KLF5 promotes the tumorigenesis and metastatic potential of thyroid cancer cells through the NF-κB signaling pathway

Ma,Yuehua; Wang,Qingzhu; Liu,Fei; Ma,Xiaojun; Wu,Lina; Guo,Feng; Zhao,Shuiying; Huang,Fengjuan; Qin,Guijun

doi:10.3892/or.2018.6687

KLF5 promotes the tumorigenesis and metastatic potential of thyroid cancer cells through the NF-κB signaling pathway

Authors:
- Yuehua Ma
- Qingzhu Wang
- Fei Liu
- Xiaojun Ma
- Lina Wu
- Feng Guo
- Shuiying Zhao
- Fengjuan Huang
- Guijun Qin
View Affiliations

Affiliations: Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: September 6, 2018 https://doi.org/10.3892/or.2018.6687
Pages: 2608-2618
Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The purpose of the present study was to identify the potential function of Kruppel-like factor 5 (KLF5) in thyroid cancer and investigate the underlying mechanisms. The protein levels of KLF5 in 98 thyroid cancer tissues were analyzed using an immunohistochemistry assay. SW579 cells transfected with small interfering RNA against KLF5 and B-CPAP cells transfected with KLF5 expressing vectors were used for functional studies. Western blot analysis, immunofluorescence and co-immunoprecipitation assays were used to investigate the mechanisms of KLF5. In vivo tumorigenicity was assessed using a subcutaneous xenograft experiment. The results revealed that KLF5 was highly expressed in thyroid cancer tissues and associated with lymph node metastasis. Knockdown of KLF5 in SW579 cells suppressed proliferation, anchorage-independent growth, migration and invasion in vitro, while the overexpression of KLF5 resulted in opposite effects in B-CPAP cells. Mechanistically, it was demonstrated that KLF5 promoted the cytoplasm-nuclear translocation of nuclear factor-κB. Additionally, it was revealed that insufficient F-box/WD repeat-containing protein 7 expression may be responsible for the dysfunction of KLF5 in thyroid cancer. These results revealed that KLF5 promotes the tumorigenesis and metastasis of thyroid cancer cells and may be a potential therapeutic target in patients with thyroid cancer.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F and Negri E: Thyroid cancer mortality and incidence: A global overview. Int J Cancer. 136:2187–2195. 2015. View Article : Google Scholar : PubMed/NCBI
3	Xing M: Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 13:184–199. 2013. View Article : Google Scholar : PubMed/NCBI
4	Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Höppener JW, van Amstel HK, Romeo G, et al: A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 367:375–376. 1994. View Article : Google Scholar : PubMed/NCBI
5	Russo D, Damante G, Puxeddu E, Durante C and Filetti S: Epigenetics of thyroid cancer and novel therapeutic targets. J Mol Endocrinol. 46:R73–R81. 2011. View Article : Google Scholar : PubMed/NCBI
6	Sogawa K, Imataka H, Yamasaki Y, Kusume H, Abe H and Fujii-Kuriyama Y: cDNA cloning and transcriptional properties of a novel GC box-binding protein, BTEB2. Nucleic Acids Res. 21:1527–1532. 1993. View Article : Google Scholar : PubMed/NCBI
7	Dong JT, Boyd JC and Frierson HF Jr: Loss of heterozygosity at 13q14 and 13q21 in high grade, high stage prostate cancer. Prostate. 49:166–171. 2001. View Article : Google Scholar : PubMed/NCBI
8	Chen C, Brabham WW, Stultz BG, Frierson HF Jr, Barrett JC, Sawyers CL, Isaacs JT and Dong JT: Defining a common region of deletion at 13q21 in human cancers. Genes Chromosomes Cancer. 31:333–344. 2001. View Article : Google Scholar : PubMed/NCBI
9	Kojima S, Kobayashi A, Gotoh O, Ohkuma Y, Fujii-Kuriyama Y and Sogawa K: Transcriptional activation domain of human BTEB2, a GC box-binding factor. J Biochem. 121:389–396. 1997. View Article : Google Scholar : PubMed/NCBI
10	Dong JT and Chen C: Essential role of KLF5 transcription factor in cell proliferation and differentiation and its implications for human diseases. Cell Mol Life Sci. 66:2691–2706. 2009. View Article : Google Scholar : PubMed/NCBI
11	Du C, Gao Y, Xu S, Jia J, Huang Z, Fan J, Wang X, He D and Guo P: KLF5 promotes cell migration by up-regulating FYN in bladder cancer cells. FEBS Lett. 590:408–418. 2016. View Article : Google Scholar : PubMed/NCBI
12	Maehara O, Sato F, Natsuizaka M, Asano A, Kubota Y, Itoh J, Tsunematsu S, Terashita K, Tsukuda Y, Nakai M, et al: A pivotal role of Krüppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma. Cancer Biol Ther. 16:1453–1461. 2015. View Article : Google Scholar : PubMed/NCBI
