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Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation

  • Authors:
    • Xijuan Chen
    • Qinchao Hu
    • Tong Wu
    • Chunyang Wang
    • Juan Xia
    • Linglan Yang
    • Bin Cheng
    • Xiaobing Chen
  • View Affiliations / Copyright

    Affiliations: Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510060, P.R. China
    Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 733-742
    |
    Published online on: January 3, 2018
       https://doi.org/10.3892/ijo.2018.4235
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Abstract

The majority of cases of oral squamous cell carcinoma (OSCC) develop from oral potentially malignant disorders, which have been confirmed to be involved in chronic oxidative stimulation. However, no effective treatment approaches have been used to prevent the development of dysplasia into cancerous lesions thus far. In the present study, a well-established OSCC model was used to detect proteomics profiles at different stages during oral malignant transformation. Of the 15 proteins that were found to be upregulated in both the dysplasia and carcinoma stages, the oxidative stress-associated proteins, thioredoxin-1 (Trx-1), glutaredoxin-1 and peroxiredoxin-2 were note as the proteins with significant changes in expression Trx-1 was identified to be the most significantly upregulated protein in the precancerous stage. Validation experiments confirmed that Trx-1 was overexpressed both in dysplasia and cancerous tissue samples, and the inhibition of Trx-1 was able to promote the apoptosis of OSCC cells under hypoxic conditions. Furthermore, the experimental application of a Trx-1-specific inhibitory agent in an animal model led to a lower cancerization rate and a delay in tumor formation. The possible mechanisms were associated with the increased apoptosis via a reactive oxygen species (ROS)-dependent pathway. Taken together, our findings indicate that Trx-1 may be an important target for delaying oral malignant transformation, which provides a novel therapeutic strategy for the prevention and treatment of OSCC.
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1 

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Arduino PG, Bagan J, El-Naggar AK and Carrozzo M: Urban legends series: Oral leukoplakia. Oral Dis. 19:642–659. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Choudhari SK, Chaudhary M, Gadbail AR, Sharma A and Tekade S: Oxidative and antioxidative mechanisms in oral cancer and precancer: A review. Oral Oncol. 50:10–18. 2014. View Article : Google Scholar

5 

Zhang X, Han S, Han HY, Ryu MH, Kim KY, Choi EJ, Cha IH and Kim J: Risk prediction for malignant conversion of oral epithelial dysplasia by hypoxia related protein expression. Pathology. 45:478–483. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Dionne KR, Warnakulasuriya S, Zain RB and Cheong SC: Potentially malignant disorders of the oral cavity: Current practice and future directions in the clinic and laboratory. Int J Cancer. 136:503–515. 2015.

7 

Liu F, Zhang Y, Men T, Jiang X, Yang C, Li H, Wei X, Yan D, Feng G, Yang J, et al: Quantitative proteomic analysis of gastric cancer tissue reveals novel proteins in platelet-derived growth factor b signaling pathway. Oncotarget. 8:22059–22075. 2017.PubMed/NCBI

8 

Wang Z, Jiang L, Huang C, Li Z, Chen L, Gou L, Chen P, Tong A, Tang M, Gao F, et al: Comparative proteomics approach to screening of potential diagnostic and therapeutic targets for oral squamous cell carcinoma. Mol Cell Proteomics. 7:1639–1650. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Qing S, Tulake W, Ru M, Li X, Yuemaier R, Lidifu D, Rouzibilali A, Hasimu A, Yang Y, Rouziahong R, et al: Proteomic identification of potential biomarkers for cervical squamous cell carcinoma and human papillomavirus infection. Tumour Biol. 39:1010428317697547. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Dey KK, Pal I, Bharti R, Dey G, Kumar BN, Rajput S, Parekh A, Parida S, Halder P, Kulavi I, et al: Identification of RAB2A and PRDX1 as the potential biomarkers for oral squamous cell carcinoma using mass spectrometry-based comparative proteomic approach. Tumour Biol. 36:9829–9837. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Hung KF, Liu CJ, Chiu PC, Lin JS, Chang KW, Shih WY, Kao SY and Tu HF: MicroRNA-31 upregulation predicts increased risk of progression of oral potentially malignant disorder. Oral Oncol. 53:42–47. 2016. View Article : Google Scholar

