Decreased expression of TXNIP predicts poor prognosis in patients with clear cell renal cell carcinoma

Gao,Yuan; Qi,Jin‑Chun; Li,Xiaoyu; Sun,Jian‑Ping; Ji,Hong; Li,Qing‑Huai

doi:10.3892/ol.2019.11165

Decreased expression of TXNIP predicts poor prognosis in patients with clear cell renal cell carcinoma

Authors:
- Yuan Gao
- Jin‑Chun Qi
- Xiaoyu Li
- Jian‑Ping Sun
- Hong Ji
- Qing‑Huai Li
View Affiliations

Affiliations: Department of Hemodialysis, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
Published online on: November 29, 2019 https://doi.org/10.3892/ol.2019.11165
Pages: 763-770
Copyright: © Gao 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

Accumulating evidence has demonstrated that thioredoxin interacting protein (TXNIP) is abnormally expressed in a variety of malignant tumors and functions as a tumor suppressor. However, the association between TXNIP and clear cell renal cell carcinoma (CCRCC) has not yet been fully elucidated. The aim of the present study was to evaluate the role of TXNIP in CCRCC using The Cancer Genome Atlas (TCGA) database. The RNA sequencing data and corresponding clinical data were collected from TCGA database. The association between TXNIP and patient clinicopathological characteristics was analyzed using analysis of variance and logistic regression. The Kaplan‑Meier method and Cox proportional hazards model were used to assess the association between TXNIP and overall survival. Gene Set Enrichment Analysis (GSEA) was used to explore the associated signaling pathways. TXNIP expression was identified to be decreased in CCRCC tissues compared with normal tissues. The decreased expression of TXNIP in CCRCC was significantly associated with clinical stage [OR=0.509 for III vs. I (P=0.002); OR=0.527 for IV vs. I (P=0.012)], T stage [OR=0.552 for T3 vs. T1 (P=0.002)] and grade [OR=0.261 for G4 vs. G1 (P=0.027)]. Kaplan‑Meier survival analysis indicated that cases of CCRCC with low TXNIP expression were associated with poorer prognoses compared with those with a high expression level (P=0.002). Univariate and multivariate Cox analyses indicated that TXNIP was an independent prognostic factor in CCRCC. GSEA revealed that 6 pathways exhibited significant differential enrichment in the TXNIP high‑expression phenotype, including the WNT signaling pathway, the mitogen‑activated protein kinase (MAPK) signaling pathway, the phosphatidylinositol signaling system, the transforming growth factor‑β (TGF‑β) signaling pathway, autophagy and the Janus kinase (JAK)‑STAT signaling pathway. Taken together, the results of the present study indicate that TXNIP expression may be a potential prognostic marker for patients with CCRCC. In addition, the WNT signaling pathway, MAPK signaling pathway, phosphatidylinositol signaling system, TGF‑β signaling pathway, autophagy and the JAK‑STAT signaling pathway may be the crucial pathways regulated by TXNIP in CCRCC.

