Role of TXNDC5 in tumorigenesis of colorectal cancer cells: In vivo and in vitro evidence

Tan,Fengbo; Zhu,Hong; He,Xiao; Yu,Nanhui; Zhang,Xingwen; Xu,Haifan; Pei,Haiping

doi:10.3892/ijmm.2018.3664

Role of TXNDC5 in tumorigenesis of colorectal cancer cells: In vivo and in vitro evidence

Authors:
- Fengbo Tan
- Hong Zhu
- Xiao He
- Nanhui Yu
- Xingwen Zhang
- Haifan Xu
- Haiping Pei
View Affiliations

Affiliations: Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Mammary, Hunan Cancer Hospital, Changsha, Hunan 410013, P.R. China, Department of Emergency, Hunan Provincial People's Hospital, Changsha, Hunan 410005, P.R. China, Department of Mammary and Thyroid, The First Affiliated Hospital of South China University, Hengyang, Hunan 421001, P.R. China
Published online on: May 9, 2018 https://doi.org/10.3892/ijmm.2018.3664
Pages: 935-945
Copyright: © Tan 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

Thioredoxin domain‑containing 5 (TXNDC5) is reportedly overexpressed in colorectal cancer (CRC) and is therefore considered an oncogene. However, the role of TXNDC5 in CRC tumorigenesis remains unclear. The present study aimed to explore the role of TXNDC5 in CRC tumorigenesis in vitro and in vivo under hypoxic and normoxic conditions. Analyses of patient tissue samples revealed a positive association between the expression of hypoxia‑inducible factor‑1α (HIF‑1α) or TXNDC5 and the TNM stage of CRC. In addition, a positive correlation between the expression levels of HIF‑1α and TXNDC5 was observed in CRC tissues. Furthermore, culturing RKO and HCT‑116 human CRC cell lines under hypoxic conditions significantly increased the expression levels of HIF‑1α and TXNDC5, whereas knockdown of HIF‑1α abolished the hypoxia‑induced expression of TXNDC5. Knockdown of TXNDC5 significantly decreased cell proliferation and colony formation, and increased apoptosis of both cell lines. Furthermore, knockdown of TXNDC5 markedly increased hypoxia‑induced reactive oxygen species (ROS) generation, and the expression of hypoxia‑induced endoplasmic reticulum stress (ER) markers (CCAAT‑enhancer‑binding protein homologous protein, glucose‑regulated protein 78 and activating transcription factor 4) and apoptotic markers (B‑cell lymphoma 2‑associated X protein and cleaved caspase‑8). In addition, the expression levels of TXNDC5 were significantly increased in tumor tissues compared with in adenoma and normal tissues in a mouse model of CRC tumorigenesis. In conclusion, the in vivo data demonstrated that TXNDC5 is overexpressed in CRC tissues, and this overexpression may be associated with unfavorable clinicopathological features. The in vitro data indicated that hypoxia may induce TXNDC5 expression via upregulating HIF‑1α; this effect promoted CRC cell proliferation and survival under hypoxic conditions, likely via inhibiting hypoxia‑induced ROS/ER stress signaling. These findings suggested that TXNDC5 functions as an important stress survival factor to maintain tumorigenesis of CRC cells under hypoxia by regulating hypoxia‑induced ROS/ER stress signaling. The present study provided novel insights into the role of TXNDC5 in the tumorigenesis of CRC.

