TOX3 is a favorable prognostic indicator and potential immunomodulatory factor in lung adenocarcinoma

Zeng,De; Lin,Haoyu; Cui,Jianxiong; Liang,Weiquan

doi:10.3892/ol.2019.10748

TOX3 is a favorable prognostic indicator and potential immunomodulatory factor in lung adenocarcinoma

Authors:
- De Zeng
- Haoyu Lin
- Jianxiong Cui
- Weiquan Liang
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Affiliations: Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515000, P.R. China, Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515000, P.R. China
Published online on: August 16, 2019 https://doi.org/10.3892/ol.2019.10748
Pages: 4144-4152
Copyright: © Zeng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Thymocyte selection‑associated high mobility group box (TOX) genes represent a novel family of genes. Deregulated expression of TOXs has been reported in a variety of cancer types, including lung cancer. It has also been reported that TOXs are crucial regulators of the immune system. The present study systematically evaluated the prognostic values of TOX family members using a set of publicly accessible databases, including Oncomine, Kaplan‑Meier plotter and cBioPortal. It was revealed that TOX expression profiles differed between lung cancer and normal tissues, and high expression of TOX mRNAs generally predicted improved survival outcomes. Notably, TOX3 expression was significantly increased in lung adenocarcinoma, compared with other pathological subtypes of lung cancer. Survival analysis demonstrated that elevated TOX3 expression was significantly associated with improved progression‑free and overall survival in patients with lung adenocarcinoma. Furthermore, correlation analysis indicated that TOX3 expression was negatively correlated with the expression of programmed death‑1 receptor (PD‑1), PD‑ligand 1 and Hepatitis A virus cellular receptor 2 in lung adenocarcinoma. These results indicated that TOX3 is a prognostic indicator and promising immunomodulatory factor in lung adenocarcinoma. Future studies investigating the role of TOX3 in lung cancer immunity are warranted.