View Figures

View References

1	Bhatt JR and Finelli A: Landmarks in the diagnosis and treatment of renal cell carcinoma. Nat Rev Urol. 11:517–525. 2014. View Article : Google Scholar : PubMed/NCBI
2	Martinez-Salamanca JI, Huang WC, Millan I, Bertini R, Bianco FJ, Carballido JA, Ciancio G, Hernández C, Herranz F, Haferkamp A, et al: Prognostic impact of the 2009 UICC/AJCC TNM staging system for renal cell carcinoma with venous extension. Eur Urol. 59:120–127. 2011. View Article : Google Scholar : PubMed/NCBI
3	Chen KS and DeLuca HF: Isolation and characterization of a novel cDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3. Biochim Biophys Acta. 1219:26–32. 1994. View Article : Google Scholar : PubMed/NCBI
4	Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, Takagi Y, Sono H, Gon Y and Yodoi J: Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem. 274:21645–21650. 1999. View Article : Google Scholar : PubMed/NCBI
5	Masaki S, Masutani H, Yoshihara E and Yodoi J: Deficiency of thioredoxin binding protein-2 (TBP-2) enhances TGF-β signaling and promotes epithelial to mesenchymal transition. PLoS One. 7:e399002012. View Article : Google Scholar : PubMed/NCBI
6	Woolston CM, Madhusudan S, Soomro IN, Lobo DN, Reece-Smith AM, Parsons SL and Martin SG: Thioredoxin interacting protein and its association with clinical outcome in gastro-oesophageal adenocarcinoma. Redox Biol. 1:285–291. 2013. View Article : Google Scholar : PubMed/NCBI
7	Jung H, Kim MJ, Kim DO, Kim WS, Yoon SJ, Park YJ, Yoon SR, Kim TD, Suh HW, Yun S, et al: TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. Cell Metab. 18:75–85. 2013. View Article : Google Scholar : PubMed/NCBI
8	Zhou J, Yu Q and Chng WJ: TXNIP (VDUP-1, TBP-2): A major redox regulator commonly suppressed in cancer by epigenetic mechanisms. Int J Biochem Cell Biol. 43:1668–1673. 2011. View Article : Google Scholar : PubMed/NCBI
9	Kwon HJ, Won YS, Suh HW, Jeon JH, Shao Y, Yoon SR, Chung JW, Kim TD, Kim HM, Nam KH, et al: Vitamin D3 upregulated protein 1 suppresses TNF α induced NF-κB activation in hepatocarcinogenesis. J Immunol. 185:3980–3989. 2010. View Article : Google Scholar : PubMed/NCBI
10	Cadenas C, Franckenstein D, Schmidt M, Gehrmann M, Hermes M, Geppert B, Schormann W, Maccoux LJ, Schug M, Schumann A, et al: Role of thioredoxin reductase 1 and thioredoxin interacting protein in prognosis of breast cancer. Breast Cancer Res. 12:R442010. View Article : Google Scholar : PubMed/NCBI
11	Zhu G, Zhou L, Liu H, Shan Y and Zhang X: MicroRNA-224 promotes pancreatic cancer cell proliferation and migration by targeting the TXNIP-mediated HIF1α Pathway. Cell Physiol Biochem. 48:1735–1746. 2018. View Article : Google Scholar : PubMed/NCBI
12	Feingold PL, Surman DR, Brown K, Xu Y, McDuffie LA, Shukla V, Reardon ES, Crooks DR, Trepel JB, Lee S, et al: Induction of thioredoxin-interacting protein by a histone deacetylase inhibitor, entinostat, is associated with DNA damage and apoptosis in esophageal adenocarcinoma. Mol Cancer Ther. 17:2013–2023. 2018. View Article : Google Scholar : PubMed/NCBI
13	Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES and Mesirov JP: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 102:15545–15550. 2005. View Article : Google Scholar : PubMed/NCBI
14	Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, et al: PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 34:267–273. 2003. View Article : Google Scholar : PubMed/NCBI
15	Sheth SS, Bodnar JS, Ghazalpour A, Thipphavong CK, Tsutsumi S, Tward AD, Demant P, Kodama T, Aburatani H and Lusis AJ: Hepatocellular carcinoma in Txnip-deficient mice. Oncogene. 25:3528–3536. 2006. View Article : Google Scholar : PubMed/NCBI