View Figures

View References

1	Zheng R, Zeng H, Zhang S, Chen T and Chen W: National estimates of cancer prevalence in China, 2011. Cancer Lett. 370:33–38. 2016. View Article : Google Scholar
2	Pesson M, Volant A, Uguen A, Trillet K, De La Grange P, Aubry M, Daoulas M, Robaszkiewicz M, Le Gac G, Morel A, et al: A gene expression and pre-mRNA splicing signature that marks the adenoma-adenocarcinoma progression in colorectal cancer. PLoS One. 9:e877612014. View Article : Google Scholar :
3	Schell MJ, Yang M, Missiaglia E, Delorenzi M, Soneson C, Yue B, Nebozhyn MV, Loboda A, Bloom G and Yeatman TJ: A composite gene expression signature optimizes prediction of colorectal cancer metastasis and outcome. Clin Cancer Res. 22:734–745. 2016. View Article : Google Scholar :
4	Keith B and Simon MC: Hypoxia-inducible factors, stem cells, and cancer. Cell. 129:465–472. 2007. View Article : Google Scholar
5	Saito S, Lin YC, Tsai MH, Lin CS, Murayama Y, Sato R and Yokoyama KK: Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells. Kaohsiung J Med Sci. 31:279–286. 2015. View Article : Google Scholar
6	Hotokezaka Y, van Leyen K, Lo EH, Beatrix B, Katayama I, Jin G and Nakamura T: AlphaNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia. Cell Death Differ. 16:1505–1514. 2009. View Article : Google Scholar
7	Pereira ER, Frudd K, Awad W and Hendershot LM: Endoplasmic reticulum (ER) stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 (HIF-1) transcriptional activity on targets like vascular endothelial growth factor (VEGF). J Biol Chem. 289:3352–3364. 2014. View Article : Google Scholar :
8	Chevet E, Hetz C and Samali A: Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis. Cancer Discov. 5:586–597. 2015. View Article : Google Scholar
9	Yadav RK, Chae SW, Kim HR and Chae HJ: Endoplasmic reticulum stress and cancer. J Cancer Prev. 19:75–88. 2014. View Article : Google Scholar : PubMed/NCBI
10	Clarke HJ, Chambers JE, Liniker E and Marciniak SJ: Endoplasmic reticulum stress in malignancy. Cancer Cell. 25:563–573. 2014. View Article : Google Scholar : PubMed/NCBI
11	Horna-Terrón E, Pradilla-Dieste A, Sánchez-de-Diego C and Osada J: TXNDC5, a newly discovered disulfide isomerase with a key role in cell physiology and pathology. Int J Mol Sci. 15:23501–23518. 2014. View Article : Google Scholar
12	Sullivan DC, Huminiecki L, Moore JW, Boyle JJ, Poulsom R, Creamer D, Barker J and Bicknell R: EndoPDI, a novel protein-disulfide isomerase-like protein that is preferentially expressed in endothelial cells acts as a stress survival factor. J Biol Chem. 278:47079–47088. 2003. View Article : Google Scholar : PubMed/NCBI
13	Kojima R, Okumura M, Masui S, Kanemura S, Inoue M, Saiki M, Yamaguchi H, Hikima T, Suzuki M, Akiyama S, et al: Radically different thioredoxin domain arrangement of ERp46, an efficient disulfide bond introducer of the mammalian PDI family. Structure. 22:431–443. 2014. View Article : Google Scholar : PubMed/NCBI
14	Funkner A, Parthier C, Schutkowski M, Zerweck J, Lilie H, Gyrych N, Fischer G, Stubbs MT and Ferrari DM: Peptide binding by catalytic domains of the protein disulfide isomerase-related protein ERp46. J Mol Biol. 425:1340–1362. 2013. View Article : Google Scholar : PubMed/NCBI
15	Chang X, Xu B, Wang L, Wang Y, Wang Y and Yan S: Investigating a pathogenic role for TXNDC5 in tumors. Int J Oncol. 43:1871–1884. 2013. View Article : Google Scholar : PubMed/NCBI
16	Wang Y, Ma Y, Lü B, Xu E, Huang Q and Lai M: Differential expression of mimecan and thioredoxin domain-containing protein 5 in colorectal adenoma and cancer: a proteomic study. Exp Biol Med (Maywood). 232:1152–1159. 2007. View Article : Google Scholar