13	Ci X, Xing C, Zhang B, Zhang Z, Ni JJ, Zhou W and Dong JT: KLF5 inhibits angiogenesis in PTEN-deficient prostate cancer by attenuating AKT activation and subsequent HIF1α accumulation. Mol Cancer. 14:912015. View Article : Google Scholar : PubMed/NCBI
14	Saiselet M, Floor S, Tarabichi M, Dom G, Hébrant A, van Staveren WC and Maenhaut C: Thyroid cancer cell lines: An overview. Front Endocrinol (Lausanne). 3:1332012.PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Chen HL, Chong IW, Lee YC, Tsai JR, Yuan SS, Wang HM, Liu WL and Liu PL: Krüppel-like factor 5 mediates proinflammatory cytokine expression in lipopolysaccharide-induced acute lung injury through upregulation of nuclear factor-κB phosphorylation in vitro and in vivo. Mediators Inflamm. 2014:2819842014. View Article : Google Scholar : PubMed/NCBI
17	Jing H and Lee S: NF-κB in cellular senescence and cancer treatment. Mol Cells. 37:189–195. 2014. View Article : Google Scholar : PubMed/NCBI
18	Yang Y, Goldstein BG, Nakagawa H and Katz JP: Krüppel-like factor 5 activates MEK/ERK signaling via EGFR in primary squamous epithelial cells. FASEB J. 21:543–550. 2007. View Article : Google Scholar : PubMed/NCBI
19	Zhao D, Zheng HQ, Zhou Z and Chen C: The Fbw7 tumor suppressor targets KLF5 for ubiquitin-mediated degradation and suppresses breast cell proliferation. Cancer Res. 70:4728–4738. 2010. View Article : Google Scholar : PubMed/NCBI
20	Grebe SK and Hay ID: Thyroid cancer nodal metastases: Biologic significance and therapeutic considerations. Surg Oncol Clin N Am. 5:43–63. 1996. View Article : Google Scholar : PubMed/NCBI
21	Fu RJ, He W, Wang XB, Li L, Zhao HB, Liu XY, Pang Z, Chen GQ, Huang L and Zhao KW: DNMT1-maintained hypermethylation of Krüppel-like factor 5 involves in the progression of clear cell renal cell carcinoma. Cell Death Dis. 8:e29522017. View Article : Google Scholar : PubMed/NCBI
22	Oishi Y, Manabe I, Tobe K, Tsushima K, Shindo T, Fujiu K, Nishimura G, Maemura K, Yamauchi T, Kubota N, et al: Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. Cell Metab. 1:27–39. 2005. View Article : Google Scholar : PubMed/NCBI
23	Jia L, Zhou Z, Liang H, Wu J, Shi P, Li F, Wang Z, Wang C, Chen W, Zhang H, et al: KLF5 promotes breast cancer proliferation, migration and invasion in part by upregulating the transcription of TNFAIP2. Oncogene. 35:2040–2051. 2016. View Article : Google Scholar : PubMed/NCBI
24	Parisi S, Passaro F, Aloia L, Manabe I, Nagai R, Pastore L and Russo T: Klf5 is involved in self-renewal of mouse embryonic stem cells. J Cell Sci. 121:2629–2634. 2008. View Article : Google Scholar : PubMed/NCBI
25	Qiu W, Xia X, Qiu Z, Guo M and Yang Z: RasGRP3 controls cell proliferation and migration in papillary thyroid cancer by regulating the Akt-MDM2 pathway. Gene. 633:35–41. 2017. View Article : Google Scholar : PubMed/NCBI
26	Guan H, Guo Z, Liang W, Li H, Wei G, Xu L, Xiao H and Li Y: Trop2 enhances invasion of thyroid cancer by inducing MMP2 through ERK and JNK pathways. BMC Cancer. 17:4862017. View Article : Google Scholar : PubMed/NCBI
27	Xiang S, Xiang T, Xiao Q, Li Y, Shao B and Luo T: Zinc-finger protein 545 is inactivated due to promoter methylation and functions as a tumor suppressor through the Wnt/β-catenin, PI3K/AKT and MAPK/ERK signaling pathways in colorectal cancer. Int J Oncol. 51:801–811. 2017. View Article : Google Scholar : PubMed/NCBI
28	Lv N, Shan Z, Gao Y, Guan H, Fan C, Wang H and Teng W: Twist1 regulates the epithelial-mesenchymal transition via the NF-κB pathway in papillary thyroid carcinoma. Endocrine. 51:469–477. 2016. View Article : Google Scholar : PubMed/NCBI
29	Chen C, Sun X, Ran Q, Wilkinson KD, Murphy TJ, Simons JW and Dong JT: Ubiquitin-proteasome degradation of KLF5 transcription factor in cancer and untransformed epithelial cells. Oncogene. 24:3319–3327. 2005. View Article : Google Scholar : PubMed/NCBI
30	Zhi X, Zhao D, Zhou Z, Liu R and Chen C: YAP promotes breast cell proliferation and survival partially through stabilizing the KLF5 transcription factor. Am J Pathol. 180:2452–2461. 2012. View Article : Google Scholar : PubMed/NCBI
31	Liu N, Li H, Li S, Shen M, Xiao N, Chen Y, Wang Y, Wang W, Wang R, Wang Q, et al: The Fbw7/human CDC4 tumor suppressor targets proproliferative factor KLF5 for ubiquitination and degradation through multiple phosphodegron motifs. J Biol Chem. 285:18858–18867. 2010. View Article : Google Scholar : PubMed/NCBI