PTBP1 knockdown in renal cell carcinoma inhibits cell migration, invasion and angiogenesis in vitro and metastasis in vivo via the hypoxia inducible factor-1α pathway

Shan,Haixia; Hou,Pingfu; Zhang,Meng; Li,Liantao; Pan,Yu; Chen,Fang; Jiang,Tao; Bai,Jin; Zheng,Junnian

doi:10.3892/ijo.2018.4296

PTBP1 knockdown in renal cell carcinoma inhibits cell migration, invasion and angiogenesis in vitro and metastasis in vivo via the hypoxia inducible factor-1α pathway

Authors:
- Haixia Shan
- Pingfu Hou
- Meng Zhang
- Liantao Li
- Yu Pan
- Fang Chen
- Tao Jiang
- Jin Bai
- Junnian Zheng
View Affiliations

Affiliations: The Fourth Clinical College of Nanjing Medical University, Nanjing, Jiangsu 211100, P.R. China, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China, Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China
Published online on: March 2, 2018 https://doi.org/10.3892/ijo.2018.4296
Pages: 1613-1622

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

Polypyrimidine tract-binding protein 1 (PTBP1), a heterogeneous nuclear ribonucleoprotein, is a multi-functional RNA-binding protein. PTBP1 participates in a number of biological processes, including maintaining cell structure and motility, immunity, protein metabolism and the cell cycle. The present study aimed to investigate the association between PTBP1 expression and the prognosis and clinicopathological characteristics of patients with renal cell cancer (RCC). The potential mechanism of action of PTBP1 in the metastasis of RCC was also investigated. The results demonstrated that PTBP1 was overexpressed in RCC tissues compared with normal renal tissues. Furthermore, PTBP1 expression was negatively associated with patient prognosis and positively associated with tumor size, pathological tumor (pT) and pathological metastasis (pM) status and tumor lymph node metastasis (TNM) stage. PTBP1 knockdown in vitro inhibited RCC cell migration, invasion, proliferation and angiogenesis, and it was demonstrated that PTBP1 affected RCC cells primarily via the hypoxia inducible factor-1α pathway. Furthermore, PTBP1 knockdown decreased RCC lung metastasis in vivo. The present study demonstrated that PTBP1 knockdown suppresses tumor progression and metastasis, indicating that PTBP1 is an important prognostic factor in RCC and that it may be developed as a novel method of treating patients with RCC.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
3	Irani J: Sunitinib versus interferon-alpha in metastatic renal-cell carcinoma. Prog Urol. 17:9962007.In French. View Article : Google Scholar
4	Siegel R, Desantis C and Jemal A: Colorectal cancer statistics, 2014. CA Cancer J Clin. 64:104–117. 2014. View Article : Google Scholar : PubMed/NCBI
5	Motzer RJ, Bander NH and Nanus DM: Renal-cell carcinoma. N Engl J Med. 335:865–875. 1996. View Article : Google Scholar : PubMed/NCBI
6	Lam JS, Leppert JT, Belldegrun AS and Figlin RA: Novel approaches in the therapy of metastatic renal cell carcinoma. World J Urol. 23:202–212. 2005. View Article : Google Scholar : PubMed/NCBI
7	Gupta K, Miller JD, Li JZ, Russell MW and Charbonneau C: Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): A literature review. Cancer Treat Rev. 34:193–205. 2008. View Article : Google Scholar : PubMed/NCBI
8	Patton JG, Mayer SA, Tempst P and Nadal-Ginard B: Characterization and molecular cloning of polypyrimidine tract-binding protein: A component of a complex necessary for pre-mRNA splicing. Genes Dev. 5:1237–1251. 1991. View Article : Google Scholar : PubMed/NCBI
9	Romanelli MG, Diani E and Lievens PM: New insights into functional roles of the polypyrimidine tract-binding protein. Int J Mol Sci. 14:22906–22932. 2013. View Article : Google Scholar : PubMed/NCBI
10	Xue Y, Zhou Y, Wu T, Zhu T, Ji X, Kwon YS, Zhang C, Yeo G, Black DL, Sun H, et al: Genome-wide analysis of PTB-RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping. Mol Cell. 36:996–1006. 2009. View Article : Google Scholar
11	Llorian M, Schwartz S, Clark TA, Hollander D, Tan LY, Spellman R, Gordon A, Schweitzer AC, de la Grange P, Ast G, et al: Position-dependent alternative splicing activity revealed by global profiling of alternative splicing events regulated by PTB. Nat Struct Mol Biol. 17:1114–1123. 2010. View Article : Google Scholar : PubMed/NCBI
12	McCutcheon IE, Hentschel SJ, Fuller GN, Jin W and Cote GJ: Expression of the splicing regulator polypyrimidine tract-binding protein in normal and neoplastic brain. Neuro Oncol. 6:9–14. 2004. View Article : Google Scholar : PubMed/NCBI
13	Cheung HC, Hai T, Zhu W, Baggerly KA, Tsavachidis S, Krahe R and Cote GJ: Splicing factors PTBP1 and PTBP2 promote proliferation and migration of glioma cell lines. Brain. 132:2277–2288. 2009. View Article : Google Scholar : PubMed/NCBI
14	Takahashi H, Nishimura J, Kagawa Y, Kano Y, Takahashi Y, Wu X, Hiraki M, Hamabe A, Konno M, Haraguchi N, et al: Significance of polypyrimidine tract-binding protein 1 expression in colorectal cancer. Mol Cancer Ther. 14:1705–1716. 2015. View Article : Google Scholar : PubMed/NCBI