17	Shen H, Huang J, Pei H, Zeng S, Tao Y, Shen L, Zeng L and Zhu H: Comparative proteomic study for profiling differentially expressed proteins between Chinese left- and right-sided colon cancers. Cancer Sci. 104:135–141. 2013. View Article : Google Scholar
18	Affer M, Chesi M, Chen WD, Keats JJ, Demchenko YN, Tamizhmani K, Garbitt VM, Riggs DL, Brents LA, Roschke AV, et al: Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia. 28:1725–1735. 2014. View Article : Google Scholar :
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔC(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
20	Dang DT, Chen F, Gardner LB, Cummins JM, Rago C, Bunz F, Kantsevoy SV and Dang LH: Hypoxia-inducible factor-1alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts. Cancer Res. 66:1684–1936. 2006. View Article : Google Scholar
21	Shweta, Mishra KP, Chanda S, Singh SB and Ganju L: A comparative immunological analysis of CoCl₂ treated cells with in vitro hypoxic exposure. Biometals. 28:175–185. 2015. View Article : Google Scholar
22	Neufert C, Becker C and Neurath MF: An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat Protoc. 2:1998–2004. 2007. View Article : Google Scholar : PubMed/NCBI
23	George AL, Rajoria S, Suriano R, Mittleman A and Tiwari RK: Hypoxia and estrogen are functionally equivalent in breast cancer-endothelial cell interdependence. Mol Cancer. 11:802012. View Article : Google Scholar : PubMed/NCBI
24	Wang L, Zheng Y, Xu H, Yan X and Chang X: Investigate pathogenic mechanism of TXNDC5 in rheumatoid arthritis. PLoS One. 8:e533012013. View Article : Google Scholar : PubMed/NCBI
25	Chang X, Cui Y, Zong M, Zhao Y, Yan X, Chen Y and Han J: Identification of proteins with increased expression in rheumatoid arthritis synovial tissues. J Rheumatol. 36:872–880. 2009. View Article : Google Scholar
26	Vincent EE, Elder DJ, Phillips L, Heesom KJ, Pawade J, Luckett M, Sohail M, May MT, Hetzel MR and Tavaré JM: Overexpression of the TXNDC5 protein in non-small cell lung carcinoma. Anticancer Res. 31:1577–1582. 2011.PubMed/NCBI
27	Mizukami Y, Kohgo Y and Chung DC: Hypoxia inducible factor-1 independent pathways in tumor angiogenesis. Clin Cancer Res. 13:5670–5674. 2007. View Article : Google Scholar : PubMed/NCBI
28	Nagaraju GP, Bramhachari PV, Raghu G and El-Rayes BF: Hypoxia inducible factor-1α: its role in colorectal carcinogenesis and metastasis. Cancer Lett. 366:11–18. 2015. View Article : Google Scholar
29	Zhang L, Hou Y, Li N, Wu K and Zhai J: The influence of TXNDC5 gene on gastric cancer cell. J Cancer Res Clin Oncol. 136:1497–1505. 2010. View Article : Google Scholar : PubMed/NCBI
30	Lee SO, Jin UH, Kang JH, Kim SB, Guthrie AS, Sreevalsan S, Lee JS and Safe S: The orphan nuclear receptor NR4A1 (Nur77) regulates oxidative and endoplasmic reticulum stress in pancreatic cancer cells. Mol Cancer Res. 12:527–538. 2014. View Article : Google Scholar : PubMed/NCBI
31	Malhotra JD and Kaufman RJ: Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword. Antioxid Redox Signal. 9:2277–2293. 2007. View Article : Google Scholar
32	Clarke R, Cook KL, Hu R, Facey CO, Tavassoly I, Schwartz JL, Baumann WT, Tyson JJ, Xuan J, Wang Y, et al: Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate. Cancer Res. 72:1321–1331. 2012.
33	Wang WA, Groenendyk J and Michalak M: Endoplasmic reticulum stress associated responses in cancer. Biochim Biophys Acta. 1843:2143–2149. 2014. View Article : Google Scholar : PubMed/NCBI
34	Gu MX, Fu Y, Sun XL, Ding YZ, Li CH, Pang W, Pan S and Zhu Y: Proteomic analysis of endothelial lipid rafts reveals a novel role of statins in antioxidation. J Proteome Res. 11:2365–2373. 2012. View Article : Google Scholar