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Maternal embryonic leucine zipper kinase serves as a potential prognostic marker and leads to sorafenib chemoresistance modified by miR-142-5p in hepatocellular carcinoma

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Abstract

Background

Chemotherapy is an important treatment strategy for advanced hepatocellular carcinoma (HCC). Sorafenib is a first-line systemic drug that has been commonly used clinically for patients with advanced HCC. However, the high resistance rate of sorafenib in HCC patients often hinders its long-term efficacy. Therefore, it is vital to reveal the molecular mechanisms of sorafenib resistance in patients with HCC.

Methods

In current study, we screened out fourteen genes that over-expressed in HCC specimens through integrative bioinformatics analysis. Here, maternal embryonic leucine zipper kinase (MELK) was highlighted as one of the most probable molecules. The Database for Annotation Visualization and Integrated Discovery (DAVID) program was utilized for functional pathway enrichment analysis. Real-time PCR (RT-PCR) and western blot were used to examine the expression levels of MELK. CCK-8, transwell, colony formation assays and flow cytometry were used to detect cell proliferation, the cell cycle. The dual luciferase assays were performed to study the targeting relationship between MELK and miR-142-5p.

Results

MELK expressions were correlated significantly with cell proliferation by regulating cell cycle and DNA replication. High MELK expression in patients with HCC indicated a poor prognosis both the overall and diseases free survival rates. MELK knockdown suppresses cell proliferation, migration and invasion in vitro. miR-142-5p regulates MELK expression through binding to the complementary sequence in the 3′-UTR regions. MELK knockdown enhances sensitivity of sorafenib in HCC sorafenib-resistant (HCC/SR) cells.

Conclusions

MELK may serve as a potential prognostic marker in HCC and MELK knockdown enhanced sensitivity of HepG2/SR cells to sorafenib treatment. Our findings suggest that MELK/miR-142-5p axis could be a potentially therapeutic target for reversing the sorafenib resistance in HCC treatment.

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Data availability

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

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359-386

    Article  CAS  Google Scholar 

  2. Yang L, Parkin DM, Ferlay J, Li L, Chen Y (2005) Estimates of cancer incidence in China for 2000 and projections for 2005. Cancer Epidemiol Biomark Prev 14:243–250

    Article  Google Scholar 

  3. El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365:1118–1127

    Article  CAS  Google Scholar 

  4. Ricke J, Klumpen HJ, Amthauer H, Bargellini I, Bartenstein P, de Toni EN, Gasbarrini A, Pech M, Peck-Radosavljevic M, Popovic P et al (2019) Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol 71:1164–1174

    Article  CAS  Google Scholar 

  5. Lin Z, Xia S, Liang Y, Ji L, Pan Y, Jiang S, Wan Z, Tao L, Chen J, Lin C et al (2020) LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription. Theranostics 10:8834–8850

    Article  CAS  Google Scholar 

  6. Asghar U, Meyer T (2012) Are there opportunities for chemotherapy in the treatment of hepatocellular cancer? J Hepatol 56:686–695

    Article  Google Scholar 

  7. Nakano I, Paucar AA, Bajpai R, Dougherty JD, Zewail A, Kelly TK, Kim KJ, Ou J, Groszer M, Imura T et al (2005) Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation. J Cell Biol 170:413–427

    Article  CAS  Google Scholar 

  8. Vulsteke V, Beullens M, Boudrez A, Keppens S, Van Eynde A, Rider MH, Stalmans W, Bollen M (2004) Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1. J Biol Chem 279:8642–8647

    Article  CAS  Google Scholar 

  9. Beullens M, Vancauwenbergh S, Morrice N, Derua R, Ceulemans H, Waelkens E, Bollen M (2005) Substrate specificity and activity regulation of protein kinase MELK. J Biol Chem 280:40003–40011

    Article  CAS  Google Scholar 

  10. Kuner R, Falth M, Pressinotti NC, Brase JC, Puig SB, Metzger J, Gade S, Schafer G, Bartsch G, Steiner E et al (2013) The maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer. J Mol Med (Berl) 91:237–248

    Article  CAS  Google Scholar 

  11. Gu C, Banasavadi-Siddegowda YK, Joshi K, Nakamura Y, Kurt H, Gupta S, Nakano I (2013) Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. Stem Cells 31:870–881

    Article  CAS  Google Scholar 

  12. Xu Q, Ge Q, Zhou Y, Yang B, Yang Q, Jiang S, Jiang R, Ai Z, Zhang Z, Teng Y (2020) MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway. EBioMedicine 51:102609

    Article  Google Scholar 

  13. Kohler RS, Kettelhack H, Knipprath-Meszaros AM, Fedier A, Schoetzau A, Jacob F, Heinzelmann-Schwarz V (2017) MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells. Gynecol Oncol 145:159–166

    Article  CAS  Google Scholar 

  14. Du T, Qu Y, Li J, Li H, Su L, Zhou Q, Yan M, Li C, Zhu Z, Liu B (2014) Maternal embryonic leucine zipper kinase enhances gastric cancer progression via the FAK/Paxillin pathway. Mol Cancer 13:100

    Article  Google Scholar 

  15. He C, Dong X, Zhai B, Jiang X, Dong D, Li B, Jiang H, Xu S, Sun X (2015) MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget 6:28867–28881

