Home Life Sciences MicroRNA-6838-5p suppresses the self-renewal and metastasis of human liver cancer stem cells through downregulating CBX4 expression and inactivating ERK signaling
Article
Licensed
Unlicensed Requires Authentication

MicroRNA-6838-5p suppresses the self-renewal and metastasis of human liver cancer stem cells through downregulating CBX4 expression and inactivating ERK signaling

  • Zhimin Dou , Fei Lu , Jinjing Hu , Haiping Wang , Bin Li and Xun Li ORCID logo EMAIL logo
Published/Copyright: October 11, 2022
Biological Chemistry
From the journal Biological Chemistry Volume 404 Issue 1

Abstract

Hepatocellular carcinoma (HCC) is the most common primary human liver malignancy with high mortality. Liver cancer stem cells (CSCs) have been demonstrated to contribute to the recurrence, metastasis and drug resistance of liver cancer. Human HCC cohort analysis indicated that the epigenetic regulator polycomb chromobox homologue 4 (CBX4) was overexpressed in human HCC. Moreover, we found that CBX4 expression was significantly higher in CD44+ CD133+ Hep3B CSCs. Functionally, we demonstrated that CBX4 regulated cell proliferation, self-renewal, and metastasis ability of Hep3B CSCs. Bioinformatics analysis predicted that CBX4 was a direct target of microRNA-6838-5p (miR-6838-5p), which was further confirmed by luciferase reporter assay. MiR-6838-6p was down-regulated in HCC tumors and overexpression of miR-6838-5p attenuated the malignant traits of human liver CSCs in vitro. In addition, we found that miR-6838-5p/CBX4 axis modulates the biological properties of human liver CSCs via regulating ERK signaling. Overexpression of miR-6838-5p suppressed Hep3B xenograft tumor growth in vivo, while CBX4 overexpression abrogated the suppression effect, restored the angiogenesis, epithelial-to-mesenchymal transition (EMT), and ERK signaling in Hep3B tumor. In summary, our findings suggest that miR-6838-5p/CBX4 axis regulates liver tumor development and metastasis, which could be utilized as potential therapeutic target for HCC treatment.

Keywords: cancer stem cell; CBX4; hepatocellular carcinoma; miR-6838-5p; self-renewal
Corresponding author: Xun Li, Department of the First Clinical Medical College, Lanzhou University, No.1, Donggang West Road, Chengguan District, Lanzhou, Gansu, 730000, China; Department of First School of Clinical Medicine, Key Laboratory of Biotherapy and Regenerative Medicine, and Critical Care Medicine, Lanzhou University, The First Hospital of Lanzhou University, No.1, Donggang West Road, Chengguan District, Lanzhou, Gansu, 730000, China; and Department of General Surgery, The First Hospital of Lanzhou University, No.1, Donggang West Road, Chengguan District, Lanzhou, Gansu, 730000, China, E-mail:

Funding source: Natural Science Foundation of Gansu Province

Award Identifier / Grant number: 20JR10RA710

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 82060119

Funding source: Science and Technology Plan Project of Lanzhou

Award Identifier / Grant number: 2020-ZD-77

  1. Author contributions: Zhimin Dou and Xun Li conceived and designed the experiments. Fei Lu and Jingping Hu performed the experiments. Jingping Hu, Haiping Wang and Bin Li analyzed and interpreted the data. Zhimin Dou wrote the manuscript. Xun Li revised the manuscript. All authors read and approved the final manuscript.

  2. Research funding: The work was supported by National Natural Science Foundation of China (No. 82060119), Natural Science Foundation of Gansu Province (No. 20JR10RA710), and Science and Technology Plan Project of Lanzhou (2020-ZD-77).

  3. Conflict of interest statement: The authors declare that they have no competing interests.

  4. Ethics approval and consent to participate: Animal experiments were approved by the Institutional Animal Care and Use Committee of the First Hospital of Lanzhou University.

