FUBP1 mediates the growth and metastasis through TGFβ/Smad signaling in pancreatic adenocarcinoma

Zhang,Yue; Chen,Jinlian; Zhou,Nvshi; Lu,Yun; Lu,Jingwen; Xing,Xin; Chen,Hua; Zhang,Xingxing

doi:10.3892/ijmm.2021.4899

FUBP1 mediates the growth and metastasis through TGFβ/Smad signaling in pancreatic adenocarcinoma

Authors:
- Yue Zhang
- Jinlian Chen
- Nvshi Zhou
- Yun Lu
- Jingwen Lu
- Xin Xing
- Hua Chen
- Xingxing Zhang
View Affiliations

Affiliations: Department of Gastroenterology, Anhui University of Science and Technology Affiliated Fengxian Hospital, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai Fengxian District Central Hospital, Shanghai 201499, P.R. China, School of Medicine, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China, Department of Pathology, Anhui University of Science and Technology Affiliated Fengxian Hospital, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai Fengxian District Central Hospital, Shanghai 201499, P.R. China, Central Laboratory, Anhui University of Science and Technology Affiliated Fengxian Hospital, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai Fengxian District Central Hospital, Shanghai 201499, P.R. China
Published online on: February 26, 2021 https://doi.org/10.3892/ijmm.2021.4899
Article Number: 66
Copyright: © Zhang 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

