. Proteome analysis for downstream targets of oncogenic KRAS--the potential participation of CLIC4 in carcinogenesis in the lung. PLoS One. 2014; 9(2): e87193.
  59. CLIC4 mediates TGF-β1-induced fibroblast-to-myofibroblast transdifferentiation in ovarian cancer. Oncology Reports. 2009; 22(03).
  60. Bian T, Zhang W, Wang F, et al. Identification of as a Prognostic Biomarker and Correlated Immunomodulator for Lung Adenocarcinoma. Comb Chem High Throughput Screen. 2023; 26(14): 2452–2468.
  61. Flores-Téllez TNJ, Lopez TV, Vásquez Garzón VR, et al. Co-Expression of Ezrin-CLIC5-Podocalyxin Is Associated with Migration and Invasiveness in Hepatocellular Carcinoma. PLoS One. 2015; 10(7): e0131605.
  62. Wang W, Huang G, Lin H, et al. Corrigendum: Label-free LC-MS/MS proteomics analyses reveal CLIC1 as a predictive biomarker for bladder cancer staging and prognosis. Front Oncol. 2023; 13: 1216134.
  63. Gromov P, Gromova I, Bunkenborg J, et al. Up-regulated proteins in the fluid bathing the tumour cell microenvironment as potential serological markers for early detection of cancer of the breast. Mol Oncol. 2010; 4(1): 65–89.
  64. Neveu B, Spinella JF, Richer C, et al. CLIC5: a novel ETV6 target gene in childhood acute lymphoblastic leukemia. Haematologica. 2016; 101(12): 1534–1543.



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