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09-04-2024 | Colorectal Cancer | Research

Dexmedetomidine promotes colorectal cancer progression via Piwil2 signaling

Authors: Jing Dong, Ji Che, Yuanyuan Wu, Yixu Deng, Xuliang Jiang, Zhiyong He, Jun Zhang

Abstract

Purpose

α2-adrenoceptor agonist dexmedetomidine (DEX) has been reported to promote tumorigenesis. Stem-cell protein Piwil2 is associated with cancer progression. Whether Piwil2 plays a role in tumor-promoting effects of DEX is unknown.

Methods

We examined the expression of Piwil2 in human colorectal cancer (CRC) cell lines with/without DEX treatment. We also studied the roles of Piwil2 in proliferation, invasion, migration, as well as expressions of epithelial-mesenchymal transition (EMT)-related proteins in DEX-treated in vitro and in vivo CRC models. And the experiments with genetic and pharmacological treatments were conducted to investigate the underlying molecular mechanism.

Results

RNA-sequencing (RNA-seq) analysis found Piwil2 is one of most upregulated genes upon DEX treatment in CRC cells. Furthermore, Piwil2 protein levels significantly increased in DEX-treated CRC cancer cells, which promoted proliferation, invasion, and migration in both CRC cell lines and human tumor xenografts model. Mechanistically, DEX increased nuclear factor E2-related factor 2 (Nrf2) expression, which enhanced Piwil2 transcription via binding to its promoter. Furthermore, in vitro experiments with Piwil2 knockdown or Siah2 inhibition indicated that DEX promoted EMT process and tumorigenesis through Siah2/PHD3/HIF1α pathway. The experiments with another α2-adrenoceptor agonist Brimonidine and antagonists yohimbine and atipamezole also suggested the role of Piwil2 signaling in tumor-promoting effects via an α2 adrenoceptor-dependent manner.

Conclusion

DEX promotes CRC progression may via activating α2 adrenoceptor-dependent Nrf2/Piwil2/Siah2 pathway and thus EMT process. Our work provides a novel insight into the mechanism underlying tumor-promoting effects of α2-adrenoceptor agonists.

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J.P. Cata, V. Singh, B.M. Lee, J. Villarreal, J.R. Mehran, J. Yu, V. Gottumukkala, H. Lavon, S. Ben-Eliyahu, J. Anaesthesiol. Clin. Pharmacol. 33, 317–323 (2017). https://doi.org/10.4103/joacp.JOACP_299_16

Y. Liu, J. Sun, T. Wu, X. Lu, Y. Du, H. Duan, W. Yu, D. Su, J. Lu, J. Tian, Cancer Med. 8, 7603–7612 (2019). https://doi.org/10.1002/cam4.2654

J. Hu, C. Gong, X. Xiao, L. Chen, Y. Zhang, X. Li, Y. Li, X. Zang, P. Huang, S. Zhou, C. Chen, Front. Oncol. 13, 906514 (2023). https://doi.org/10.3389/fonc.2023.906514

P. Owusu-Agyemang, J.P. Cata, R. Kapoor, A.M. Zavala, U.U. Williams, A. Van Meter, J.Y. Tsai, W.H. Zhang, L. Feng, A. Hayes-Jordan, Int. J. Hyperthermia 35, 435–440 (2018). https://doi.org/10.1080/02656736.2018.1506167

H. Lavon, P. Matzner, A. Benbenishty, L. Sorski, E. Rossene, R. Haldar, E. Elbaz, J.P. Cata, V. Gottumukkala, S. Ben-Eliyahu, Br. J. Anaesth. 120, 188–196 (2018). https://doi.org/10.1016/j.bja.2017.11.004

H.Y. Chen, G.H. Li, G.C. Tan, H. Liang, X.H. Lai, Q. Huang, J.Y. Zhong, Exp. Ther. Med. 18, 4820–4828 (2019). https://doi.org/10.3892/etm.2019.8136

C. Wang, T. Datoo, H. Zhao, L. Wu, A. Date, C. Jiang, R.D. Sanders, G. Wang, C. Bevan, D. Ma, Anesthesiology 129, 1000–1014 (2018). https://doi.org/10.1097/aln.0000000000002401

P. Chen, X. Luo, G. Dai, Y. Jiang, Y. Luo, S. Peng, H. Wang, P. Xie, C. Qu, W. Lin, J. Hong, X. Ning, A. Li, Exp. Mol. Med. 52, 1062–1074 (2020). https://doi.org/10.1038/s12276-020-0461-6

A. Bruzzone, C.P. Piñero, L.F. Castillo, M.G. Sarappa, P. Rojas, C. Lanari, I.A. Lüthy, Br. J. Pharmacol. 155, 494–504 (2008). https://doi.org/10.1038/bjp.2008.278

10.

