Abstract
Background
Krüppel-like factors (KLFs) have been identified in multi-cancers and act as oncogenes or tumor suppressors. The function of KLF15, one member of KLFs, has not been well elucidated, especially in gastric cancer (GC).
Aims
This study was designed to investigate the prognostic value and biological functions of KLF15 in GC.
Methods
KLF15 protein expression in GC patients was evaluated by immunohistochemistry assays in 50 paired GC tissues and adjacent normal tissues, and correlations between KLF15 expression and clinicopathological characteristics and prognosis were analyzed. Then, we investigated the over-expression of KLF15 on cell proliferation and its mechanism in GC cells.
Results
KLF15 expression levels were significantly down-regulated in GC tissues compared to adjacent normal tissues. And KLF15 expression was negatively correlated with clinical stage, lymphatic metastasis, and distant metastasis. Furthermore, KLF15 expression could predict prognosis in patients with GC. Moreover, over-expression of KLF15 could inhibit cell proliferation partly via regulating CDKN1A/p21 and CDKN1C/p57.
Conclusion
These findings demonstrate that KLF15 plays a significant role in GC progression and could be a therapeutic target for GC.
Similar content being viewed by others
References
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–132.
Ohtsu A. Chemotherapy for metastatic gastric cancer: past, present, and future. J Gastroenterol. 2008;43:256–264.
Fenech M. The Genome Health Clinic and Genome Health Nutrigenomics concepts: diagnosis and nutritional treatment of genome and epigenome damage on an individual basis. Mutagenesis. 2005;20:255–269.
Komori T, Takemasa I, Yamasaki M, et al. Gene expression of colorectal cancer: preoperative genetic diagnosis using endoscopic biopsies. Int J Oncol. 2008;32:367–375.
Udler M, Maia AT, Cebrian A, et al. Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. J Clin Oncol. 2007;25:3015–3023.
Wang J, Galvao J, Beach KM, et al. Novel roles and mechanism for Krüppel-like factor 16 (KLF16) regulation of neurite outgrowth and ephrin receptor A5 (EphA5) expression in retinal ganglion cells. J Biol Chem. 2016;291:18084–18095.
Liang K, Liu T, Chu N, et al. KLF8 is required for bladder cancer cell proliferation and migration. Biotechnol Appl Biochem. 2015;62:628–633.
Pearson R, Fleetwood J, Eaton S, Crossley M, Bao S. Krüppel-like transcription factors: a functional family. Int J Biochem Cell Biol. 2008;40:1996–2001.
Limame R, de Beeck KO, Lardon F, De Wever O, Pauwels P. Krüppel-like factors in cancer progression: three fingers on the steering wheel. Oncotarget. 2014;5:29–48.
Ray S, Pollard JW. KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing. Proc Natl Acad Sci USA. 2012;109:E1334–E1343.
Kaczynski J, Cook T, Urrutia R. Sp1- and Krüppel-like transcription factors. Genome Biol. 2003;4:206.
Xu Q, Liu M, Zhang J, et al. Overexpression of KLF4 promotes cell senescence through microRNA-203-survivin-p21 pathway. Oncotarget. 2016;7:60290–60302.
Yin L, Wang JP, Xu TP, et al. Downregulation of Krüppel-like factor 2 is associated with poor prognosis for nonsmall-cell lung cancer. Tumour Biol. 2015;36:3075–3084.
Chia NY, Deng N, Das K, et al. Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development. Gut. 2015;64:707–719.
Tseng WC, Chuang CW, Yang MH, Pan CC, Tarng DC. Krüppel-like factor 4 is a novel prognostic predictor for urothelial carcinoma of bladder and it regulates TWIST1-mediated epithelial-mesenchymal transition. Urol Oncol. 2016;34:485 e415–485 e424.
Benzeno S, Narla G, Allina J, et al. Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1. Can Res. 2004;64:3885–3891.
Uchida S, Tanaka Y, Ito H, et al. Transcriptional regulation of the CLC-K1 promoter by myc-associated zinc finger protein and kidney-enriched Krüppel-like factor, a novel zinc finger repressor. Mol Cell Biol. 2000;20:7319–7331.
Fernandez-Zapico ME, Lomberk GA, Tsuji S, et al. A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth. Biochem J. 2011;435:529–537.
Gray S, Feinberg MW, Hull S, et al. The Krüppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4. J Biol Chem. 2002;277:34322–34328.
Yoda T, McNamara KM, Miki Y, et al. KLF15 in breast cancer: a novel tumor suppressor? Cell Oncol (Dordr). 2015;38:227–235.
Xu TP, Huang MD, Xia R, et al. Decreased expression of the long non-coding RNA FENDRR is associated with poor prognosis in gastric cancer and FENDRR regulates gastric cancer cell metastasis by affecting fibronectin1 expression. J Hematol Oncol. 2014;7:63.