  5. Data availability: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

Chen, J., Yu, Y., Chen, X., He, Y., Hu, Q., Li, H., Han, Q., Ren, F., Li, J., Li, C., et al.. (2018). MiR-139-5p is associated with poor prognosis and regulates glycolysis by repressing PKM2 in gallbladder carcinoma. Cell Prolif 51: e12510, https://doi.org/10.1111/cpr.12510.Search in Google Scholar PubMed PubMed Central

Gao, Y., Lyu, L., Feng, Y., Li, F., and Hu, Y. (2021). A review of cutting-edge therapies for hepatocellular carcinoma (HCC): perspectives from patents. Int. J. Med. Sci. 18: 3066–3081, https://doi.org/10.7150/ijms.59930.Search in Google Scholar PubMed PubMed Central

Kagey, M.H., Melhuish, T.A., and Wotton, D. (2003). The polycomb protein Pc2 is a SUMO E3. Cell 113: 127–137, https://doi.org/10.1016/s0092-8674(03)00159-4.Search in Google Scholar PubMed

Kakodkar, R. and Soin, A.S. (2012). Liver transplantation for HCC: a review. Indian J. Surg. 74: 100–117, https://doi.org/10.1007/s12262-011-0387-2.Search in Google Scholar PubMed PubMed Central

Khan, A.Q., Ahmed, E.I., Elareer, N.R., Junejo, K., Steinhoff, M., and Uddin, S. (2019). Role of miRNA-regulated cancer stem cells in the pathogenesis of human malignancies. Cells 8: 840, doi:https://doi.org/10.3390/cells8080840.Search in Google Scholar PubMed PubMed Central

Lee, T.K., Guan, X.Y., and Ma, S. (2022). Cancer stem cells in hepatocellular carcinoma – from origin to clinical implications. Nat. Rev. Gastroenterol. Hepatol. 19: 26–44, https://doi.org/10.1038/s41575-021-00508-3.Search in Google Scholar PubMed

Li, B., Zhou, J., Liu, P., Hu, J., Jin, H., Shimono, Y., Takahashi, M., and Xu, G. (2007). Polycomb protein Cbx4 promotes SUMO modification of de novo DNA methyltransferase Dnmt3a. Biochem. J. 405: 369–378, https://doi.org/10.1042/bj20061873.Search in Google Scholar PubMed PubMed Central

Li, J., Xu, Y., Long, X.D., Wang, W., Jiao, H.K., Mei, Z., Yin, Q.Q., Ma, L.N., Zhou, A.W., Wang, L.S., et al.. (2014). Cbx4 governs HIF-1alpha to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity. Cancer Cell 25: 118–131, https://doi.org/10.1016/j.ccr.2013.12.008.Search in Google Scholar PubMed

Liu, G., Wang, P., and Zhang, H. (2019). MiR-6838-5p suppresses cell metastasis and the EMT process in triple-negative breast cancer by targeting WNT3A to inhibit the Wnt pathway. J. Gene Med. 21: e3129, https://doi.org/10.1002/jgm.3129.Search in Google Scholar PubMed

Lu, A.Q., Lv, B., Qiu, F., Wang, X.Y., and Cao, X.H. (2017). Upregulation of miR-137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in hepatocellular carcinoma. Oncol. Rep. 37: 2071–2078, https://doi.org/10.3892/or.2017.5498.Search in Google Scholar PubMed

Luis, N.M., Morey, L., Mejetta, S., Pascual, G., Janich, P., Kuebler, B., Cozutto, L., Roma, G., Nascimento, E., Frye, M., et al.. (2011). Regulation of human epidermal stem cell proliferation and senescence requires polycomb-dependent and -independent functions of Cbx4. Cell Stem Cell 9: 233–246, https://doi.org/10.1016/j.stem.2011.07.013.Search in Google Scholar PubMed

Malek, N.P., Sebastian, S., Petra, H., Manns, M.P., and Greten, T.F. (2014). The diagnosis and treatment of hepatocellular carcinoma. Deutsches Arzteblatt Int. 111: 101–106, https://doi.org/10.3238/arztebl.2014.0101.Search in Google Scholar PubMed PubMed Central

Meng, R., Fang, J., Yu, Y., Hou, L.K., Chi, J.R., Chen, A.X., Zhao, Y., and Cao, X.C. (2018). miR-129-5p suppresses breast cancer proliferation by targeting CBX4. Neoplasma 65: 572–578, https://doi.org/10.4149/neo_2018_170814n530.Search in Google Scholar

O’Brien, J., Hayder, H., Zayed, Y., and Peng, C. (2018). Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. (Lausanne) 9: 402, https://doi.org/10.3389/fendo.2018.00402.Search in Google Scholar PubMed PubMed Central