S.M. Vázquez, A.G. Mladovan, C. Pérez, A. Bruzzone, A. Baldi, I.A. Lüthy, Cancer Chemother. Pharmacol. 58, 50–61 (2006). https://doi.org/10.1007/s00280-005-0130-4

11.

J. Höck, G. Meister, Genome Biol. 9, 210 (2008). https://doi.org/10.1186/gb-2008-9-2-210

12.

L. Li, C. Yu, H. Gao, Y. Li, BMC Cancer 10(38) (2010). https://doi.org/10.1186/1471-2407-10-38

13.

J.H. Lee, C. Jung, P. Javadian-Elyaderani, S. Schweyer, D. Schütte, M. Shoukier, F. Karimi-Busheri, M. Weinfeld, A. Rasouli-Nia, J.G. Hengstler, A. Mantilla, H.R. Soleimanpour-Lichaei, W. Engel, C.N. Robson, K. Nayernia, Cancer Res. 70, 4569–4579 (2010). https://doi.org/10.1158/0008-5472.Can-09-2670

14.

J.J. Liu, R. Shen, L. Chen, Y. Ye, G. He, K. Hua, D. Jarjoura, T. Nakano, G.K. Ramesh, C.L. Shapiro, S.H. Barsky, J.X. Gao, Int. J. Clin. Exp. Pathol. 3, 328–337 (2010)

15.

D. Li, X. Sun, D. Yan, J. Huang, Q. Luo, H. Tang, Z. Peng, Exp. Biol. Med. (Maywood) 237, 1231–1240 (2012). https://doi.org/10.1258/ebm.2012.011380

16.

Y. Zhang, X. Zheng, H. Tan, Y. Lu, D. Tao, Y. Liu, Y. Ma, Cell Death Dis. 9, 423 (2018). https://doi.org/10.1038/s41419-018-0462-8

17.

R.C. Sun, N.C. Denko, Cell Metab. 19, 285–292 (2014). https://doi.org/10.1016/j.cmet.2013.11.022

18.

K.C.G. Berg, P.W. Eide, I.A. Eilertsen, B. Johannessen, J. Bruun, S.A. Danielsen, M. Bjørnslett, L.A. Meza-Zepeda, M. Eknæs, G.E. Lind, O. Myklebost, R.I. Skotheim, A. Sveen, R.A. Lothe, Mol. Cancer 16, 116 (2017). https://doi.org/10.1186/s12943-017-0691-y

19.

R.D. Sanders, P. Sun, S. Patel, M. Li, M. Maze, D. Ma, Acta Anaesthesiol. Scand. 54, 710–716 (2010). https://doi.org/10.1111/j.1399-6576.2009.02177.x

20.

W. Chen, Z. Qi, P. Fan, N. Zhang, L. Qian, C. Chen, Y. Huang, S. Jin, Br. J. Anaesth. 130, 142–153 (2023). https://doi.org/10.1016/j.bja.2022.10.036

21.

L. Sorski, B. Levi, L. Shaashua, E. Neeman, M. Benish, P. Matzner, A. Hoffman, S. Ben-Eliyahu, Surg. Today 44, 1925–1934 (2014). https://doi.org/10.1007/s00595-013-0768-1

22.

G.L. Zou, X.R. Zhang, Y.L. Ma, Q. Lu, R. Zhao, Y.Z. Zhu, Y.Y. Wang, Am. J. Cancer Res. 10, 2752–2767 (2020)

23.

B.H. Choi, J.M. Kim, M.K. Kwak, Arch. Pharm. Res. 44, 263–280 (2021). https://doi.org/10.1007/s12272-021-01316-8

24.

D.F. Zhang, X. Su, Z.T. Meng, H.L. Li, D.X. Wang, L. Xue-Ying, M. Maze, D. Ma, Ann. Surg. 270, 356–363 (2019). https://doi.org/10.1097/sla.0000000000002801

25.

M.W. Xing, C.J. Li, C. Guo, B.J. Wang, D.L. Mu, D.X. Wang, J. Clin. Anesth. 86, 111068 (2023). https://doi.org/10.1016/j.jclinane.2023.111068

26.

Q. Cai, G. Liu, L. Huang, Y. Guan, H. Wei, Z. Dou, D. Liu, Y. Hu, M. Gao, Drug Des. Devel. Ther. 16, 2161–2175 (2022). https://doi.org/10.2147/dddt.S358042

27.

