Top

07-02-2024 | Repaglinide | Research

Repaglinide restrains HCC development and progression by targeting FOXO3/lumican/p53 axis

Authors: Yifei Tan, Yongjie Zhou, Wei Zhang, Zhenru Wu, Qing Xu, Qiong Wu, Jian Yang, Tao Lv, Lvnan Yan, Hong Luo, Yujun Shi, Jiayin Yang

Published in: Cellular Oncology

Abstract

Purpose

The recent focus on the roles of N-linked glycoproteins in carcinogenesis across various malignancies has prompted our exploration of aberrantly expressed glycoproteins responsible for HCC progression and potential therapeutic strategy.

Methods

Mass spectrometry was applied to initially identify abnormally expressed glycoproteins in HCC, which was further assessed by immunohistochemistry (IHC) staining. The role of selected glycoprotein on HCC development and underlying mechanism was systematically investigated by colony formation, mouse xenograft, RNA-sequencing and western blot assays, etc. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to explore potential transcription factors (TFs) of selected glycoprotein. The regulation of repaglinide (RPG) on expression of lumican and downstream effectors was assessed by western blot and IHC, while its impact on malignant phenotypes of HCC was explored through in vitro and in vivo analyses, including a murine NASH-HCC model established using western diet and carbon tetrachloride (CCl₄).

Results

Lumican exhibited upregulation in both serum and tumor tissue, with elevated expression associated with an inferior prognosis in HCC patients. Knockdown of lumican resulted in significantly reduced growth of HCC in vitro and in vivo. Mechanically, lumican promoted HCC malignant phenotypes by inhibiting the p53/p21 signaling pathway. Forkhead Box O3 (FOXO3) was identified as the TF of lumican that transcriptionally enhanced its expression. Without silencing FOXO3, RPG blocked the binding of FOXO3 to the promoter region of lumican, thereby inhibiting the activation of lumican/p53/p21 axis. Mice treated with RPG developed fewer and smaller HCCs than those in the control group at 24 weeks after establishment.

Conclusion

Our results indicate that RPG prevented the development and progression of HCC via alteration of FOXO3/lumican/p53 axis.

Available only for authorised users

H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, CA Cancer J. Clin. 71, 209–249 (2021). https://doi.org/10.3322/caac.21660CrossRefPubMed

Q. Zhang, Y. Lou, J. Yang, J. Wang, J. Feng, Y. Zhao, L. Wang, X. Huang, Q. Fu, M. Ye, X. Zhang, Y. Chen, C. Ma, H. Ge, J. Wang, J. Wu, T. Wei, Q. Chen, J. Wu, C. Yu, Y. Xiao, X. Feng, G. Guo, T. Liang, X. Bai, Gut 68, 2019–2031 (2019). https://doi.org/10.1136/gutjnl-2019-318912CrossRefPubMed

S.S. Pinho, C.A. Reis, Nat. Rev. Cancer 15, 540–555 (2015). https://doi.org/10.1038/nrc3982CrossRefPubMed

C. Liao, J. An, S. Yi, Z. Tan, H. Wang, H. Li, X. Guan, J. Liu, Q. Wang, J. Cancer 12, 4109–4120 (2021). https://doi.org/10.7150/jca.58268CrossRefPubMedPubMedCentral

G. Antonarelli, V. Pieri, F.M. Porta, N. Fusco, G. Finocchiaro, G. Curigliano, C. Criscitiello, Cells 12 (2023). https://doi.org/10.3390/cells12060840

Y. Zhou, T. Fukuda, Q. Hang, S. Hou, T. Isaji, A. Kameyama, J. Gu, Sci. Rep. 7, 11563 (2017). https://doi.org/10.1038/s41598-017-11911-9ADSCrossRefPubMedPubMedCentral

F. Li, S. Zhao, Y. Cui, T. Guo, J. Qiang, Q. Xie, W. Yu, W. Guo, W. Deng, C. Gu, T. Wu, Am. J. Cancer Res. 10, 816–837 (2020)PubMedPubMedCentral

P. Agrawal, B. Fontanals-Cirera, E. Sokolova, S. Jacob, C.A. Vaiana, D. Argibay, V. Davalos, M. McDermott, S. Nayak, F. Darvishian, M. Castillo, B. Ueberheide, I. Osman, D. Fenyö, L.K. Mahal, E. Hernando, Cancer Cell 31, 804–819 e807 (2017)CrossRefPubMedPubMedCentral

G.S.M. Kammeijer, J. Nouta, J. de la Rosette, T.M. de Reijke, M. Wuhrer, Anal. Chem. 90, 4414–4421 (2018). https://doi.org/10.1021/acs.analchem.7b04281CrossRefPubMedPubMedCentral

10.