Pan, Y., Li, Q., Cao, Z., and Zhao, S. (2021). The SUMO E3 ligase CBX4 is identified as a poor prognostic marker of gastric cancer through multipronged OMIC analyses. Genes Dis 8: 827–837, https://doi.org/10.1016/j.gendis.2020.08.010.Search in Google Scholar PubMed PubMed Central

Sancisi, V. and Ciarrocchi, A. (2017). Role of CBX4 in the colorectal carcinoma metastasis-letter. Cancer Res. 77: 2548–2549, https://doi.org/10.1158/0008-5472.can-17-0249.Search in Google Scholar

Siegel, R.L., Miller, K.D., and Jemal, A. (2018). Cancer statistics, 2018. Ca – Cancer J. Clin. 60: 277–300, https://doi.org/10.3322/caac.21442.Search in Google Scholar PubMed

Tan, C., Bei, C., Zhu, X., Zhang, Y., Qin, L., and Tan, S. (2019). Single nucleotide polymorphisms of CBX4 and CBX7 decrease the risk of hepatocellular carcinoma. BioMed Res. Int. 2019: 6436825.10.1155/2019/6436825Search in Google Scholar

Wang, B., Tang, J., Liao, D., Wang, G., Zhang, M., Sang, Y., Cao, J., Wu, Y., Zhang, R., Li, S., et al.. (2013). Chromobox homolog 4 is correlated with prognosis and tumor cell growth in hepatocellular carcinoma. Ann. Surg Oncol. 20(Suppl. 3): S684–S692, https://doi.org/10.1245/s10434-013-3171-7.Search in Google Scholar PubMed

Wang, D., Song, X., Zhang, N., and Guo, Y. (2022). MiR-1179 represses cell proliferation, migration and invasion of hepatocellular carcinoma through suppression of NUAK2. Am. J. Transl. Res. 14: 223–239.Search in Google Scholar

Wang, X., Qin, G., Liang, X., Wang, W., Wang, Z., Liao, D., Zhong, L., Zhang, R., Zeng, Y.X., Wu, Y., et al.. (2020). Targeting the CK1alpha/CBX4 axis for metastasis in osteosarcoma. Nat. Commun. 11: 1141, https://doi.org/10.1038/s41467-020-14870-4.Search in Google Scholar PubMed PubMed Central

Wei, W., Zhao, W., and Zhang, Y. (2021). CBX4 provides an alternate mode of colon cancer development via potential influences on circadian rhythm and immune infiltration. Front. Cell Dev. Biol. 9: 669254, https://doi.org/10.3389/fcell.2021.669254.Search in Google Scholar PubMed PubMed Central

Wen, L.J., Wang, Y.S., and Tan, P.Y. (2021). miR-515-5p inhibits the proliferation, migration and invasion of human breast cancer cells by targeting CBX4. Exp. Ther. Med. 22: 1328, https://doi.org/10.3892/etm.2021.10763.Search in Google Scholar PubMed PubMed Central

Wu, Y., Zhang, J., Zhang, X., Zhou, H., Liu, G., and Li, Q. (2020). Cancer stem cells: a potential breakthrough in HCC-targeted therapy. Front. Pharmacol. 11: 198, https://doi.org/10.3389/fphar.2020.00198.Search in Google Scholar PubMed PubMed Central

Xu, X., Wang, S., Wang, H., Pan, C., Yang, W., and Yu, J. (2021). Hsa_circ_0008434 regulates USP9X expression by sponging miR-6838-5p to promote gastric cancer growth, migration and invasion. BMC Cancer 21: 1289, https://doi.org/10.1186/s12885-021-09052-4.Search in Google Scholar PubMed PubMed Central

Yan, X., Liu, X., Wang, Z., Cheng, Q., Ji, G., Yang, H., Wan, L., Ge, C., Zeng, Q., Huang, H., et al.. (2019). MicroRNA4865p functions as a tumor suppressor of proliferation and cancer stemlike cell properties by targeting Sirt1 in liver cancer. Oncol. Rep. 41: 1938–1948.10.3892/or.2018.6930Search in Google Scholar

Zhai, X., Wu, Y., Zhang, D., Li, H., Chong, T., and Zhao, J. (2021). MiR-6838-5p facilitates the proliferation and invasion of renal cell carcinoma cells through inhibiting the DMTF1/ARF-p53 axis. J. Bioenerg. Biomembr. 53: 191–202, https://doi.org/10.1007/s10863-021-09888-2.Search in Google Scholar PubMed