12 

Kanojia D and Vaidya MM: 4-nitroquinoline-1-oxide induced experimental oral carcinogenesis. Oral Oncol. 42:655–667. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Wu T, Hong Y, Jia L, Wu J, Xia J, Wang J, Hu Q and Cheng B: Modulation of IL-1β reprogrammes the tumor microenvironment to interrupt oral carcinogenesis. Sci Rep. 6:202082016. View Article : Google Scholar

14 

Lan A, Li W, Liu Y, Xiong Z, Zhang X, Zhou S, Palko O, Chen H, Kapita M, Prigge JR, et al: Chemoprevention of oxidative stress-associated oral carcinogenesis by sulforaphane depends on NRF2 and the isothiocyanate moiety. Oncotarget. 7:53502–53514. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Li GZ, Liang HF, Liao B, Zhang L, Ni YA, Zhou HH, Zhang EL, Zhang BX and Chen XP: PX-12 inhibits the growth of hepatocelluar carcinoma by inducing S-phase arrest, ROS-dependent apoptosis and enhances 5-FU cytotoxicity. Am J Transl Res. 7:1528–1540. 2015.PubMed/NCBI

16 

Hong Y, Yang L, Li C, Xia H, Rhodus NL and Cheng B: Frequent mutation of p16(CDKN2A) exon 1 during rat tongue carcinogenesis induced by 4-nitroquinoline-1-oxide. Mol Carcinog. 46:85–90. 2007. View Article : Google Scholar

17 

Jiang X, Wang J, Chen X, Hong Y, Wu T, Chen X, Xia J and Cheng B: Elevated autocrine chemokine ligand 18 expression promotes oral cancer cell growth and invasion via Akt activation. Oncotarget. 7:16262–16272. 2016.PubMed/NCBI

18 

Hanschmann EM, Godoy JR, Berndt C, Hudemann C and Lillig CH: Thioredoxins, glutaredoxins, and peroxiredoxins - molecular mechanisms and health significance: From cofactors to antioxidants to redox signaling. Antioxid Redox Signal. 19:1539–1605. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Höckel M and Vaupel P: Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 93:266–276. 2001. View Article : Google Scholar : PubMed/NCBI

20 

Zhang L, Hu Y, Xi N, Song J, Huang W, Song S, Liu Y, Liu X and Xie Y: Partial oxygen pressure affects the expression of prognostic biomarkers HIF-1 alpha, Ki67, and CK20 in the microenvironment of colorectal cancer tissue. Oxid Med Cell Longev. 2016:12047152016. View Article : Google Scholar : PubMed/NCBI

21 

Zheng Y, Ni Y, Huang X, Wang Z and Han W: Overexpression of HIF-1α indicates a poor prognosis in tongue carcinoma and may be associated with tumour metastasis. Oncol Lett. 5:1285–1289. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Liu Z, Tu K, Wang Y, Yao B, Li Q, Wang L, Dou C, Liu Q and Zheng X: Hypoxia accelerates aggressiveness of hepatocellular carcinoma cells involving oxidative stress, epithelial-mesenchymal transition and non-canonical hedgehog signaling. Cell Physiol Biochem. 44:1856–1868. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Noike T, Miwa S, Soeda J, Kobayashi A and Miyagawa S: Increased expression of thioredoxin-1, vascular endothelial growth factor, and redox factor-1 is associated with poor prognosis in patients with liver metastasis from colorectal cancer. Hum Pathol. 39:201–208. 2008. View Article : Google Scholar

24 

Mishra R: Glycogen synthase kinase 3 beta: Can it be a target for oral cancer. Mol Cancer. 9:1442010. View Article : Google Scholar : PubMed/NCBI

25 

Cairns RA, Harris IS and Mak TW: Regulation of cancer cell metabolism. Nat Rev Cancer. 11:85–95. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Zhou J, Schmid T, Schnitzer S and Brüne B: Tumor hypoxia and cancer progression. Cancer Lett. 237:10–21. 2006. View Article : Google Scholar

27 

DE Lima PO, Jorge CC, Oliveira DT and Pereira MC: Hypoxic condition and prognosis in oral squamous cell carcinoma. Anticancer Res. 34:605–612. 2014.PubMed/NCBI

28 

Kujan O, Shearston K and Farah CS: The role of hypoxia in oral cancer and potentially malignant disorders: A review. J Oral Pathol Med. 46:246–252. 2017. View Article : Google Scholar