H. Yin, Z. Lin, S. Nie, J. Wu, Z. Tan, J. Zhu, J. Dai, Z. Feng, J. Marrero, D.M. Lubman, J. Proteome Res. 13, 2887–2896 (2014)CrossRefPubMedPubMedCentral

11.

H. Yin, Z. Tan, J. Wu, J. Zhu, K.A. Shedden, J. Marrero, D.M. Lubman, J. Proteome Res. 14, 4876–4884 (2015). https://doi.org/10.1021/acs.jproteome.5b00718CrossRefPubMedPubMedCentral

12.

S. Shang, A. Plymoth, S. Ge, Z. Feng, H.R. Rosen, S. Sangrajrang, P. Hainaut, J.A. Marrero, L. Beretta, Hepatology 55, 483–490 (2012). https://doi.org/10.1002/hep.24703CrossRefPubMed

13.

A.D. Nardo, N.G. Grun, M. Zeyda, M. Dumanic, G. Oberhuber, E. Rivelles, T.H. Helbich, D.F. Markgraf, M. Roden, T. Claudel, M. Trauner, T.M. Stulnig, Liver Int. 40, 1620–1633 (2020). https://doi.org/10.1111/liv.14464CrossRefPubMedPubMedCentral

14.

X. Gao, Y. Sheng, J. Yang, C. Wang, R. Zhang, Y. Zhu, Z. Zhang, K. Zhang, S. Yan, H. Sun, J. Wei, X. Wang, X. Yu, Y. Zhang, Q. Luo, Y. Zheng, P. Qiao, Y. Zhao, Q. Dong, L. Qin, J. Exp. Clin. Cancer Res. 37, 179 (2018)CrossRefPubMedPubMedCentral

15.

K. Stavenhagen, H. Hinneburg, M. Thaysen-Andersen, L. Hartmann, D. Varón Silva, J. Fuchser, S. Kaspar, E. Rapp, P.H. Seeberger, D. Kolarich, J. Mass Spectrom. 48, 627–639 (2013). https://doi.org/10.1002/jms.3210ADSCrossRefPubMed

16.

L. Cao, N. Tolić, Y. Qu, D. Meng, R. Zhao, Q. Zhang, R.J. Moore, E.M. Zink, M.S. Lipton, L. Paša-Tolić, S. Wu, Anal. Biochem. 452, 96–102 (2014)CrossRefPubMedPubMedCentral

17.

Y. Tan, J. Zhu, C.D. Gutierrez Reyes, Y. Lin, Z. Tan, Z. Wu, J. Zhang, A. Cano, S. Verschleisser, Y. Mechref, A.G. Singal, N.D. Parikh, D.M. Lubman, ACS Omega 8, 12467–12480 (2023). https://doi.org/10.1021/acsomega.3c00519CrossRefPubMedPubMedCentral

18.

L. Yang, W.L. Deng, B.G. Zhao, Y. Xu, X.W. Wang, Y. Fang, H.J. Xiao, Cancer Gene Ther. 29, 326–340 (2022). https://doi.org/10.1038/s41417-021-00312-wCrossRefPubMed

19.

W. Chen, J. Jiang, L. Gong, Z. Shu, D. Xiang, X. Zhang, K. Bi, H. Diao, J. Exp. Clin. Cancer Res. 40(1) (2021). https://doi.org/10.1186/s13046-020-01803-8

20.

Y. Cheng, P. Zhan, J. Lu, Y. Lu, C. Luo, X. Cen, F. Wang, C. Xie, Z. Yin, Liver Int. 43, 1577–1592 (2023). https://doi.org/10.1111/liv.15611CrossRefPubMed

21.

