Abstract
Tumor metastasis is the main reason of cancer-related death for gastric cancer (GC) patients and gene expression microarray data indicate that kinesin family member 26B (KIF26B) is one of the most upregulated genes in metastatic GC samples. Specifically, KIF26B expression was upregulated in a stepwise manner from non-tumorous gastric mucosa, primary GC tissues without metastasis, via primary GC tissues with metastasis, to secondary lymph node metastatic (LNM) foci. Increased expression of KIF26B was correlated with tumor size, positive LNM or distant metastases and poor prognosis. KIF26B, negatively regulated by miR-372, promoted GC cell proliferation and metastasis in vitro and in vivo. Mechanistic investigations confirmed that the main target of KIF26B was the vascular endothelial growth factor (VEGF) signaling pathway, particularly by inhibition or overexpression of VEGFA, PXN, FAK, PIK3CA, BCL2 and CREB1. Thus, KIF26B, a novel oncogene regulated by miR-372, promotes proliferation and metastasis through the VEGF pathway in GC.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
Change history
23 March 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41388-022-02268-z
References
Brenner H, Rothenbacher D, Arndt V . Epidemiology of stomach cancer. Methods Mol Biol 2009; 472: 467–477.
Gupta GP, Massague J . Cancer metastasis: building a framework. Cell 2006; 127: 679–695.
Coghlin C, Murray GI . Current and emerging concepts in tumour metastasis. J Pathol 2010; 222: 1–15.
Fidler IJ . Critical factors in the biology of human cancer metastasis: twenty-eighth G. H. A. Clowes Memorial Award Lecture. Cancer Res 1990; 50: 6130–6138.
Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM et al. MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 2003; 22: 8031–8041.
Waller T, Gubała T, Sarapata K, Piwowar M, Jurkowski W . DNA microarray integromics analysis platform. BioData Min 2015; 8: 18.
Adomas A, Heller G, Olson A, Osborne J, Karlsson M, Nahalkova J et al. Comparative analysis of transcript abundance in Pinus sylvestris after challenge with a saprotrophic, pathogenic or mutualistic fungus. Tree Physiol 2008; 28: 885–897.
Hippo Y, Taniguchi H, Tsutsumi S, Machida N, Chong JM, Fukayama M et al. Global gene expression analysis of gastric cancer by oligonucleotide microarrays. Cancer Res 2002; 62: 233–240.
Chen X, Leung SY, Yuen ST, Chu KM, Ji J, Li R et al. Variation in gene expression patterns in human gastric cancers. Mol Biol Cell 2003; 14: 3208–3215.
Hirokawa N, Noda Y, Tanaka Y, Niwa S . Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol 2009; 10: 682–696.
Uchiyama Y, Sakaguchi M, Terabayashi T, Inenaga T, Inoue S, Kobayashi C et al. Kif26b, a kinesin family gene, regulates adhesion of the embryonic kidney mesenchyme. Proc Natl Acad Sci USA 2010; 107: 9240–9245.
Petri A, Lindow M, Kauppinen S . MicroRNA silencing in primates: towards development of novel therapeutics. Cancer Res 2009; 69: 393–395.
Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 2015 Jul; 18: 476–484.
Zhao Y, Adjei AA . Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. Oncologist 2015; 20: 660–673.
Liu X, Gong H, Huang K . Oncogenic role of kinesin proteins and targeting kinesin therapy. Cancer Sci 2013; 104: 651–656.
Terabayashi T, Sakaguchi M, Shinmyozu K, Ohshima T, Johjima A, Ogura T et al. Phosphorylation of Kif26b promotes its polyubiquitination and subsequent proteasomal degradation during kidney development. PLoS One 2012; 7: e39714.
Calin GA, Croce CM . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–866.
Gao P, Xing AY, Zhou GY, Zhang TG, Zhang JP, Gao C et al. The molecular mechanism of microRNA-145 to suppress invasion-metastasis cascade in gastric cancer. Oncogene 2013; 32: 491–501.
Wu G, Liu H, He H, Wang Y, Lu X, Yu Y et al. miR-372 down-regulates the oncogene ATAD2 to influence hepatocellular carcinoma proliferation and metastasis. BMC Cancer 2014; 14: 107.
