Skip to main content

Advertisement

SpringerLink
Log in

The kinesin motor protein KIF4A as a potential therapeutic target in renal cell carcinoma

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

A Correction to this article was published on 27 May 2023

This article has been updated

Summary

Kinesin family member 4A (KIF4A) is located in the human chromosome band Xq13.1. It has a highly conserved kinesin motor region at its N-terminus, which is followed by a central coiled-coil region and a C-terminus cargo-binding domain that contains a cysteine-rich motif. It is aberrantly expressed in a variety of cancers. Our study aimed to determine the expression of KIF4A in renal cell carcinoma (RCC) and to gain new insights into the underlying molecular mechanisms of this disease. Here, we found that KIF4A expression in RCC specimens increased relative to that in normal renal tissues. A significant correlation existed between the expression of KIF4A and the clinicopathologic features of RCC. Elevated KIF4A expression was associated with poor overall survival and disease-free survival. Univariate and multivariate Cox regression analysis revealed that KIF4A was an independent prognostic factor for poor survival in human patients with RCC. CCK-8 proliferation assay, cell cycle analysis, and subcutaneous tumor formation analysis in nude mice consistently showed that KIF4A promoted RCC proliferation. Our findings also indicated that KIF4A functions as an accelerator of RCC metastasis as certified through transwell chamber analysis, wound healing assay, and angiogenesis assay. The expression levels of cyclin D1, cyclin E2, matrix metalloproteinase-2, matrix metalloproteinase-9, hypoxia-inducible factor 1α, and vascular endothelial growth factor in the KIF4A knockdown group were lower than those in the control group and were consistent with those in classic oncogenic pathways. These findings implied that the expression of KIF4A was significantly related to the tumor incidence, metastasis, and prognosis of patients with RCC. Our work provides new breakthroughs for the diagnosis and treatment of RCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Change history

References

  1. Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, Hes O, Moch H, Montironi R, Tickoo SK, Zhou M, Argani P (2013) The international society of urological pathology (ISUP) vancouver classification of renal neoplasia. Am J Surg Pathol 37(10):1469–1489. https://doi.org/10.1097/PAS.0b013e318299f2d1

    Article  PubMed  Google Scholar 

  2. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM (2016) The 2016 WHO classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol 70(1):93–105. https://doi.org/10.1016/j.eururo.2016.02.029

    Article  PubMed  Google Scholar 

  3. Ljungberg B, Albiges L, Abu-Ghanem Y, Bensalah K, Dabestani S, Fernandez-Pello S, Giles RH, Hofmann F, Hora M, Kuczyk MA, Kuusk T, Lam TB, Marconi L, Merseburger AS, Powles T, Staehler M, Tahbaz R, Volpe A, Bex A (2019) European association of urology guidelines on renal cell carcinoma: the 2019 update. Eur Urol 75(5):799–810. https://doi.org/10.1016/j.eururo.2019.02.011

    Article  PubMed  Google Scholar 

  4. Liu X, Chong Y, Liu H, Han Y, Niu M (2016) CRM1 inhibitor S109 suppresses cell proliferation and induces cell cycle arrest in renal cancer cells. Korean J Physiol Pharmacol 20(2):161–168. https://doi.org/10.4196/kjpp.2016.20.2.161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ru-Min W, Yi-Jing Z, Sha M, Ying-Li X, Yan-Su C, Hai-Long L, Jin B, Jun-Nian Z (2015) Preoperative Neutrophil to Lymphocyte Ratio as a Prognostic Factor in Patients with Non-metastatic Renal Cell Carcinoma. Asian Pac J Cancer Prev 16(9)

  6. Song J, Chen X, Bai J, Liu Q, Li H, Xie J, Jing H, Zheng J (2016) Discoidin domain receptor 1 (DDR1), a promising biomarker, induces epithelial to mesenchymal transition in renal cancer cells. Tumor Biol 37(8):11509–11521. https://doi.org/10.1007/s13277-016-5021-2

    Article  CAS  Google Scholar 

  7. Beksac AT, Paulucci DJ, Blum KA, Yadav SS, Sfakianos JP, Badani KK (2017) Heterogeneity in renal cell carcinoma. Urol Oncol 35(8):507–515. https://doi.org/10.1016/j.urolonc.2017.05.006

    Article  CAS  PubMed  Google Scholar 

  8. Miki H, Okada Y, Hirokawa N (2005) Analysis of the kinesin superfamily: insights into structure and function. Trends Cell Biol 15(9):467–476. https://doi.org/10.1016/j.tcb.2005.07.006