M. Ballmann, D. Hubert, B.M. Assael, D. Staab, A. Hebestreit, L. Naehrlich, T. Nickolay, N. Prinz, R.W. Holl, Lancet Diabetes Endocrinol. 6, 114–121 (2018). https://doi.org/10.1016/s2213-8587(17)30400-xCrossRefPubMed

22.

S. Salcher, G. Spoden, J.M. Huber, G. Golderer, H. Lindner, M.J. Ausserlechner, U. Kiechl-Kohlendorfer, K. Geiger, P. Obexer, Cells 9 (2019). https://doi.org/10.3390/cells9010001

23.

A. Jin, Y. Hong, Y. Yang, H. Xu, X. Huang, X. Gao, X. Gong, Q. Dai, L. Jiang, J. Dent. Res. 101, 196–205 (2022). https://doi.org/10.1177/00220345211021534CrossRefPubMed

24.

Y. Zhou, Y. Chen, X. Zhang, Q. Xu, Z. Wu, X. Cao, M. Shao, Y. Shu, T. Lv, C. Lu, M. Xie, T. Wen, J. Yang, Y. Shi, H. Bu, Hepatology 74, 797–815 (2021). https://doi.org/10.1002/hep.31780CrossRefPubMed

25.

T. Tsuchida, Y.A. Lee, N. Fujiwara, M. Ybanez, B. Allen, S. Martins, M.I. Fiel, N. Goossens, H.I. Chou, Y. Hoshida, S.L. Friedman, J. Hepatol. 69, 385–395 (2018)CrossRefPubMedPubMedCentral

26.

S. Sribenja, K. Sawanyawisuth, R. Kraiklang, C. Wongkham, K. Vaeteewoottacharn, S. Obchoei, Q. Yao, S. Wongkham, C. Chen, BMC Cancer 13, 430 (2013). https://doi.org/10.1186/1471-2407-13-430CrossRefPubMedPubMedCentral

27.

K. Engeland, Cell Death Differ. 29, 946–960 (2022). https://doi.org/10.1038/s41418-022-00988-zCrossRefPubMedPubMedCentral

28.

F. Fontana, M. Marzagalli, M. Raimondi, V. Zuco, N. Zaffaroni, P. Limonta, Cell Prolif. 54, e13111 (2021). https://doi.org/10.1111/cpr.13111CrossRefPubMedPubMedCentral

29.

E.M. Kim, C.H. Jung, J. Kim, S.G. Hwang, J.K. Park, H.D. Um, Cancer Res. 77, 3092–3100 (2017). https://doi.org/10.1158/0008-5472.Can-16-2098CrossRefPubMed

30.

Z. Ma, Z. Li, S. Wang, Z. Zhou, C. Liu, H. Zhuang, Q. Zhou, S. Huang, C. Zhang, B. Hou, J. Exp. Clin. Cancer Res. 41, 130 (2022). https://doi.org/10.1186/s13046-022-02310-8CrossRefPubMedPubMedCentral

31.

E.S. Wong, D. Thybert, B.M. Schmitt, K. Stefflova, D.T. Odom, P. Flicek, Genome Res. 25, 167–178 (2015). https://doi.org/10.1101/gr.177840.114CrossRefPubMedPubMedCentral

32.

O. Fornes, J.A. Castro-Mondragon, A. Khan, R. van der Lee, X. Zhang, P.A. Richmond, B.P. Modi, S. Correard, M. Gheorghe, D. Baranasic, W. Santana-Garcia, G. Tan, J. Cheneby, B. Ballester, F. Parcy, A. Sandelin, B. Lenhard, W.W. Wasserman, A. Mathelier, Nucleic Acids Res. 48, D87–D92 (2020). https://doi.org/10.1093/nar/gkz1001CrossRefPubMed

33.

S. Li, X. Wei, J. He, Q. Cao, D. Du, X. Zhan, Y. Zeng, S. Yuan, L. Sun, Cancer Metastasis Rev. 40, 925–948 (2021). https://doi.org/10.1007/s10555-021-09973-3CrossRefPubMed

34.

H. Hu, Y.R. Miao, L.H. Jia, Q.Y. Yu, Q. Zhang, A.Y. Guo, Nucleic Acids Res. 47, D33–D38 (2019)CrossRefPubMed

35.

