Blockage of PTPRJ promotes cell growth and resistance to 5-FU through activation of JAK1/STAT3 in the cervical carcinoma cell line C33A

Yan,Chun-Mei; Zhao,Ying-Ling; Cai,Hong-Yi; Miao,Guo-Ying; Ma,Wen

doi:10.3892/or.2015.3769

Blockage of PTPRJ promotes cell growth and resistance to 5-FU through activation of JAK1/STAT3 in the cervical carcinoma cell line C33A

Authors:
- Chun-Mei Yan
- Ying-Ling Zhao
- Hong-Yi Cai
- Guo-Ying Miao
- Wen Ma
View Affiliations

Affiliations: Lanzhou Jiao Tong University Hospital, Lanzhou 730000, P.R. China, Department of Hematology, Gansu Provincial Hospital, Lanzhou 730000, P.R. China, Department of Radiotherapy Oncology, Gansu Provincial Hospital, Lanzhou 730000, P.R. China
Published online on: January 29, 2015 https://doi.org/10.3892/or.2015.3769
Pages: 1737-1744

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

Gene therapy is a promising therapeutic approach for chemoresistant cervical cancers. Therapeutic interventions targeting the key factors contributing to the initiation and progression of cervical cancer may be a more effective treatment strategy. In the present study, we firstly determined the expression of protein tyrosine phosphatase receptor J (PTPRJ) in 8-paired human cervical tumor and non-tumor tissues. We observed a striking downregulation of PTPRJ in the human cervical tumor tissues. Next, we investigated the roles and the function mechanism of PTPRJ in the human cervical carcinoma cell line C33A by loss- and gain-of-function experiments. Our study indicated that C33A cells with loss of PTPRJ expression showed a significantly increased cell viability, rising growth and migration rate, as well as a G1-S transition. We obtained the opposite results when we overexpressed PTPRJ in C33A cells. Our further study indicated that PTPRJ levels were highly correlated with cell survival when the C33A cells were treated with 5-fluorouracil (5-FU), an important chemotherapeutic agent for cervical cancer. In addition, the signaling pathway screening assay showed an obvious alteration of the Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) pathway. PTPRJ negatively regulated the activation of the JAK1/STAT3 pathway by decreasing the phosphorylation levels of JAK1 and STAT3. In addition, PTPRJ also regulated the expression of the downstream factors of STAT3, such as cyclin D, Bax, VEGF and MMP2. Our results suggest that PTPRJ may be a promising gene therapy target and its therapeutic potential can be fulfilled when used alone, or in combination with other anticancer agents.

