DOI QR코드

DOI QR Code

Inhibition of ClC-5 suppresses proliferation and induces apoptosis in cholangiocarcinoma cells through the Wnt/β-catenin signaling pathway

  • Shi, Zhe (Department of General Surgery, Affiliated Hospital of Hebei Engineering University) ;
  • Zhou, Liyuan (Department of Gynaecology, Affiliated Hospital of Hebei Engineering University) ;
  • Zhou, Yan (Department of Nursing, Medical College, Hebei University of Engineering) ;
  • Jia, Xiaoyan (Department of General Surgery, Affiliated Hospital of Hebei Engineering University) ;
  • Yu, Xiangjun (Department of General Surgery, Affiliated Hospital of Hebei Engineering University) ;
  • An, Xiaohong (Department of Hospital Infection-Control, Jize County People's Hospital) ;
  • Han, Yanzhen (Department of General Surgery, Affiliated Hospital of Hebei Engineering University)
  • 투고 : 2022.03.07
  • 심사 : 2022.04.28
  • 발행 : 2022.06.30

초록

Chloride channel-5 (ClC-5), an important branch of the ClC family, is involved in the regulation of the proliferation and cell-fate of a variety of cells, including tumor cells. However, its function in cholangiocarcinoma (CCA) cells remains enigmatic. Here, we discovered that ClC-5 was up-regulated in CCA tissues and CCA cell lines, while ClC-5 silencing inhibited CCA cell proliferation and induced apoptosis. Further mechanism studies revealed that ClC-5 inhibition could inhibit Wnt/β-catenin signaling activity and further activate the mitochondria apoptotic pathway in CCA cells. Furthermore, rescuing Wnt/β-catenin signaling activation eliminated the anti-tumor function of ClC-5 knockdown. Together, our research findings illustrated that ClC-5 inhibition plays an anti-tumor role in CCA cells via inhibiting the activity of the Wnt/β-catenin pathway, which in turn activates the mitochondrial apoptotic pathway.

키워드

과제정보

This work was supported by the Scientific research project of Hebei Administration of Traditional Chinese Medicine (2020227).