16	Li J, Yue Z, Xiong W, Sun P, You K and Wang J: TXNIP overexpression suppresses proliferation and induces apoptosis in SMMC7221 cells through ROS generation and MAPK pathway activation. Oncol Rep. 37:3369–3376. 2017. View Article : Google Scholar : PubMed/NCBI
17	Shen L, O'Shea JM, Kaadige MR, Cunha S, Wilde BR, Cohen AL, Welm AL and Ayer DE: Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP. Proc Natl Acad Sci USA. 112:5425–5430. 2015. View Article : Google Scholar : PubMed/NCBI
18	Han SH, Jeon JH, Ju HR, Jung U, Kim KY, Yoo HS, Lee YH, Song KS, Hwang HM and Na YS: VDUP1 upregulated by TGF-beta1 and 1,25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression. Oncogene. 22:4035–4046. 2003. View Article : Google Scholar : PubMed/NCBI
19	Morrison JA, Pike LA, Sams SB, Sharma V, Zhou Q, Severson JJ, Tan AC, Wood WM and Haugen BR: Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer. Mol Cancer. 13:622014. View Article : Google Scholar : PubMed/NCBI
20	Ikarashi M, Takahashi Y, Ishii Y, Nagata T, Asai S and Ishikawa K: Vitamin D3 up-regulated protein 1 (VDUP1) expression in gastrointestinal cancer and its relation to stage of disease. Anticancer Res. 22:4045–4048. 2002.PubMed/NCBI
21	Park JW, Lee SH, Woo GH, Kwon HJ and Kim DY: Downregulation of TXNIP leads to high proliferative activity and estrogen-dependent cell growth in breast cancer. Biochem Biophys Res Commun. 498:566–572. 2018. View Article : Google Scholar : PubMed/NCBI
22	Nie W, Huang W, Zhang W, Xu J, Song W, Wang Y, Zhu A, Luo J, Huang G, Wang Y and Guan X: TXNIP interaction with the Her-1/2 pathway contributes to overall survival in breast cancer. Oncotarget. 6:3003–3012. 2015. View Article : Google Scholar : PubMed/NCBI
23	Wang G, Zhang ZJ, Jian WG, Liu PH, Xue W, Wang TD, Meng YY, Yuan C, Li HM, Yu YP, et al: Novel long noncoding RNA OTUD6B-AS1 indicates poor prognosis and inhibits clear cell renal cell carcinoma proliferation via the Wnt β-catenin signaling pathway. Mol Cancer. 18:152019. View Article : Google Scholar : PubMed/NCBI
24	Hong B, Zhou J, Ma K, Zhang J, Xie H, Zhang K, Li L, Cai L, Zhang N, Zhang Z and Gong K: TRIB3 promotes the proliferation and invasion of renal cell carcinoma cells via activating MAPK signaling pathway. Int J Biol Sci. 15:587–597. 2019. View Article : Google Scholar : PubMed/NCBI
25	Syed V: TGF-β Signaling in Cancer. J Cell Biochem. 117:1279–1287. 2016. View Article : Google Scholar : PubMed/NCBI
26	Sitaram RT, Mallikarjuna P, Landstrom M and Ljungberg B: Transforming growth factor-β promotes aggressiveness and invasion of clear cell renal cell carcinoma. Oncotarget. 7:35917–35931. 2016. View Article : Google Scholar : PubMed/NCBI
27	Kang HM, Noh KH, Chang TK, Park D, Cho HS 1, Lim JH and Jung CR: Ubiquitination of MAP1LC3B by pVHL is associated with autophagy and cell death in renal cell carcinoma. Cell Death Dis. 10:2792019. View Article : Google Scholar : PubMed/NCBI
28	Zhang Y, Fan Y, Huang S, Wang G, Han R, Lei F, Luo A, Jing X, Zhao L, Gu S and Zhao X: Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway. Cancer Sci. 109:3865–3873. 2018. View Article : Google Scholar : PubMed/NCBI
29	Wang ZL, Deng Q, Chong T and Wang ZM: Autophagy suppresses the proliferation of renal carcinoma cell. Eur Rev Med Pharmacol Sci. 22:343–350. 2018.PubMed/NCBI
30	Shang D, Liu Y, Ito N, Kamoto T and Ogawa O: Defective Jak-Stat activation in renal cell carcinoma is associated with interferon-alpha resistance. Cancer Sci. 98:1259–1264. 2007. View Article : Google Scholar : PubMed/NCBI