Wang K, Ren Y, Liu Y, Zhang J, He JJ. MiR-4262 promotes proliferation and invasion of human breast cancer cells through directly targeting KLF6 and KLF15. Oncol Res. 2016;25:277–283.
Li JR, Sun CH, Li W, et al. Cancer RNA-Seq Nexus: a database of phenotype-specific transcriptome profiling in cancer cells. Nucleic Acids Res. 2016;44:D944–D951.
Yang Y, Tarapore RS, Jarmel MH, Tetreault MP, Katz JP. p53 mutation alters the effect of the esophageal tumor suppressor KLF5 on keratinocyte proliferation. Cell Cycle. 2012;11:4033–4039.
Huang MD, Chen WM, Qi FZ, et al. Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2. Mol Cancer. 2015;14:165.
Li Q, Dong Z, Zhou F, Cai X, Gao Y, Wang LW. Krüppel-like factor 5 promotes lung tumorigenesis through upregulation of Sox4. Cell Physiol Biochem. 2014;33:1–10.
Jiang Z, Zhang Y, Cao R, et al. MiR-5195-3p inhibits proliferation and invasion of human bladder cancer cells by directly targeting oncogene KLF5. Oncol Res. 2017. doi:10.3727/096504016X14831120463349.
Xu TP, Liu XX, Xia R, et al. SP1-induced upregulation of the long noncoding RNA TINCR regulates cell proliferation and apoptosis by affecting KLF2 mRNA stability in gastric cancer. Oncogene. 2015;34:5648–5661.
Nagata T, Shimada Y, Sekine S, et al. KLF4 and NANOG are prognostic biomarkers for triple-negative breast cancer. Breast Cancer. 2016;24:326–335.
Zhang N, Zhang J, Shuai L, et al. Krüppel-like factor 4 negatively regulates beta-catenin expression and inhibits the proliferation, invasion and metastasis of gastric cancer. Int J Oncol. 2012;40:2038–2048.
Yu F, Shi Y, Wang J, Li J, Fan D, Ai W. Deficiency of Krüppel-like factor KLF4 in mammary tumor cells inhibits tumor growth and pulmonary metastasis and is accompanied by compromised recruitment of myeloid-derived suppressor cells. Int J Cancer. 2013;133:2872–2883.
Yu T, Chen X, Lin T, et al. KLF4 deletion alters gastric cell lineage and induces MUC2 expression. Cell Death Dis. 2016;7:e2255.
Wang J, Wang B, Chen LQ, et al. miR-10b promotes invasion by targeting KLF4 in osteosarcoma cells. Biomed Pharmacother. 2016;84:947–953.
Soon MS, Hsu LS, Chen CJ, et al. Expression of Krüppel-like factor 5 in gastric cancer and its clinical correlation in Taiwan. Virchows Arch. 2011;459:161–166.
Meyer SE, Hasenstein JR, Baktula A, et al. Krüppel-like factor 5 is not required for K-RasG12D lung tumorigenesis, but represses ABCG2 expression and is associated with better disease-specific survival. Am J Pathol. 2010;177:1503–1513.
Li X, Liu X, Xu Y, et al. KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α. Int J Oncol. 2014;45:1507–1514.
Wade HE, Kobayashi S, Eaton ML, et al. Multimodal regulation of E2F1 gene expression by progestins. Mol Cell Biol. 2010;30:1866–1877.
Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14:159–169.
Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–166.
Acknowledgments
The authors are thankful to the National Natural Science Foundation of China for supporting this study (Grant Numbers 81672896, 81302012).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The study was performed according to the ethical standards of the institutional research committee and the standards set in the Declaration of Helsinki 1975. This article does not contain any studies with animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Yongqian Shu is the first corresponding author of this article.
Chongqi Sun, Pei Ma, Yanfen Wang, and Weitao Liu contributed equally to this work and should be regarded as joint first authors.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplemental Figure 1
Effects of KLF15 on KLF2 or KLF5 in GC cell lines. A. Real-time PCR analysis of KLF2 mRNA expression after over-expression of KLF15 in AGS and SGC-7901. Bars: SD. B. Real-time PCR analysis of KLF2 mRNA expression after over-expression of KLF15 in AGS and SGC-7901. Bars: SD (TIFF 2966 kb)
Rights and permissions
About this article
Cite this article
Sun, C., Ma, P., Wang, Y. et al. KLF15 Inhibits Cell Proliferation in Gastric Cancer Cells via Up-Regulating CDKN1A/p21 and CDKN1C/p57 Expression. Dig Dis Sci 62, 1518–1526 (2017). https://doi.org/10.1007/s10620-017-4558-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-017-4558-2