    Article  CAS  PubMed  Google Scholar 

  9. Rath O, Kozielski F (2012) Kinesins and cancer. Nat Rev Cancer 12(8):527–539. https://doi.org/10.1038/nrc3310

    Article  CAS  PubMed  Google Scholar 

  10. Gul A, Rini BI (2019) Adjuvant therapy in renal cell carcinoma. Cancer 125(17):2935–2944. https://doi.org/10.1002/cncr.32144

    Article  PubMed  Google Scholar 

  11. Haider S, Wang J, Nagano A, Desai A, Arumugam P, Dumartin L, Fitzgibbon J, Hagemann T, Marshall JF, Kocher HM, Crnogorac-Jurcevic T, Scarpa A, Lemoine NR, Chelala C (2014) A multi-gene signature predicts outcome in patients with pancreatic ductal adenocarcinoma. Genome Med 6(12):105. https://doi.org/10.1186/s13073-014-0105-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang Y, Wang H, Lian Y, Wu X, Zhou L, Wang J, Deng M, Huang Y (2018) Upregulation of kinesin family member 4A enhanced cell proliferation via activation of Akt signaling and predicted a poor prognosis in hepatocellular carcinoma. Cell Death Dis 9(2):141. https://doi.org/10.1038/s41419-017-0114-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Minakawa Y, Kasamatsu A, Koike H, Higo M, Nakashima D, Kouzu Y, Sakamoto Y, Ogawara K, Shiiba M, Tanzawa H, Uzawa K (2013) Kinesin family member 4A: a potential predictor for progression of human oral cancer. PloS one 8(12):e85951. https://doi.org/10.1371/journal.pone.0085951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhou Y, Yang L, Zhang X, Chen R, Chen X, Tang W, Zhang M (2019) Identification of potential biomarkers in glioblastoma through bioinformatic analysis and evaluating their prognostic value. Biomed Res Int 2019:6581576. https://doi.org/10.1155/2019/6581576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gao J, Sai N, Wang C, Sheng X, Shao Q, Zhou C, Shi Y, Sun S, Qu X, Zhu C (2011) Overexpression of chromokinesin KIF4 inhibits proliferation of human gastric carcinoma cells both in vitro and in vivo. Tumour Biol 32(1):53–61. https://doi.org/10.1007/s13277-010-0090-0

    Article  CAS  PubMed  Google Scholar 

  16. Zhang H, Zou J, Yin Y, Zhang B, Hu Y, Wang J, Mu H (2019) Bioinformatic analysis identifies potentially key differentially expressed genes in oncogenesis and progression of clear cell renal cell carcinoma. PeerJ 7:e8096. https://doi.org/10.7717/peerj.8096

    Article  PubMed  PubMed Central  Google Scholar 

  17. Liu QH, Wang Y, Yong HM, Hou PF, Pan J, Bai J, Zheng JN (2017) XRCC1 serves as a potential prognostic indicator for clear cell renal cell carcinoma and inhibits its invasion and metastasis through suppressing MMP-2 and MMP-9. Oncotarget 8(65):109382–109392. https://doi.org/10.18632/oncotarget.22680

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hou PF, Jiang T, Chen F, Shi PC, Li HQ, Bai J, Song J (2018) KIF4A facilitates cell proliferation via induction of p21-mediated cell cycle progression and promotes metastasis in colorectal cancer. Cell Death Dis 9(5):477. https://doi.org/10.1038/s41419-018-0550-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bai J, Yong HM, Chen FF, Mei PJ, Liu H, Li C, Pan ZQ, Wu YP, Zheng JN (2013) Cullin1 is a novel marker of poor prognosis and a potential therapeutic target in human breast cancer. Ann Oncol 24(8):2016–2022. https://doi.org/10.1093/annonc/mdt147

    Article  CAS  PubMed  Google Scholar 

  20. Xiao-Yi H, Ping-Fu H, Teng-Teng L, Hao-Yu Q, Min-Le L, Tian L, Jin-Jin L, Jin B, Jun-Nian Z (2018) The roles of Wnt/β-catenin signaling pathway related lncRNAs in cancer. Int J Biol Sci 14:14

    Google Scholar 

  21. Wu X, Chen H, Gao Q, Bai J, Wang X, Zhou J, Qiu S, Xu Y, Shi Y, Wang X, Zhou J, Fan J (2014) Downregulation of JWA promotes tumor invasion and predicts poor prognosis in human hepatocellular carcinoma. Mol Carcinog 53(4):325–336. https://doi.org/10.1002/mc.21981