View Figures

View References

1	Parkin DM and Bray F: Chapter 2: The burden of HPV-related cancers. Vaccine. 24(Suppl 3): S3/11–25. 2006. View Article : Google Scholar
2	Ronco G, Dillner J, Elfström KM, et al: Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 383:524–532. 2013. View Article : Google Scholar : PubMed/NCBI
3	Pinion SB, Kennedy JH, Miller RW and MacLean AB: Oncogene expression in cervical intraepithelial neoplasia and invasive cancer of cervix. Lancet. 337:819–820. 1991. View Article : Google Scholar : PubMed/NCBI
4	Jeon YH, Lee HW, Lee YL, et al: Combined E7-dendritic cell-based immunotherapy and human sodium/iodide symporter radioiodine gene therapy with monitoring of antitumor effects by bioluminescent imaging in a mouse model of uterine cervical cancer. Cancer Biother Radiopharm. 26:671–679. 2011. View Article : Google Scholar : PubMed/NCBI
5	Koch M and Wiese M: Gene expression signatures of angiocidin and darapladib treatment connect to therapy options in cervical cancer. J Cancer Res Clin Oncol. 139:259–267. 2013. View Article : Google Scholar
6	Zheng Y, Chen H, Zeng X, et al: Surface modification of TPGS-b-(PCL-ran-PGA) nanoparticles with polyethyleneimine as a co-delivery system of TRAIL and endostatin for cervical cancer gene therapy. Nanoscale Res Lett. 8:1612013. View Article : Google Scholar : PubMed/NCBI
7	Keane MM, Lowrey GA, Ettenberg SA, Dayton MA and Lipkowitz S: The protein tyrosine phosphatase DEP-1 is induced during differentiation and inhibits growth of breast cancer cells. Cancer Res. 56:4236–4243. 1996.PubMed/NCBI
8	Iuliano R, Trapasso F, Le Pera I, et al: An adenovirus carrying the rat protein tyrosine phosphatase eta suppresses the growth of human thyroid carcinoma cell lines in vitro and in vivo. Cancer Res. 63:882–886. 2003.PubMed/NCBI
9	Massa A, Barbieri F, Aiello C, et al: The expression of the phosphotyrosine phosphatase DEP-1/PTPeta dictates the responsivity of glioma cells to somatostatin inhibition of cell proliferation. J Biol Chem. 279:29004–29012. 2004. View Article : Google Scholar : PubMed/NCBI
10	Trapasso F, Iuliano R, Boccia A, et al: Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27(Kip1). Mol Cell Biol. 20:9236–9246. 2000. View Article : Google Scholar : PubMed/NCBI
11	Godfrey R, Arora D, Bauer R, et al: Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ. Blood. 119:4499–4511. 2012. View Article : Google Scholar : PubMed/NCBI
12	Kovalenko M, Denner K, Sandstrom J, et al: Site-selective dephosphorylation of the platelet-derived growth factor beta-receptor by the receptor-like protein-tyrosine phosphatase DEP-1. J Biol Chem. 275:16219–16226. 2000. View Article : Google Scholar : PubMed/NCBI
13	Lampugnani MG, Orsenigo F, Gagliani MC, Tacchetti C and Dejana E: Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments. J Cell Biol. 174:593–604. 2006. View Article : Google Scholar : PubMed/NCBI
14	Palka HL, Park M and Tonks NK: Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase DEP-1. J Biol Chem. 278:5728–5735. 2003. View Article : Google Scholar
15	Sacco F, Tinti M, Palma A, et al: Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases. J Biol Chem. 284:22048–22058. 2009. View Article : Google Scholar : PubMed/NCBI
16	Ortuso F, Paduano F, Carotenuto A, et al: Discovery of PTPRJ agonist peptides that effectively inhibit in vitro cancer cell proliferation and tube formation. ACS Chem Biol. 8:1497–1506. 2013. View Article : Google Scholar : PubMed/NCBI
17	Longley DB, Harkin DP and Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 3:330–338. 2003. View Article : Google Scholar : PubMed/NCBI
18	Paduano F, Ortuso F, Campiglia P, et al: Isolation and functional characterization of peptide agonists of PTPRJ, a tyrosine phosphatase receptor endowed with tumor suppressor activity. ACS Chem Biol. 7:1666–1676. 2012. View Article : Google Scholar : PubMed/NCBI
19	Omerovic J, Clague MJ and Prior IA: Phosphatome profiling reveals PTPN2, PTPRJ and PTEN as potent negative regulators of PKB/Akt activation in Ras-mutated cancer cells. Biochem J. 426:65–72. 2010. View Article : Google Scholar
20	Aggarwal BB, Kunnumakkara AB, Harikumar KB, et al: Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann NY Acad Sci. 1171:59–76. 2009. View Article : Google Scholar : PubMed/NCBI
21	Aggarwal BB, Sethi G, Ahn KS, et al: Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann NY Acad Sci. 1091:151–169. 2006. View Article : Google Scholar
22	Ihle JN: Cytokine receptor signalling. Nature. 377:591–594. 1995. View Article : Google Scholar : PubMed/NCBI
23	Sobti RC, Singh N, Hussain S, Suri V, Bharti AC and Das BC: Overexpression of STAT3 in HPV-mediated cervical cancer in a north Indian population. Mol Cell Biochem. 330:193–199. 2009. View Article : Google Scholar : PubMed/NCBI
24	Choi CH, Song SY, Kang H, et al: Prognostic significance of p-STAT3 in patients with bulky cervical carcinoma undergoing neoadjuvant chemotherapy. J Obstet Gynaecol Res. 36:304–310. 2010. View Article : Google Scholar : PubMed/NCBI
25	Smart CE, Askarian Amiri ME, Wronski A, et al: Expression and function of the protein tyrosine phosphatase receptor J (PTPRJ) in normal mammary epithelial cells and breast tumors. PLoS One. 7:e407422012. View Article : Google Scholar : PubMed/NCBI
26	Toland AE, Rozek LS, Presswala S, Rennert G and Gruber SB: PTPRJ haplotypes and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 17:2782–2785. 2008. View Article : Google Scholar : PubMed/NCBI
27	Mita Y, Yasuda Y, Sakai A, et al: Missense polymorphisms of PTPRJ and PTPN13 genes affect susceptibility to a variety of human cancers. J Cancer Res Clin Oncol. 136:249–259. 2010. View Article : Google Scholar
28	Lv XG, Ji MY, Dong WG, et al: EBP50 gene transfection promotes 5-fluorouracil-induced apoptosis in gastric cancer cells through Bax- and Bcl-2-triggered mitochondrial pathways. Mol Med Rep. 5:1220–1226. 2012.PubMed/NCBI
29	Taiyoh H, Kubota T, Fujiwara H, et al: NK4 gene expression enhances 5-fluorouracil-induced apoptosis of murine colon cancer cells. Anticancer Res. 31:2217–2224. 2011.PubMed/NCBI
30	Tian F, Fan T, Jiang Y, Zhang X and Wang X: A small interfering RNA targeting NF-kappaB p65 alone or combined with 5-FU inhibits growth of esophageal squamous cell carcinoma in nude mice. Pathol Res Pract. 208:32–38. 2012. View Article : Google Scholar
31	Xie Q, Liang BL, Wu YH, et al: Synergistic anticancer effect of rAd/P53 combined with 5-fluorouracil or iodized oil in the early therapeutic response of human colon cancer in vivo. Gene. 499:303–308. 2012. View Article : Google Scholar : PubMed/NCBI
32	McCubrey JA, Steelman LS, Abrams SL, et al: Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 46:249–279. 2006. View Article : Google Scholar : PubMed/NCBI
33	Zhang LH, Yin AA, Cheng JX, et al: TRIM24 promotes glioma progression and enhances chemoresistance through activation of the PI3K/Akt signaling pathway. Oncogene. Jan 27–2014.(Epub ahead of prin). View Article : Google Scholar
34	Kamran MZ, Patil P and Gude RP: Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int. 2013:4218212013. View Article : Google Scholar : PubMed/NCBI
35	Gong J, Muñoz AR, Chan D, Ghosh R and Kumar AP: STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth. Oncotarget. 5:2529–2541. 2014.PubMed/NCBI