Gandhi NS, Tekade RK, Chougule MB . Nanocarrier mediated delivery of siRNA/miRNA in combination with chemotherapeutic agents for cancer therapy: current progress and advances. J Control Release 2014; 194: 238–256.
Wang Q, Zhao ZB, Wang G, Hui Z, Wang MH, Pan JF et al. High expression of KIF26B in breast cancer associates with poor prognosis. PLoS One 2013; 8: e61640.
Wang J, Cui F, Wang X, Xue Y, Chen J, Yu Y et al. Elevated kinesin family member 26B is a prognostic biomarker and a potential therapeutic target for colorectal cancer. J Exp Clin Cancer Res 2015; 34: 13.
Grothey A . VEGF inhibition beyond tumour progression. Lancet Oncol 2013; 14: 2–3.
Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L . VEGF-receptor signal transduction. Trends Biochem Sci 2003; 28: 488–494.
Wu DW, Chen CY, Chu CL, Lee H . Paxillin confers resistance to tyrosine kinase inhibitors in EGFR-mutant lung cancers via modulating BIM and Mcl-1 protein stability. Oncogene 2015; 35: 621–630.
Gilmore AP, Romer LH . Inhibition of focal adhesion kinase (FAK) signalling in focal adhesions decreases cell motility and proliferation. Mol Biol Cell 1996; 7: 1209–1224.
Irby RB, Yeatman TJ . Role of Src expression and activation in human cancer. Oncogene 2000; 19: 5636–5642.
Paul-Samojedny M, Suchanek R, Borkowska P, Pudełko A, Owczarek A, Kowalczyk M et al. Knockdown of AKT3 (PKBgamma) and PI3KCA suppresses cell viability and proliferation and induces the apoptosis of glioblastoma multiforme T98G cells. Biomed Res Int 2014; 2014: 768181.
Hata AN, Engelman JA, Faber AC . The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov 2015; 5: 475–487.
Sakamoto KM, Frank DA . CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy. Clin. Cancer Res 2009; 15: 2583–2587.
Wang YW, Chen X, Gao JW, Zhang H, Ma RR, Gao ZH et al. High expression of cAMP-responsive element-binding protein 1 (CREB1) is associated with metastasis, tumor stage and poor outcome in gastric cancer. Oncotarget 2015; 6: 10646–10657.
Ferrara N, Gerber HP, LeCouter J . The biology of VEGF and its receptors. Nat Med 2003; 9: 669–676.
Kieran MW, Kalluri R, Cho YJ . The VEGF pathway in cancer and disease: responses, resistance, and the path forward. Cold Spring Harb Perspect Med 2012; 2: a006593.
Crociani O, Lastraioli E, Boni L, Pillozzi S, Romoli MR, D'Amico M et al. hERG1 channels regulate VEGF-A secretion in human gastric cancer: clinicopathological correlations and therapeutical implications. Clin Cancer Res 2014; 20: 1502–1512.
Zhou R, Niwa S, Homma N, Takei Y, Hirokawa N . KIF26A is an unconventional kinesin and regulates GDNF-Ret signaling in enteric neuronal development. Cell 2009; 139: 802–813.
Gao P, Wong CC, Tung EK, Lee JM, Wong CM, Ng IO . Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis. J Hepatol 2011; 54: 1177–1184.
Acknowledgements
We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of the manuscript. This study was supported by the National Natural Science Foundation of China (grant no. 81372856 and 81672842) and the Taishan Scholars Program of Shandong Province (grant no. ts201511096).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Zhang, H., Ma, RR., Wang, XJ. et al. KIF26B, a novel oncogene, promotes proliferation and metastasis by activating the VEGF pathway in gastric cancer. Oncogene 36, 5609–5619 (2017). https://doi.org/10.1038/onc.2017.163
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2017.163
This article is cited by
-
The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside
Biomarker Research (2024)
-
CENPF knockdown inhibits adriamycin chemoresistance in triple-negative breast cancer via the Rb-E2F1 axis
Scientific Reports (2023)
-
Establishment and validation of a novel invasion-related gene signature for predicting the prognosis of ovarian cancer
Cancer Cell International (2022)
-
Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis
Nature Communications (2022)
-
E2F1-initiated transcription of PRSS22 promotes breast cancer metastasis by cleaving ANXA1 and activating FPR2/ERK signaling pathway
Cell Death & Disease (2022)