Recent studies have reported that the expression levels of far upstream element‑binding protein 1 (FUBP1) were upregulated and served a crucial role in several types of cancer. However, the underlying molecular mechanisms and clinical significance of FUBP1 in pancreatic adenocarcinoma (PAAD) remain unclear. The present study aimed to determine the expression levels of FUBP1 in patients with PAAD and subsequently investigated the biological functions and mechanisms of FUBP1 using in vitro assays. FUBP1 expression levels and survival outcomes in patients with PAAD were analyzed using The Cancer Genome Atlas and starBase databases. Reverse transcription‑quantitative PCR was used to analyze the mRNA expression levels of FUBP1 in PAAD and adjacent normal tissues. In addition, the expression of FUBP1 was knocked down with small interfering RNA and overexpressed using FUBP1‑overexpressed plasmids, and the effects on biological functions, including cell proliferation, migration and invasion, were investigated. Western blotting and immunofluorescence assays were used to determine the role of FUBP1 in epithelial‑mesenchymal transition (EMT). The results of the present study revealed that the expression levels of FUBP1 were upregulated in PAAD tissues compared with adjacent normal tissues and the upregulated expression was significantly associated with poor survival. The knockdown of FUBP1 expression significantly inhibited the proliferative, migratory and invasive abilities of the PAAD PaTu8988 cell line, while the overexpression of FUBP1 promoted cell proliferation, migration and invasion in the PAAD SW1990 cell line. Furthermore, the knockdown of FUBP1 downregulated the expression levels of EMT‑related markers, including N‑cadherin, β‑catenin and vimentin, while the expression levels of E‑cadherin were upregulated. The knockdown of FUBP1 was also revealed to regulate the TGFβ/Smad signaling cascade by downregulating phosphorylated‑Smad2/3 and TGFβ1 expression levels. Conversely, the overexpression of FUBP1 reversed these effects. In conclusion, the findings of the present study indicated that FUBP1 may be a potential oncogene that mediates the EMT of PAAD via TGFβ/Smad signaling. These data suggested that FUBP1 may represent a potential biomarker for the diagnosis of PAAD or a target for the treatment of patients with PAAD.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
2	Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, Jemal A, Kramer JL and Siegel RL: Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 69:363–385. 2019. View Article : Google Scholar : PubMed/NCBI
3	Stornello C, Archibugi L, Stigliano S, Vanella G, Graglia B, Capalbo C, Nigri G and Capurso G: Diagnostic delay does not influence survival of pancreatic cancer patients. United European Gastroenterol J. 8:81–90. 2020. View Article : Google Scholar : PubMed/NCBI
4	Zhang J and Chen QM: Far upstream element binding protein 1: A commander of transcription, translation and beyond. Oncogene. 32:2907–2916. 2013. View Article : Google Scholar
5	Debaize L and Troadec MB: The master regulator FUBP1: Its emerging role in normal cell function and malignant development. Cell Mol Life Sci. 76:259–281. 2019. View Article : Google Scholar
6	Frost JR, Mendez M, Soriano AM, Crisostomo L, Olanubi O, Radko S and Pelka P: Adenovirus 5 E1A-Mediated Suppression of p53 via FUBP1. J Virol. 92:e00439–18. 2018. View Article : Google Scholar : PubMed/NCBI
7	Rabenhorst U, Thalheimer FB, Gerlach K, Kijonka M, Böhm S, Krause DS, Vauti F, Arnold HH, Schroeder T, Schnütgen F, et al: Single-stranded DNA-binding transcriptional regulator FUBP1 is essential for fetal and adult hematopoietic stem cell self-renewal. Cell Rep. 11:1847–1855. 2015. View Article : Google Scholar : PubMed/NCBI
8	Fu PY, Hu B, Ma XL, Tang WG, Yang ZF, Sun HX, Yu MC, Huang A, Hu JW, Zhou CH, et al: Far upstream element-binding protein 1 facilitates hepatocellular carcinoma invasion and metastasis. Carcinogenesis. 41:950–960. 2020. View Article : Google Scholar
9	Baumgarten P, Harter PN, Tonjes M, Capper D, Blank AE, Sahm F, von Deimling A, Kolluru V, Schwamb B, Rabenhorst U, et al: Loss of FUBP1 expression in gliomas predicts FUBP1 mutation and is associated with oligodendroglial differentiation, IDH1 mutation and 1p/19q loss of heterozygosity. Neuropathol Appl Neurobiol. 40:205–216. 2014. View Article : Google Scholar
10	Jiang P, Huang M, Qi W, Wang F, Yang T, Gao T, Luo C, Deng J, Yang Z, Zhou T, et al: FUBP1 promotes neuroblastoma proliferation via enhancing glycolysis-a new possible marker of malignancy for neuroblastoma. J Exp Clin Cancer Res. 38:4002019. View Article : Google Scholar : PubMed/NCBI
11	Duan J, Bao X, Ma X, Zhang Y, Ni D, Wang H, Zhang F, Du Q, Fan Y, Chen J, et al: Upregulation of far upstream element-binding protein 1 (FUBP1) promotes tumor proliferation and tumorigenesis of clear cell renal cell carcinoma. PLoS One. 12:e01698522017. View Article : Google Scholar : PubMed/NCBI
12	Muller B, Bovet M, Yin Y, Stichel D, Malz M, González-Vallinas M, Middleton A, Ehemann V, Schmitt J, Muley T, et al: Concomitant expression of far upstream element (FUSE) binding protein (FBP) interacting repressor (FIR) and its splice variants induce migration and invasion of non-small cell lung cancer (NSCLC) cells. J Pathol. 237:390–401. 2015. View Article : Google Scholar : PubMed/NCBI
13	Chen Y, Liu J, Geng N and Feng C: Upregulation of far upstream element-binding protein 1 (FUBP1) promotes tumor proliferation and unfavorable prognosis in tongue squamous cell carcinoma. Int J Biol Markers. 35:56–65. 2020. View Article : Google Scholar : PubMed/NCBI
14	Yang L, Zhu JY, Zhang JG, Bao BJ, Guan CQ, Yang XJ, Liu YH, Huang YJ, Ni RZ and Ji LL: Far upstream element-binding protein 1 (FUBP1) is a potential c-Myc regulator in esophageal squamous cell carcinoma (ESCC) and its expression promotes ESCC progression. Tumour Biol. 37:4115–4126. 2016. View Article : Google Scholar
15	Venturutti L, Cordo Russo RI, Rivas MA, Mercogliano MF, Izzo F, Oakley RH, Pereyra MG, De Martino M, Proietti CJ, Yankilevich P, et al: MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1. Oncogene. 35:6189–6202. 2016. View Article : Google Scholar : PubMed/NCBI
16	Zhang F, Tian Q and Wang Y: Far upstream element-binding protein 1 (FUBP1) is overexpressed in human gastric cancer tissue compared to non-cancerous tissue. Onkologie. 36:650–655. 2013. View Article : Google Scholar : PubMed/NCBI
17	Jia MY and Wang YJ: Far upstream element-binding protein 1 (FUBP1) expression differs between human colorectal cancer and non-cancerous tissue. Neoplasma. 61:533–540. 2014. View Article : Google Scholar
18	Fan P, Ma J and Jin X: Far upstream element-binding protein 1 is up-regulated in pancreatic cancer and modulates immune response by increasing programmed death ligand 1. Biochem Biophys Res Commun. 505:830–836. 2018. View Article : Google Scholar : PubMed/NCBI
19	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
20	Goldman MJ, Craft B, Hastie M, Repečka K, McDade F, Kamath A, Banerjee A, Luo Y, Rogers D, Brooks AN, et al: Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 38:675–678. 2020. View Article : Google Scholar : PubMed/NCBI
21	Li JH, Liu S, Zhou H, Qu LH and Yang JH: StarBase v2.0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 42:D92–97. 2014. View Article : Google Scholar
22	van Staalduinen J, Baker D, Ten Dijke P and van Dam H: Epithelial-mesenchymal-transition-inducing transcription factors: New targets for tackling chemoresistance in cancer? Oncogene. 37:6195–6211. 2018. View Article : Google Scholar : PubMed/NCBI
23	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
24	Zhang X, Feng W, Zhang J, Ge L, Zhang Y, Jiang X, Peng W, Wang D, Gong A and Xu M: Long noncoding RNA PVT1 promotes epithelialmesenchymal transition via the TGFβ/Smad pathway in pancreatic cancer cells. Oncol Rep. 40:1093–1102. 2018.PubMed/NCBI
25	Zhao L, Liu S, Che X, Hou K, Ma Y, Li C, Wen T, Fan Y, Hu X, Liu Y and Qu X: Bufalin inhibits TGF-β-induced epithelial-to-mesenchymal transition and migration in human lung cancer A549 cells by downregulating TGF-β receptors. Int J Mol Med. 36:645–652. 2015. View Article : Google Scholar : PubMed/NCBI
26	Park JH, Yoon J, Lee KY and Park B: Effects of geniposide on hepatocytes undergoing epithelial-mesenchymal transition in hepatic fibrosis by targeting TGFβ/Smad and ERK-MAPK signaling pathways. Biochimie. 113:26–34. 2015. View Article : Google Scholar : PubMed/NCBI
27	Valcourt U, Kowanetz M, Niimi H, Heldin CH and Moustakas A: TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 16:1987–2002. 2005. View Article : Google Scholar : PubMed/NCBI