참고문헌

  1. Khan AS and Dageforde LA (2019) Cholangiocarcinoma. Surg Clin North Am 99, 315-335 https://doi.org/10.1016/j.suc.2018.12.004
  2. Sarcognato S, Sacchi D, Fassan M et al (2021) Cholangiocarcinoma. Pathologica 113, 158-169 https://doi.org/10.32074/1591-951X-252
  3. Khan SA, Tavolari S and Brandi G (2019) Cholangiocarcinoma: epidemiology and risk factors. Liver Int 39 Suppl 1, 19-31 https://doi.org/10.1111/liv.14095
  4. Doherty B, Nambudiri VE and Palmer WC (2017) Update on the diagnosis and treatment of cholangiocarcinoma. Curr Gastroenterol Rep 19, 2 https://doi.org/10.1007/s11894-017-0542-4
  5. Friman S (2011) Cholangiocarcinoma--current treatment options. Scand J Surg 100, 30-34 https://doi.org/10.1177/145749691110000106
  6. Blechacz B (2017) Cholangiocarcinoma: current knowledge and new developments. Gut Liver 11, 13-26 https://doi.org/10.5009/gnl15568
  7. Wang H, Xu M, Kong Q et al (2017) Research and progress on ClC-2 (review). Mol Med Rep 16, 11-22 https://doi.org/10.3892/mmr.2017.6600
  8. Jentsch TJ and Pusch M (2018) CLC chloride channels and transporters: structure, function, physiology, and disease. Physiol Rev 98, 1493-1590 https://doi.org/10.1152/physrev.00047.2017
  9. Altamura C, Desaphy JF, Conte D, De Luca A and Imbrici P (2020) Skeletal muscle ClC-1 chloride channels in health and diseases. Pflugers Arch 472, 961-975 https://doi.org/10.1007/s00424-020-02376-3
  10. Cheng W, Zheng S, Li L et al (2019) Chloride channel 3 (CIC-3) predicts the tumor size in hepatocarcinoma. Acta Histochem 121, 284-288 https://doi.org/10.1016/j.acthis.2019.01.006
  11. Peng F, Cai W, Li J and Li H (2021) ClC-5 downregulation induces osteosarcoma cell apoptosis by promoting Bax and tBid complex formation. Front Oncol 10, 556908 https://doi.org/10.3389/fonc.2020.556908
  12. Olsen ML, Schade S, Lyons SA, Amaral MD and Sontheimer H (2003) Expression of voltage-gated chloride channels in human glioma cells. J Neurosci 23, 5572-5582 https://doi.org/10.1523/jneurosci.23-13-05572.2003
  13. Jiang B, Hattori N, Liu B, Kitagawa K and Inagaki C (2002) Expression of swelling- and/or pH-regulated chloride channels (ClC-2, 3, 4 and 5) in human leukemic and normal immune cells. Life Sci 70, 1383-1394 https://doi.org/10.1016/S0024-3205(01)01517-X
  14. Ruiz-Lafuente N, Alcaraz-Garcia MJ, Sebastian-Ruiz S et al (2015) IL-4 up-regulates miR-21 and the miRNAs hosted in the CLCN5 gene in chronic lymphocytic leukemia. PLoS One 10, e0124936 https://doi.org/10.1371/journal.pone.0124936
  15. Zhang H, Pang Y, Ma C, Li J, Wang H and Shao Z (2018) ClC5 decreases the sensitivity of multiple myeloma cells to bortezomib via promoting prosurvival autophagy. Oncol Res 26, 421-429 https://doi.org/10.3727/096504017X15049221237147
  16. Bremer E, van Dam G, Kroesen BJ, de Leij L and Helfrich W (2006) Targeted induction of apoptosis for cancer therapy: current progress and prospects. Trends Mol Med 12, 382-393 https://doi.org/10.1016/j.molmed.2006.06.002
  17. Sun X, Zhang H, Zhang Y, Yang Q and Zhao S (2018) Caspase-dependent mitochondrial apoptotic pathway is involved in astilbin-mediated cytotoxicity in breast carcinoma cells. Oncol Rep 40, 2278-2286
  18. Zhang Y and Wang X (2020) Targeting the Wnt/beta-catenin signaling pathway in cancer. J Hematol Oncol 13, 165 https://doi.org/10.1186/s13045-020-00990-3
  19. Rapetti-Mauss R, Bustos V, Thomas W et al (2017) Bidirectional KCNQ1:beta-catenin interaction drives colorectal cancer cell differentiation. Proc Natl Acad Sci U S A 114, 4159-4164 https://doi.org/10.1073/pnas.1702913114
  20. Sagredo AI, Sagredo EA, Cappelli C et al (2018) TRPM4 regulates Akt/GSK3-β activity and enhances β-catenin signaling and cell proliferation in prostate cancer cells. Mol Oncol 12, 151-165 https://doi.org/10.1002/1878-0261.12100
  21. Rapetti-Mauss R, Berenguier C, Allegrini B and Soriani O (2020) Interplay between ion channels and the Wnt/β-Catenin signaling pathway in cancers. Front Pharmacol 11, 525020 https://doi.org/10.3389/fphar.2020.525020
  22. Than BL, Linnekamp JF, Starr TK et al (2016) CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene 35, 4179-4187 https://doi.org/10.1038/onc.2015.482
  23. Jin Y, Ibrahim D, Magness ST and Blikslager AT (2018) Knockout of ClC-2 reveals critical functions of adherens junctions in colonic homeostasis and tumorigenicity. Am J Physiol Gastrointest Liver Physiol 315, G966-G979 https://doi.org/10.1152/ajpgi.00087.2018
  24. Mu H, Mu L and Gao J (2020) Suppression of CLC-3 reduces the proliferation, invasion and migration of colorectal cancer through Wnt/β-catenin signaling pathway. Biochem Biophys Res Commun 533, 1240-1246 https://doi.org/10.1016/j.bbrc.2020.09.125
  25. Li X, Hu W, Zhou J et al (2017) CLCA1 suppresses colorectal cancer aggressiveness via inhibition of the Wnt/betacatenin signaling pathway. Cell Commun Signal 15, 38 https://doi.org/10.1186/s12964-017-0192-z
  26. Zhang GF, Qiu L, Yang SL, Wu JC and Liu TJ (2020) Wnt/beta-catenin signaling as an emerging potential key pharmacological target in cholangiocarcinoma. Biosci Rep 40, BSR20193353 https://doi.org/10.1042/bsr20193353
  27. Hu X, Tan Z, Yang Y and Yang P (2019) Long non-coding RNA MIR22HG inhibits cell proliferation and migration in cholangiocarcinoma by negatively regulating the Wnt/beta-catenin signaling pathway. J Gene Med 21, e3085 https://doi.org/10.1002/jgm.3085
  28. Zhang F, Wan M, Xu Y et al (2017) Long noncoding RNA PCAT1 regulates extrahepatic cholangiocarcinoma progression via the Wnt/beta-catenin-signaling pathway. Biomed Pharmacother 94, 55-62 https://doi.org/10.1016/j.biopha.2017.07.025
  29. Wu X, Deng G, Hao X et al (2014) A caspase-dependent pathway is involved in Wnt/beta-catenin signaling promoted apoptosis in Bacillus Calmette-Guerin infected RAW264.7 macrophages. Int J Mol Sci 15, 5045-5062 https://doi.org/10.3390/ijms15035045
  30. Wu X, Zhang Y, Guo J et al (2020) MAC30 knockdown inhibits proliferation and enhance apoptosis of gastric cancer by suppressing Wnt/beta-Catenin signaling pathway. Gastroenterol Res Pract 2020, 6358685
  31. Wang TL, Ouyang CS and Lin LZ (2018) beta-Asarone suppresses Wnt/beta-catenin signaling to reduce viability, inhibit migration/invasion/adhesion and induce mitochondria-related apoptosis in lung cancer cells. Biomed Pharmacother 106, 821-830 https://doi.org/10.1016/j.biopha.2018.07.009