15	He X, Pool M, Darcy KM, Lim SB, Auersperg N, Coon JS and Beck WT: Knockdown of polypyrimidine tract-binding protein suppresses ovarian tumor cell growth and invasiveness in vitro. Oncogene. 26:4961–4968. 2007. View Article : Google Scholar : PubMed/NCBI
16	Sugiyama T, Taniguchi K, Matsuhashi N, Tajirika T, Futamura M, Takai T, Akao Y and Yoshida K: MiR-133b inhibits growth of human gastric cancer cells by silencing pyruvate kinase muscle-splicer polypyrimidine tract-binding protein 1. Cancer Sci. 107:1767–1775. 2016. View Article : Google Scholar : PubMed/NCBI
17	He X, Arslan AD, Ho TT, Yuan C, Stampfer MR and Beck WT: Involvement of polypyrimidine tract-binding protein (PTBP1) in maintaining breast cancer cell growth and malignant properties. Oncogenesis. 3:e842014. View Article : Google Scholar : PubMed/NCBI
18	Cheung HC, Corley LJ, Fuller GN, McCutcheon IE and Cote GJ: Polypyrimidine tract binding protein and Notch1 are independently re-expressed in glioma. Mod Pathol. 19:1034–1041. 2006. View Article : Google Scholar : PubMed/NCBI
19	Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL and Cantley LC: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 452:230–233. 2008. View Article : Google Scholar : PubMed/NCBI
20	David CJ, Chen M, Assanah M, Canoll P and Manley JL: HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 463:364–368. 2010. View Article : Google Scholar :
21	Taniguchi K, Sugito N, Kumazaki M, Shinohara H, Yamada N, Nakagawa Y, Ito Y, Otsuki Y, Uno B, Uchiyama K, et al: MicroRNA-124 inhibits cancer cell growth through PTB1/PKM1/PKM2 feedback cascade in colorectal cancer. Cancer Lett. 363:17–27. 2015. View Article : Google Scholar : PubMed/NCBI
22	Wang MJ and Lin S: A region within the 5′-untranslated region of hypoxia-inducible factor-1alpha mRNA mediates its turnover in lung adenocarcinoma cells. J Biol Chem. 284:36500–36510. 2009. View Article : Google Scholar : PubMed/NCBI
23	Bielli P, Bordi M, Di Biasio V and Sette C: Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5′ splice site selection. Nucleic Acids Res. 42:12070–12081. 2014. View Article : Google Scholar : PubMed/NCBI
24	Yoon J and Herts BR: Staging renal cell carcinoma with helical CT: The revised 1997 AJCC and UICC TNM criteria. Crit Rev Computed Tomogr. 44:229–249. 2003. View Article : Google Scholar
25	Remmele W and Stegner HE: Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 8:138–140. 1987.In German. PubMed/NCBI
26	Li HL, Han L, Chen HR, Meng F, Liu QH, Pan ZQ, Bai J and Zheng JN: PinX1 serves as a potential prognostic indicator for clear cell renal cell carcinoma and inhibits its invasion and metastasis by suppressing MMP-2 via NF-κB-dependent transcription. Oncotarget. 6:21406–21420. 2015.PubMed/NCBI
27	Hou P, Zhao Y, Li Z, Yao R, Ma M, Gao Y, Zhao L, Zhang Y, Huang B and Lu J: LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis. 5:e12872014. View Article : Google Scholar : PubMed/NCBI
28	Thompson Coon J1, Hoyle M, Green C, Liu Z, Welch K, Moxham T and Stein K: Bevacizumab, sorafenib tosylate, sunitinib and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation. Health Technol Assess. 14:1–184. iii–iv. 2010. View Article : Google Scholar
29	Kitamura H, Takahashi A, Takei F, Hotta H, Miyao N, Shindo T, Igarashi M, Tachiki H, Kunishima Y, Muranaka T, et al Sapporo Medical University Urologic Oncology Consortium: Molecular-targeted therapy and surgery may prolong survival of renal cell carcinoma patients with bone metastasis: A multi-institutional retrospective study in Japan. Anticancer Res. 36:5531–5536. 2016. View Article : Google Scholar : PubMed/NCBI
30	Audenet F, Yates DR, Cancel-Tassin G, Cussenot O and Rouprêt M: Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: Genomics towards personalized medicine. BJU Int. 109:1864–1870. 2012. View Article : Google Scholar
31	Hynes RO: Metastatic potential: Generic predisposition of the primary tumor or rare, metastatic variants-or both? Cell. 113:821–823. 2003. View Article : Google Scholar : PubMed/NCBI
32	Valastyan S and Weinberg RA: Tumor metastasis: Molecular insights and evolving paradigms. Cell. 147:275–292. 2011. View Article : Google Scholar : PubMed/NCBI
33	Semenza GL: Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE. 2007:cm82007. View Article : Google Scholar : PubMed/NCBI
34	Ke Q and Costa M: Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 70:1469–1480. 2006. View Article : Google Scholar : PubMed/NCBI
35	Chen F, Fujinaga T, Shoji T, Miyahara R, Bando T, Okubo K, Hirata T and Date H: Pulmonary resection for metastasis from renal cell carcinoma. Interact Cardiovasc Thorac Surg. 7:825–828. 2008. View Article : Google Scholar : PubMed/NCBI
36	Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al TARGET Study Group: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 356:125–134. 2007. View Article : Google Scholar : PubMed/NCBI