    Article  CAS  PubMed  Google Scholar 

  22. Bai J, Yong HM, Chen FF, Song WB, Li C, Liu H, Zheng JN (2013) RUNX3 is a prognostic marker and potential therapeutic target in human breast cancer. J Cancer Res Clin Oncol 139(11):1813–1823. https://doi.org/10.1007/s00432-013-1498-x

    Article  CAS  PubMed  Google Scholar 

  23. Cao WJ, Mao LL, Zheng JN, Pei DS (2015) p42.3: an abductor of cell cycle. Anticancer Agents Med Chem 15(2):157–162. https://doi.org/10.2174/1871520614666140818200202

    Article  CAS  PubMed  Google Scholar 

  24. Mei PJ, Bai J, Miao FA, Li ZL, Chen C, Zheng JN, Fan YC (2019) Relationship between expression of XRCC1 and tumor proliferation, migration, invasion, and angiogenesis in glioma. Invest New Drugs 37(4):646–657. https://doi.org/10.1007/s10637-018-0667-9

    Article  CAS  PubMed  Google Scholar 

  25. Sati L, Seval-Celik Y, Unek G, Korgun ET, Demir R (2009) The presence of kinesin superfamily motor proteins KIFC1 and KIF17 in normal and pathological human placenta. Placenta 30(10):848–854. https://doi.org/10.1016/j.placenta.2009.07.005

    Article  CAS  PubMed  Google Scholar 

  26. Tikhonenko I, Nag DK, Robinson DN, Koonce MP (2009) Microtubule-nucleus interactions in Dictyostelium discoideum mediated by central motor kinesins. Eukaryot Cell 8(5):723–731. https://doi.org/10.1128/ec.00018-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Taniwaki M, Takano A, Ishikawa N, Yasui W, Inai K, Nishimura H, Tsuchiya E, Kohno N, Nakamura Y, Daigo Y (2007) Activation of KIF4A as a prognostic biomarker and therapeutic target for lung cancer. Clin Cancer Res 13(22 Pt 1):6624–6631. https://doi.org/10.1158/1078-0432.Ccr-07-1328

    Article  CAS  PubMed  Google Scholar 

  28. Gu Y, Lu L, Wu L, Chen H, Zhu W, He Y (2017) Identification of prognostic genes in kidney renal clear cell carcinoma by RNAseq data analysis. Mol Med Rep 15(4):1661–1667. https://doi.org/10.3892/mmr.2017.6194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wei W, Lv Y, Gan Z, Zhang Y, Han X, Xu Z (2019) Identification of key genes involved in the metastasis of clear cell renal cell carcinoma. Oncol Lett 17(5):4321–4328. https://doi.org/10.3892/ol.2019.10130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Menyhart O, Harami-Papp H, Sukumar S, Schafer R, Magnani L, de Barrios O, Gyorffy B (2016) Guidelines for the selection of functional assays to evaluate the hallmarks of cancer. Biochim Biophys Acta 1866(2):300–319. https://doi.org/10.1016/j.bbcan.2016.10.002

    Article  CAS  PubMed  Google Scholar 

  31. Wan Q, Shen Y, Zhao H, Wang B, Zhao L, Zhang Y, Bu X, Wan M, Shen C (2019) Impaired DNA double-strand breaks repair by kinesin family member 4A inhibition renders human H1299 non-small-cell lung cancer cells sensitive to cisplatin. J Cell Physiol 234(7):10360–10371. https://doi.org/10.1002/jcp.27703

    Article  CAS  PubMed  Google Scholar 

  32. Hua L, Zhu M, Song X, Wang J, Fang Z, Zhang C, Shi Q, Zhan W, Wang L, Meng Q, Zhou X, Yu R (2014) FRK suppresses the proliferation of human glioma cells by inhibiting cyclin D1 nuclear accumulation. J Neurooncol 119(1):49–58. https://doi.org/10.1007/s11060-014-1461-y

    Article  CAS  PubMed  Google Scholar 

  33. Malumbres M, Carnero A (2003) Cell cycle deregulation: a common motif in cancer. Prog Cell Cycle Res 5:5–18

    PubMed  Google Scholar 

  34. Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M (1995) Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol 15(5):2612–2624. https://doi.org/10.1128/mcb.15.5.2612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Han ZX, Wang XX, Zhang SN, Wu JX, Qian HY, Wen YY, Tian H, Pei DS, Zheng JN (2014) Downregulation of PAK5 inhibits glioma cell migration and invasion potentially through the PAK5-Egr1-MMP2 signaling pathway. Brain Tumor Pathol 31(4):234–241. https://doi.org/10.1007/s10014-013-0161-1