P. Valet, J.M. Senard, J.C. Devedjian, V. Planat, R. Salomon, T. Voisin, G. Drean, A. Couvineau, D. Daviaud, C. Denis, et al., J. Clin. Invest. 91, 2049–2057 (1993). https://doi.org/10.1172/jci116427

28.

S.G. Shen, D. Zhang, H.T. Hu, J.H. Li, Z. Wang, Q.Y. Ma, World J. Gastroenterol. 14, 2358–2363 (2008). https://doi.org/10.3748/wjg.14.2358

29.

X. Feng, W. Guan, Y. Zhao, C. Wang, M. Song, Y. Yao, T. Yang, H. Fan, J. Cell Physiol. 234, 18994–19009 (2019). https://doi.org/10.1002/jcp.28539

30.

S. Menegon, A. Columbano, S. Giordano, Trends Mol. Med. 22, 578–593 (2016). https://doi.org/10.1016/j.molmed.2016.05.002

31.

R. Pillai, M. Hayashi, A.M. Zavitsanou, T. Papagiannakopoulos, Cancer Discov. 12, 625–643 (2022). https://doi.org/10.1158/2159-8290.Cd-21-0922

32.

C. Chen, J. Liu, G. Xu, Cancer Biomark. 13, 315–321 (2013). https://doi.org/10.3233/cbm-130360

33.

F.M. Sarvestani, A. Safaei, A. Talei, M. Dianatpour, Clin. Lab. 62, 1469–1475 (2016). https://doi.org/10.7754/Clin.Lab.2016.151206

34.

X. Zhao, L. Huang, Y. Lu, W. Jiang, Y. Song, B. Qiu, D. Tao, Y. Liu, Y. Ma, Cell Death Differ. 28, 1941–1954 (2021). https://doi.org/10.1038/s41418-020-00725-4

35.

H. Taubert, S. Wach, R. Jung, M. Pugia, B. Keck, S. Bertz, E. Nolte, R. Stoehr, J. Lehmann, C.H. Ohlmann, M. Stöckle, B. Wullich, A. Hartmann, Mol. Med. 21, 371–380 (2015). https://doi.org/10.2119/molmed.2014.00250

36.

J. Qi, K. Nakayama, S. Gaitonde, J.S. Goydos, S. Krajewski, A. Eroshkin, D. Bar-Sagi, D. Bowtell, Z. Ronai, Proc. Natl. Acad. Sci. U. S. A. 105, 16713–16718 (2008). https://doi.org/10.1073/pnas.0804063105

37.

K. Nakayama, J. Qi, Z. Ronai, Mol. Cancer Res. 7, 443–451 (2009). https://doi.org/10.1158/1541-7786.Mcr-08-0458

38.

N.J. German, H. Yoon, R.Z. Yusuf, J.P. Murphy, L.W. Finley, G. Laurent, W. Haas, F.K. Satterstrom, J. Guarnerio, E. Zaganjor, D. Santos, P.P. Pandolfi, A.H. Beck, S.P. Gygi, D.T. Scadden, K. W.g. Jr, M.C. Haigis, Mol. Cell 63, 1006–1020 (2016). https://doi.org/10.1016/j.molcel.2016.08.014

39.

M.A.S. Weerink, M. Struys, L.N. Hannivoort, C.R.M. Barends, A.R. Absalom, P. Colin, Clin. Pharmacokinet. 56, 893–913 (2017). https://doi.org/10.1007/s40262-017-0507-7

40.

R. Li, I.K. Lai, J.Z. Pan, P. Zhang, M. Maze, Anesthesiology 133, 393–407 (2020). https://doi.org/10.1097/aln.0000000000003390

41.

V. Degos, T.L. Charpentier, V. Chhor, O. Brissaud, S. Lebon, L. Schwendimann, N. Bednareck, S. Passemard, J. Mantz, P. Gressens, Anesthesiology 118, 1123–1132 (2013). https://doi.org/10.1097/ALN.0b013e318286cf36

42.

J. Zhu, S. Naulaerts, L. Boudhan, M. Martin, L. Gatto, B.J. Van den Eynde, Nature 618, 607–615 (2023). https://doi.org/10.1038/s41586-023-06110-8

Title: Dexmedetomidine promotes colorectal cancer progression via Piwil2 signaling
Authors: Jing Dong
Ji Che
Yuanyuan Wu
Yixu Deng
Xuliang Jiang
Zhiyong He
Jun Zhang
Publication date: 09-04-2024
Publisher: Springer Netherlands
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Cellular Oncology
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-024-00944-8

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