    Article  Google Scholar 

  16. Bangaru S, Marrero JA, Singal AG (2020) Review article: new therapeutic interventions for advanced hepatocellular carcinoma. Aliment Pharmacol Ther 51:78–89

    Article  CAS  Google Scholar 

  17. Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674–687

    Article  CAS  Google Scholar 

  18. Alqahtani A, Khan Z, Alloghbi A, Said Ahmed TS, Ashraf M, Hammouda DM (2019) Hepatocellular carcinoma: molecular mechanisms and targeted therapies. Medicina (Kaunas) 55:526

    Article  Google Scholar 

  19. Singh S, Singh PP, Roberts LR, Sanchez W (2014) Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 11:45–54

    Article  CAS  Google Scholar 

  20. Badouel C, Chartrain I, Blot J, Tassan JP (2010) Maternal embryonic leucine zipper kinase is stabilized in mitosis by phosphorylation and is partially degraded upon mitotic exit. Exp Cell Res 316:2166–2173

    Article  CAS  Google Scholar 

  21. Ikeda Y, Sato S, Yabuno A, Shintani D, Ogasawara A, Miwa M, Zewde M, Miyamoto T, Fujiwara K, Nakamura Y, Hasegawa K (2020) High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo. J Gynecol Oncol 31:e93

    Article  CAS  Google Scholar 

  22. Zhou W, Yang Y, Xia J, Wang H, Salama ME, Xiong W, Xu H, Shetty S, Chen T, Zeng Z et al (2013) NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers. Cancer Cell 23:48–62

    Article  CAS  Google Scholar 

  23. Svoronos AA, Engelman DM, Slack FJ (2016) OncomiR or tumor suppressor? the duplicity of microRNAs in cancer. Cancer Res 76:3666–3670

    Article  CAS  Google Scholar 

  24. Aichen Z, Kun W, Xiaochun S, Lingling T (2021) LncRNA FGD5-AS1 promotes the malignant phenotypes of ovarian cancer cells via targeting miR-142-5p. Apoptosis 26:348–360

    Article  Google Scholar 

  25. Zhang Q, Liu H, Zhang J, Shan L, Yibureyimu B, Nurlan A, Aerxiding P, Luo Q (2020) MiR-142-5p suppresses lung cancer cell metastasis by targeting Yin Yang 1 to regulate epithelial-mesenchymal transition. Cell Reprogram 22:328–336

    Article  CAS  Google Scholar 

  26. Zhu M, Zou L, Lu F, Ye L, Su B, Yang K, Lin M, Fu J, Li Y (2020) miR-142-5p promotes renal cell tumorigenesis by targeting TFAP2B. Oncol Lett 20:324

    Article  Google Scholar 

  27. Zhu W, Wang JP, Meng QZ, Zhu F, Hao XF (2020) MiR-142-5p reverses the resistance to gefitinib through targeting HOXD8 in lung cancer cells. Eur Rev Med Pharmacol Sci 24:4306–4313

    CAS  PubMed  Google Scholar 

  28. Li X, Chen W, Jin Y, Xue R, Su J, Mu Z, Li J, Jiang S (2019) miR-142-5p enhances cisplatin-induced apoptosis in ovarian cancer cells by targeting multiple anti-apoptotic genes. Biochem Pharmacol 161:98–112

    Article  CAS  Google Scholar 

  29. Sasaki R, Kanda T, Fujisawa M, Matsumoto N, Masuzaki R, Ogawa M, Matsuoka S, Kuroda K, Moriyama M (2020) Different mechanisms of action of regorafenib and lenvatinib on toll-like receptor-signaling pathways in human hepatoma cell lines. Int J Mol Sci 21:3349

    Article  CAS  Google Scholar 

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Acknowledgements

Not applicable.

Funding

This study was supported by Nantong Science and Technology Project (Nos. JC2020027, MSZ19216).

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Author notes

  1. Hualei Li and Ling Gai contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Affiliated Hospital of Nantong University, Nantong, 226001, China

    Hualei Li

  2. Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China

    Ling Gai

  3. Department of Clinical Laboratory, Nantong Hospital of Traditional Chinese Medicine, Affiliated Traditional Chinese Medicine Hospital of Nantong University, Nantong, 226001, China

    Zhimei Wu

  4. Department of Clinical Laboratory, Affiliated Hospital of Nantong University, Xisi Road, Nantong, 226001, Jiangsu, China

    Feng Li

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  1. Hualei Li
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  2. Ling Gai
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  4. Feng Li
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Contributions

FL and HL designed the study and drafted the manuscript. LG was responsible for the collection and analysis of the experimental data. ZW revised the manuscript critically for important intellectual content. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Feng Li.

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The authors have no conflicts of interest to declare.

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The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Experiments were performed under a project license (NO.: SYXK(SU)2017-0046) granted by ethics committee board of Nantong university, in compliance with national or institutional guidelines for the care and use of animals.

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Li, H., Gai, L., Wu, Z. et al. Maternal embryonic leucine zipper kinase serves as a potential prognostic marker and leads to sorafenib chemoresistance modified by miR-142-5p in hepatocellular carcinoma. Mol Biol Rep 49, 3015–3024 (2022). https://doi.org/10.1007/s11033-022-07128-3

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  • DOI: https://doi.org/10.1007/s11033-022-07128-3

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