Zhao, J., Yang, T., and Li, L. (2020). LncRNA FOXP4-AS1 is involved in cervical cancer progression via regulating miR-136-5p/CBX4 Axis. OncoTargets Ther. 13: 2347–2355, https://doi.org/10.2147/ott.s241818.Search in Google Scholar

Zhao, W., Ma, B., Tian, Z., Han, H., Tang, J., Dong, B., An, G., Cao, B., and Wang, B. (2021). Inhibiting CBX4 efficiently protects hepatocellular carcinoma cells against sorafenib resistance. Br. J. Cancer 124: 1237–1248, https://doi.org/10.1038/s41416-020-01240-6.Search in Google Scholar PubMed PubMed Central

Zheng, Z., Qiu, K., and Huang, W. (2021). Long non-coding RNA (lncRNA) RAMS11 promotes metastatis and cell growth of prostate cancer by CBX4 complex binding to Top2alpha. Cancer Manag. Res. 13: 913–923, https://doi.org/10.2147/cmar.s270144.Search in Google Scholar PubMed PubMed Central

Zhou, S., Shen, Y., Zang, S., Yin, X., and Li, P. (2021). The epigenetic role of HTR1A antagonist in facilitating GnRH expression for pubertal initiation control. Mol. Ther. Nucleic Acids 25: 198–206, https://doi.org/10.1016/j.omtn.2021.05.014.Search in Google Scholar PubMed PubMed Central

Zhou, W., Ding, X., Jin, P., and Li, P. (2020). miR-6838-5p affects cell growth, migration, and invasion by targeting GPRIN3 via the wnt/beta-catenin signaling pathway in gastric cancer. Pathobiology 87: 327–337, https://doi.org/10.1159/000511691.Search in Google Scholar PubMed

Zhu, X.Y., Huang, M.J., Su, Q.Y., Wang, X.Z., Wang, J., Long, Q.Q., Wu, X.M., Huang, X.Y., Yao, J.G., and Long, X.D. (2021). The predictive potential of genetic single nucleotide polymorphisms in CBX4 for hepatocellular carcinoma survival. Front. Biosci. (Landmark Ed.) 26: 1191–1203.10.52586/5019Search in Google Scholar PubMed

Received: 2022-04-08
Accepted: 2022-09-22
Published Online: 2022-10-11
Published in Print: 2023-01-27

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. A biochemical view on the septins, a less known component of the cytoskeleton
  4. Research Articles/Short Communications
  5. Protein Structure and Function
  6. Mathematical expressions describing enzyme velocity and inhibition at high enzyme concentration
  7. Cell Biology and Signaling
  8. MicroRNA-6838-5p suppresses the self-renewal and metastasis of human liver cancer stem cells through downregulating CBX4 expression and inactivating ERK signaling
  9. M2 macrophages-derived exosomal miR-3917 promotes the progression of lung cancer via targeting GRK6
  10. Extracellular stimulation of lung fibroblasts with arachidonic acid increases interleukin 11 expression through p38 and ERK signaling
  11. EVADR ceRNA transcript variants upregulate WNT and PI3K signaling pathways in SW480 and HCT116 cells by sponging miR-7 and miR-29b
https://doi.org/10.1515/hsz-2022-0156
Keywords for this article
cancer stem cell; CBX4; hepatocellular carcinoma; miR-6838-5p; self-renewal

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. A biochemical view on the septins, a less known component of the cytoskeleton
  4. Research Articles/Short Communications
  5. Protein Structure and Function
  6. Mathematical expressions describing enzyme velocity and inhibition at high enzyme concentration
  7. Cell Biology and Signaling
  8. MicroRNA-6838-5p suppresses the self-renewal and metastasis of human liver cancer stem cells through downregulating CBX4 expression and inactivating ERK signaling
  9. M2 macrophages-derived exosomal miR-3917 promotes the progression of lung cancer via targeting GRK6
  10. Extracellular stimulation of lung fibroblasts with arachidonic acid increases interleukin 11 expression through p38 and ERK signaling
  11. EVADR ceRNA transcript variants upregulate WNT and PI3K signaling pathways in SW480 and HCT116 cells by sponging miR-7 and miR-29b
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2026 De Gruyter Brill
Downloaded on 7.1.2026 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2022-0156/html
Scroll to top button