29 

Sahaf B, Söderberg A, Spyrou G, Barral AM, Pekkari K, Holmgren A and Rosén A: Thioredoxin expression and localization in human cell lines: Detection of full-length and truncated species. Exp Cell Res. 236:181–192. 1997. View Article : Google Scholar : PubMed/NCBI

30 

Kakolyris S, Giatromanolaki A, Koukourakis M, Powis G, Souglakos J, Sivridis E, Georgoulias V, Gatter KC and Harris AL: Thioredoxin expression is associated with lymph node status and prognosis in early operable non-small cell lung cancer. Clin Cancer Res. 7:3087–3091. 2001.PubMed/NCBI

31 

Zhu X, Huang C and Peng B: Overexpression of thioredoxin system proteins predicts poor prognosis in patients with squamous cell carcinoma of the tongue. Oral Oncol. 47:609–614. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Li C, Thompson MA, Tamayo AT, Zuo Z, Lee J, Vega F, Ford RJ and Pham LV: Over-expression of Thioredoxin-1 mediates growth, survival, and chemoresistance and is a druggable target in diffuse large B-cell lymphoma. Oncotarget. 3:314–326. 2012. View Article : Google Scholar : PubMed/NCBI

33 

Bhatia M, McGrath KL, Di Trapani G, Charoentong P, Shah F, King MM, Clarke FM and Tonissen KF: The thioredoxin system in breast cancer cell invasion and migration. Redox Biol. 8:68–78. 2016. View Article : Google Scholar : PubMed/NCBI

34 

Powis G and Kirkpatrick DL: Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol. 7:392–397. 2007. View Article : Google Scholar : PubMed/NCBI

35 

Roh JL, Jang H, Kim EH and Shin D: Targeting of the glutathione, thioredoxin, and Nrf2 antioxidant systems in head and neck cancer. Antioxid Redox Signal. 27:106–114. 2017. View Article : Google Scholar

36 

You BR, Shin HR, Han BR and Park WH: PX-12 induces apoptosis in Calu-6 cells in an oxidative stress-dependent manner. Tumour Biol. 36:2087–2095. 2015. View Article : Google Scholar

37 

Di Meo S, Reed TT, Venditti P and Victor VM: Harmful and beneficial role of ROS. Oxid Med Cell Longev. 2016:79091862016. View Article : Google Scholar : PubMed/NCBI

38 

Chen X, Lv Q, Hong Y, Chen X, Cheng B and Wu T: IL-1β maintains the redox balance by regulating glutaredoxin 1 expression during oral carcinogenesis. J Oral Pathol Med. 46:332–339. 2017. View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Chen X, Hu Q, Wu T, Wang C, Xia J, Yang L, Cheng B and Chen X: Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation. Int J Oncol 52: 733-742, 2018.
APA
Chen, X., Hu, Q., Wu, T., Wang, C., Xia, J., Yang, L. ... Chen, X. (2018). Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation. International Journal of Oncology, 52, 733-742. https://doi.org/10.3892/ijo.2018.4235
MLA
Chen, X., Hu, Q., Wu, T., Wang, C., Xia, J., Yang, L., Cheng, B., Chen, X."Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation". International Journal of Oncology 52.3 (2018): 733-742.
Chicago
Chen, X., Hu, Q., Wu, T., Wang, C., Xia, J., Yang, L., Cheng, B., Chen, X."Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation". International Journal of Oncology 52, no. 3 (2018): 733-742. https://doi.org/10.3892/ijo.2018.4235
Copy and paste a formatted citation
x
Spandidos Publications style
Chen X, Hu Q, Wu T, Wang C, Xia J, Yang L, Cheng B and Chen X: Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation. Int J Oncol 52: 733-742, 2018.
APA
Chen, X., Hu, Q., Wu, T., Wang, C., Xia, J., Yang, L. ... Chen, X. (2018). Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation. International Journal of Oncology, 52, 733-742. https://doi.org/10.3892/ijo.2018.4235
MLA
Chen, X., Hu, Q., Wu, T., Wang, C., Xia, J., Yang, L., Cheng, B., Chen, X."Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation". International Journal of Oncology 52.3 (2018): 733-742.
Chicago
Chen, X., Hu, Q., Wu, T., Wang, C., Xia, J., Yang, L., Cheng, B., Chen, X."Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation". International Journal of Oncology 52, no. 3 (2018): 733-742. https://doi.org/10.3892/ijo.2018.4235
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