    Article  CAS  PubMed  Google Scholar 

  36. Zhu X, Ohtsubo M, Bohmer RM, Roberts JM, Assoian RK (1996) Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol 133(2):391–403. https://doi.org/10.1083/jcb.133.2.391

    Article  CAS  PubMed  Google Scholar 

  37. Toyoshima H, Hunter T (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78(1):67–74. https://doi.org/10.1016/0092-8674(94)90573-8

    Article  CAS  PubMed  Google Scholar 

  38. Piedagnel R, Murphy G, Ronco PM, Lelongt B (1999) Matrix metalloproteinase 2 (MMP2) and MMP9 are produced by kidney collecting duct principal cells but are differentially regulated by SV40 large-T, arginine vasopressin, and epidermal growth factor. J Biol Chem 274(3):1614–1620. https://doi.org/10.1074/jbc.274.3.1614

    Article  CAS  PubMed  Google Scholar 

  39. Yao M, Yoshida M, Kishida T, Nakaigawa N, Baba M, Kobayashi K, Miura T, Moriyama M, Nagashima Y, Nakatani Y, Kubota Y, Kondo K (2002) VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst 94(20):1569–1575. https://doi.org/10.1093/jnci/94.20.1569

    Article  CAS  PubMed  Google Scholar 

  40. Choueiri TK, Fay AP, Gagnon R, Lin Y, Bahamon B, Brown V, Rosenberg JE, Hutson TE, Baker-Neblett KL, Carpenter C, Liu Y, Pandite L, Signoretti S (2013) The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma. Clin Cancer Res 19(18):5218–5226. https://doi.org/10.1158/1078-0432.Ccr-13-0491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shi YH, Wang YX, Bingle L, Gong LH, Heng WJ, Li Y, Fang WG (2005) In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions: involvement of PI-3K/Akt and MEK1/ERK pathways. J Pathol 205(4):530–536. https://doi.org/10.1002/path.1734

    Article  CAS  PubMed  Google Scholar 

  42. Wiesener MS, Munchenhagen PM, Berger I, Morgan NV, Roigas J, Schwiertz A, Jurgensen JS, Gruber G, Maxwell PH, Loning SA, Frei U, Maher ER, Grone HJ, Eckardt KU (2001) Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas. Cancer Res 61(13):5215–5222

    CAS  PubMed  Google Scholar 

Download references

Funding

This study was funded by grants from the National Natural Science Foundation of China (No. 81672845, 81872304), the Project of Invigorating Health Care through Science, Technology and Education from Jiangsu Province (ZDRCC2016009), the Major Research and Development Program for Science and Technology Department of Zhejiang Province (No.2019C03003). The Jiangsu Provincial Medical Youth Talent (QNRC2016773), Six Talent Peaks Project in Jiangsu Province (WSN-119), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_2185), the Jiangsu Provincial Medical Innovation Team under Grant (CXTDA2017034).

Author information

Author notes

  1. Guihong Liu, Yachun Lu and Liantao Li contributed equally to this work.

Authors and Affiliations

  1. Department of Radiotherapy Oncology, The second affiliated Hospital of Soohow University, Suzhou, Jiangsu Province, 215004, China

    Guihong Liu & Ming Chen

  2. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China

    Guihong Liu, Yachun Lu, Liantao Li, Tao Jiang, Sufang Chu, Pingfu Hou & Jin Bai

  3. Cancer Institute, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, Jiangsu Province, 221002, China

    Yachun Lu, Liantao Li, Tao Jiang, Sufang Chu, Pingfu Hou & Jin Bai

Authors
  1. Guihong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yachun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liantao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sufang Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pingfu Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jin Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ming Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jin Bai or Ming Chen.

Ethics declarations

Conflict of interest

The authors have declared no conflict of interest.

Ethical approval

All experiments involved in this study were approved by both the Institutional Review Boards of Xuzhou Medical University and the Ethics Committee of the above hospital.

Informed consent

Each patient provided a written informed consent prior to the study.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: Incorrect Figure 5 was published.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, G., Lu, Y., Li, L. et al. The kinesin motor protein KIF4A as a potential therapeutic target in renal cell carcinoma. Invest New Drugs 38, 1730–1742 (2020). https://doi.org/10.1007/s10637-020-00961-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-020-00961-y

Keywords

Search

Navigation