Y. Wu, H. Du, M. Zhan, H. Wang, P. Chen, D. Du, X. Liu, X. Huang, P. Ma, D. Peng, L. Sun, S. Yuan, J. Ding, L. Lu, J. Jiang, Cell Death Discov. 11, 248 (2020). https://doi.org/10.1038/s41419-020-2471-7CrossRef

36.

X. Wang, Q. Zhou, Z. Yu, X. Wu, X. Chen, J. Li, C. Li, M. Yan, Z. Zhu, B. Liu, L. Su, Int. J. Cancer 141, 998–1010 (2017). https://doi.org/10.1002/ijc.30801CrossRefPubMed

37.

W. Mao, M. Luo, X. Huang, Q. Wang, J. Fan, L. Gao, Y. Zhang, J. Geng, Transl. Oncol. 12, 1072–1078 (2019). https://doi.org/10.1016/j.tranon.2019.05.014CrossRefPubMedPubMedCentral

38.

K. Karamanou, M. Franchi, D. Vynios, S. Brezillon, Semin. Cancer Biol. 62, 125–133 (2020). https://doi.org/10.1016/j.semcancer.2019.08.003CrossRefPubMed

39.

C.T. Yang, J.M. Li, W.K. Chu, S.E. Chow, Cell Death Discov. 9, 414 (2018). https://doi.org/10.1038/s41419-017-0212-3CrossRef

40.

X. Chen, X. Li, X. Hu, F. Jiang, Y. Shen, R. Xu, L. Wu, P. Wei, X. Shen, Front. Oncol. 10, 605 (2020). https://doi.org/10.3389/fonc.2020.00605CrossRefPubMedPubMedCentral

41.

L.R. Pack, L.H. Daigh, M. Chung, T. Meyer, Nat. Commun. 12, 3356 (2021). https://doi.org/10.1038/s41467-021-23612-zADSCrossRefPubMedPubMedCentral

42.

A. Papoutsidakis, E.M. Giatagana, A. Berdiaki, I. Spyridaki, D.A. Spandidos, A. Tsatsakis, G.N. Tzanakakis, D. Nikitovic, Int. J. Oncol. 57, 791–803 (2020). https://doi.org/10.3892/ijo.2020.5094CrossRefPubMedPubMedCentral

43.

D. Dhar, L. Antonucci, H. Nakagawa, J.Y. Kim, E. Glitzner, S. Caruso, S. Shalapour, L. Yang, M.A. Valasek, S. Lee, K. Minnich, E. Seki, J. Tuckermann, M. Sibilia, J. Zucman-Rossi, M. Karin, Cancer Cell 33, 1061–1077 e1066 (2018). https://doi.org/10.1016/j.ccell.2018.05.003CrossRefPubMedPubMedCentral

44.

M. Lu, D. Hartmann, R. Braren, A. Gupta, B. Wang, Y. Wang, C. Mogler, Z. Cheng, T. Wirth, H. Friess, J. Kleeff, N. Huser, Y. Sunami, BMC Cancer 19, 887 (2019). https://doi.org/10.1186/s12885-019-6110-6CrossRefPubMedPubMedCentral

45.

F. Fondevila, P. Fernandez-Palanca, C. Mendez-Blanco, T. Payo-Serafin, E. Lozano, J.J.G. Marin, J. Gonzalez-Gallego, J.L. Mauriz, Cancers (Basel) 13 (2021). https://doi.org/10.3390/cancers13215349

46.

S. de Oliveira, R.A. Houseright, A.L. Graves, N. Golenberg, B.G. Korte, V. Miskolci, A. Huttenlocher, J. Hepatol. 70, 710–721 (2019). https://doi.org/10.1016/j.jhep.2018.11.034CrossRefPubMed

Title: Repaglinide restrains HCC development and progression by targeting FOXO3/lumican/p53 axis
Authors: Yifei Tan
Yongjie Zhou
Wei Zhang
Zhenru Wu
Qing Xu
Qiong Wu
Jian Yang
Tao Lv
Lvnan Yan
Hong Luo
Yujun Shi
Jiayin Yang
Publication date: 07-02-2024
Publisher: Springer Netherlands
Keywords: Repaglinide
Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Cellular Oncology
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-024-00919-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine