Formononetin Suppresses the Malignant Progression of Papillary Thyroid Carcinoma Depending on Downregulation of CBX4

Overview

Journal Exp Ther Med

Specialty Pathology

Date 2024 Oct 31

PMID 39478737

Authors

Hongbo Yu

Ji Qu

Haixin Gou

Ying Zhou

Affiliations

Soon will be listed here.

Abstract

Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the endocrine system globally. Formononetin (FMNT), an isoflavonoid, exerts anti-tumorigenic effects and chromobox homolog 4 (CBX4) exerts tumor-promoting effect in specific types of tumors. Nevertheless, the predictive values and biological functions of FMNT and CBX4 in the pathological progress of PTC have not been fully understood till now. In the present study, the human PTC cell line TPC-1 was exposed to 0, 10, 30 and 100 µM FMNT for 24 h to elucidate the precise effects of FMNT on the biological behaviors of PTC cells. Moreover, FMNT-treated TPC-1 cells were transfected with oe-CBX4 to evaluate whether CBX4 was implicated in the anticarcinogenic effects of FMNT against PTC. It was demonstrated that FMNT treatment suppressed the proliferation, clone formation, migration, invasion, EMT, angiogenesis and stemness of PTC cells in a dose-dependent manner. Furthermore, it was verified that FMNT targeted CBX4 to downregulate its expression in a dose dependent manner. The suppressive effects of FMNT on the proliferation, clone formation, migration, invasion, EMT, angiogenesis and stemness of PTC cells were partially reversed by CBX4 overexpression. Upregulation of CBX4 abolished the tumor suppression effects of FMNT in the malignant progression of PTC. In conclusion, FMNT might act as a promising anti-tumorigenic agent in PTC, which depends on the downregulation of CBX4.

References

Zhang L, Gong Y, Wang S, Gao F . Anti-Colorectal Cancer Mechanisms of Formononetin Identified by Network Pharmacological Approach. Med Sci Monit. 2019; 25:7709-7714. PMC: 6812471. DOI: 10.12659/MSM.919935. View

Zhang W, Ruan X, Li Y, Zhi J, Hu L, Hou X . KDM1A promotes thyroid cancer progression and maintains stemness through the Wnt/β-catenin signaling pathway. Theranostics. 2022; 12(4):1500-1517. PMC: 8825597. DOI: 10.7150/thno.66142. View

Davies L, Welch H . Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg. 2014; 140(4):317-22. DOI: 10.1001/jamaoto.2014.1. View

Chan H, Morey L . Emerging Roles for Polycomb-Group Proteins in Stem Cells and Cancer. Trends Biochem Sci. 2019; 44(8):688-700. DOI: 10.1016/j.tibs.2019.04.005. View

Ismail I, Gagne J, Caron M, McDonald D, Xu Z, Masson J . CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage. Nucleic Acids Res. 2012; 40(12):5497-510. PMC: 3384338. DOI: 10.1093/nar/gks222. View

Zhou R, Xu L, Ye M, Liao M, Du H, Chen H . Formononetin inhibits migration and invasion of MDA-MB-231 and 4T1 breast cancer cells by suppressing MMP-2 and MMP-9 through PI3K/AKT signaling pathways. Horm Metab Res. 2014; 46(11):753-60. DOI: 10.1055/s-0034-1376977. View

Yang C, Xie Q, Zeng X, Tao N, Xu Y, Chen Y . Novel hybrids of podophyllotoxin and formononetin inhibit the growth, migration and invasion of lung cancer cells. Bioorg Chem. 2019; 85:445-454. DOI: 10.1016/j.bioorg.2019.02.019. View

Siegel R, Miller K, Jemal A . Cancer statistics, 2016. CA Cancer J Clin. 2016; 66(1):7-30. DOI: 10.3322/caac.21332. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

10.

Fang X, Pan A . MiR-507 inhibits the progression of gastric carcinoma via targeting CBX4-mediated activation of Wnt/β-catenin and HIF-1α pathways. Clin Transl Oncol. 2022; 24(10):2021-2028. DOI: 10.1007/s12094-022-02862-3. View

11.

Xin M, Wang Y, Ren Q, Guo Y . Formononetin and metformin act synergistically to inhibit growth of MCF-7 breast cancer cells in vitro. Biomed Pharmacother. 2018; 109:2084-2089. DOI: 10.1016/j.biopha.2018.09.033. View

12.

Chen J, Zeng J, Xin M, Huang W, Chen X . Formononetin induces cell cycle arrest of human breast cancer cells via IGF1/PI3K/Akt pathways in vitro and in vivo. Horm Metab Res. 2011; 43(10):681-6. DOI: 10.1055/s-0031-1286306. View

13.

Wang B, Tang J, Liao D, Wang G, Zhang M, Sang Y . Chromobox homolog 4 is correlated with prognosis and tumor cell growth in hepatocellular carcinoma. Ann Surg Oncol. 2013; 20 Suppl 3:S684-92. DOI: 10.1245/s10434-013-3171-7. View

14.

Pan Y, Li Q, Cao Z, Zhao S . The SUMO E3 ligase CBX4 is identified as a poor prognostic marker of gastric cancer through multipronged OMIC analyses. Genes Dis. 2021; 8(6):827-837. PMC: 8427259. DOI: 10.1016/j.gendis.2020.08.010. View

15.

Wen L, Wang Y, Tan P . miR-515-5p inhibits the proliferation, migration and invasion of human breast cancer cells by targeting CBX4. Exp Ther Med. 2021; 22(5):1328. PMC: 8495589. DOI: 10.3892/etm.2021.10763. View

16.

Aiello N, Kang Y . Context-dependent EMT programs in cancer metastasis. J Exp Med. 2019; 216(5):1016-1026. PMC: 6504222. DOI: 10.1084/jem.20181827. View

17.

Jiang N, Niu G, Pan Y, Pan W, Zhang M, Zhang C . CBX4 transcriptionally suppresses KLF6 via interaction with HDAC1 to exert oncogenic activities in clear cell renal cell carcinoma. EBioMedicine. 2020; 53:102692. PMC: 7044754. DOI: 10.1016/j.ebiom.2020.102692. View

18.

Winer A, Adams S, Mignatti P . Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes. Mol Cancer Ther. 2018; 17(6):1147-1155. PMC: 5984693. DOI: 10.1158/1535-7163.MCT-17-0646. View

19.

Paduch R . The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol (Dordr). 2016; 39(5):397-410. PMC: 5052283. DOI: 10.1007/s13402-016-0281-9. View

20.

Hu C, Zhang Q, Tang Q, Zhou H, Liu W, Huang J . CBX4 promotes the proliferation and metastasis via regulating BMI-1 in lung cancer. J Cell Mol Med. 2019; 24(1):618-631. PMC: 6933416. DOI: 10.1111/jcmm.14771. View