Skip to main content
Top
Published in: Digestive Diseases and Sciences 6/2017

01-06-2017 | Original Article

KLF15 Inhibits Cell Proliferation in Gastric Cancer Cells via Up-Regulating CDKN1A/p21 and CDKN1C/p57 Expression

Authors: Chongqi Sun, Pei Ma, Yanfen Wang, Weitao Liu, Qinnan Chen, Yutian Pan, Chenhui Zhao, Yingchen Qian, Jie Liu, Wei Li, Yongqian Shu

Published in: Digestive Diseases and Sciences | Issue 6/2017

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
2.
go back to reference Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–132.CrossRefPubMed Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–132.CrossRefPubMed
3.
go back to reference Ohtsu A. Chemotherapy for metastatic gastric cancer: past, present, and future. J Gastroenterol. 2008;43:256–264.CrossRefPubMed Ohtsu A. Chemotherapy for metastatic gastric cancer: past, present, and future. J Gastroenterol. 2008;43:256–264.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
5.
go back to reference 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.PubMed 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.PubMed
6.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
8.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference 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.PubMed 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.PubMed
11.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
13.
go back to reference 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. 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.
14.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
15.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
16.
go back to reference 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.CrossRef 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.CrossRef
17.
go back to reference 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.CrossRef 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.CrossRef
18.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
19.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
20.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
21.
go back to reference Yoda T, McNamara KM, Miki Y, et al. KLF15 in breast cancer: a novel tumor suppressor? Cell Oncol (Dordr). 2015;38:227–235.CrossRef Yoda T, McNamara KM, Miki Y, et al. KLF15 in breast cancer: a novel tumor suppressor? Cell Oncol (Dordr). 2015;38:227–235.CrossRef
22.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
23.
go back to reference 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. 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.
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
26.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
27.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
29.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
30.
go back to reference 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. 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.
31.
go back to reference 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.PubMed 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.PubMed
32.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
34.
go back to reference Wang J, Wang B, Chen LQ, et al. miR-10b promotes invasion by targeting KLF4 in osteosarcoma cells. Biomed Pharmacother. 2016;84:947–953.CrossRefPubMed Wang J, Wang B, Chen LQ, et al. miR-10b promotes invasion by targeting KLF4 in osteosarcoma cells. Biomed Pharmacother. 2016;84:947–953.CrossRefPubMed
35.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
36.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
37.
go back to reference 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.PubMed 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.PubMed
39.
go back to reference Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14:159–169.CrossRefPubMed Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14:159–169.CrossRefPubMed
40.
go back to reference Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–166.CrossRefPubMed Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–166.CrossRefPubMed
Metadata
Title
KLF15 Inhibits Cell Proliferation in Gastric Cancer Cells via Up-Regulating CDKN1A/p21 and CDKN1C/p57 Expression
Authors
Chongqi Sun
Pei Ma
Yanfen Wang
Weitao Liu
Qinnan Chen
Yutian Pan
Chenhui Zhao
Yingchen Qian
Jie Liu
Wei Li
Yongqian Shu
Publication date
01-06-2017
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 6/2017
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-017-4558-2

Other articles of this Issue 6/2017

Digestive Diseases and Sciences 6/2017 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.