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1	Mayekar MK and Bivona TG: Current landscape of targeted therapy in lung cancer. Clin Pharmacol Ther. 102:757–764. 2017. View Article : Google Scholar : PubMed/NCBI
2	Somasundaram A and Burns TF: The next generation of immunotherapy: Keeping lung cancer in check. J Hematol Oncol. 10:872017. View Article : Google Scholar : PubMed/NCBI
3	Khanna P, Blais N, Gaudreau PO and Corrales-Rodriguez L: Immunotherapy comes of age in lung cancer. Clin Lung Cancer. 18:13–22. 2017. View Article : Google Scholar : PubMed/NCBI
4	Wehler T, Wehler B and Stehle I: Immunotherapy in lung cancer: Checkpoint inhibitors. Deutsche medizinische Wochenschrift. 140:1835–1838. 2015.(In German). PubMed/NCBI
5	Quaratino S, Forssmann U and Marschner JP: New approaches in immunotherapy for the treatment of lung cancer. Curr Top Microbiol Immunol. 405:1–31. 2017.PubMed/NCBI
6	Ettinger DS: Immunotherapy for lung cancer: Many questions yet to be answered. J Natl Compr Canc Netw. 14:935–938. 2016. View Article : Google Scholar : PubMed/NCBI
7	Goubet AG, Livartowski A and Romano E: Immunotherapy in lung cancer: New concepts. Rev Mal Respir. 35:642–651. 2018.(In French). View Article : Google Scholar : PubMed/NCBI
8	Sánchez de Cos Escuín J: New immunotherapy and lung cancer. Arch Bronconeumol. 53:682–687. 2017.(In English, Spanish). View Article : Google Scholar : PubMed/NCBI
9	Seehus CR and Kaye J: The role of TOX in the development of innate lymphoid cells. Mediators Inflamm. 2015:2438682015. View Article : Google Scholar : PubMed/NCBI
10	Yu X and Li Z: TOX gene: A novel target for human cancer gene therapy. Am J Cancer Res. 5:3516–3524. 2015.PubMed/NCBI
11	Han CC, Yue LL, Yang Y, Jian BY, Ma LW and Liu JC: TOX3 protein expression is correlated with pathological characteristics in breast cancer. Oncol Lett. 11:1762–1768. 2016. View Article : Google Scholar : PubMed/NCBI
12	Schrader AM, Jansen PM and Willemze R: TOX expression in cutaneous T-cell lymphomas: An adjunctive diagnostic marker that is not tumour specific and not restricted to the CD4(+) CD8(−) phenotype. Br J Dermatol. 175:382–386. 2016. View Article : Google Scholar : PubMed/NCBI
13	Tessema M, Yingling CM, Grimes MJ, Thomas CL, Liu Y, Leng S, Joste N and Belinsky SA: Differential epigenetic regulation of TOX subfamily high mobility group box genes in lung and breast cancers. PLoS One. 7:e348502012. View Article : Google Scholar : PubMed/NCBI
14	Zhang X, Zhu H, Wu X, Wang M, Gu D, Gong W, Xu Z, Tan Y, Gong Y, Zhou J, et al: A genetic polymorphism in TOX3 is associated with survival of gastric cancer in a Chinese population. PLoS One. 8:e721862013. View Article : Google Scholar : PubMed/NCBI
15	Wu W, Wagner EK, Hao Y, Rao X, Dai H, Han J, Chen J, Storniolo AMV, Liu Y and He C: Tissue-specific co-expression of long non-coding and coding RNAs associated with breast cancer. Sci Rep. 6:327312016. View Article : Google Scholar : PubMed/NCBI
16	Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI
17	Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C, Kulkarni P, et al: Oncomine 3.0: Genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 9:166–180. 2007. View Article : Google Scholar : PubMed/NCBI
18	Lin HY, Zeng, Liang YK, Wei XL and Chen CF: GATA3 and TRPS1 are distinct biomarkers and prognostic factors in breast cancer: Database mining for GATA family members in malignancies. Oncotarget. 8:34750–34761. 2017.PubMed/NCBI
19	Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q and Szallasi Z: An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 123:725–731. 2010. View Article : Google Scholar : PubMed/NCBI
20	Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 6:pl12013. View Article : Google Scholar : PubMed/NCBI
21	Stearman RS, Dwyer-Nield L, Zerbe L, Blaine SA, Chan Z, Bunn PA Jr, Johnson GL, Hirsch FR, Merrick DT, Franklin WA, et al: Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol. 167:1763–1775. 2005. View Article : Google Scholar : PubMed/NCBI
22	Landi MT, Dracheva T, Rotunno M, Figueroa JD, Liu H, Dasgupta A, Mann FE, Fukuoka J, Hames M, Bergen AW, et al: Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival. PLoS One. 3:e16512008. View Article : Google Scholar : PubMed/NCBI
23	Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, van de Rijn M, Rosen GD, Perou CM, Whyte RI, et al: Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci USA. 98:13784–13789. 2001. View Article : Google Scholar : PubMed/NCBI
24	Hou J, Aerts J, den Hamer B, van Ijcken W, den Bakker M, Riegman P, van der Leest C, van der Spek P, Foekens JA, Hoogsteden HC, et al: Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PLoS One. 5:e103122010. View Article : Google Scholar : PubMed/NCBI
25	Du L, Herbst RS and Morgensztern D: Immunotherapy in lung cancer. Hematol Oncol Clin North Am. 31:131–141. 2017. View Article : Google Scholar : PubMed/NCBI
26	Valecha GK, Vennepureddy A, Ibrahim U, Safa F, Samra B and Atallah JP: Anti-PD-1/PD-L1 antibodies in non-small cell lung cancer: The era of immunotherapy. Expert Rev Anticancer Ther. 17:47–59. 2017. View Article : Google Scholar : PubMed/NCBI
27	Seksenyan A, Kadavallore A, Walts AE, de la Torre B, Berel D, Strom SP, Aliahmad P, Funari VA and Kaye J: TOX3 is expressed in mammary ER(+) epithelial cells and regulates ER target genes in luminal breast cancer. BMC Cancer. 15:222015. View Article : Google Scholar : PubMed/NCBI
28	Li L, Guo G, Wang F, Lv P, Zhu M, Gu Y, Han M and Pei X: TOX high mobility group box family member 3 rs3803662 and breast cancer risk: A meta-analysis. J Cancer Res Ther. 14 (Suppl):S208–S212. 2018. View Article : Google Scholar : PubMed/NCBI
29	Zhang Y, Cai P, Liang T, Wang L and Hu L: TIM-3 is a potential prognostic marker for patients with solid tumors: A systematic review and meta-analysis. Oncotarget. 8:31705–31713. 2017.PubMed/NCBI
30	Riaz M, Berns EM, Sieuwerts AM, Ruigrok-Ritstier K, de Weerd V, Groenewoud A, Uitterlinden AG, Look MP, Klijn JG, Sleijfer S, et al: Correlation of breast cancer susceptibility loci with patient characteristics, metastasis-free survival, and mRNA expression of the nearest genes. Breast Cancer Res Treat. 133:843–851. 2012. View Article : Google Scholar : PubMed/NCBI
31	Nishioka Y: Cancer immunotherapy as a promising fourth standard therapy for lung cancer: Beyond 20 years for the development of immunotherapy. Respir Investig. 54:2972016. View Article : Google Scholar : PubMed/NCBI
32	Dal Bello MG, Alama A, Coco S, Vanni I and Grossi F: Understanding the checkpoint blockade in lung cancer immunotherapy. Drug Discov Today. 22:1266–1273. 2017. View Article : Google Scholar : PubMed/NCBI
33	Chae YK, Arya A, Iams W, Cruz M, Mohindra N, Villaflor V and Giles FJ: Immune checkpoint pathways in non-small cell lung cancer. Ann Transl Med. 6:882018. View Article : Google Scholar : PubMed/NCBI
34	Berghmans T, Grigoriu B, Sculier JP and Meert AP: Immune checkpoint inhibitors (antibodies to PD1 and PD-L1), a new therapeutic weapon against non-small cell bronchial carcinoma. Rev Mal Respir. 35:197–205. 2018.(In French). View Article : Google Scholar : PubMed/NCBI
35	Berghmans T and Meert AP: Immunotherapy and non-small cell lung cancer: A (r)evolution. Rev Med Brux. 38:175–177. 2017.(In French). PubMed/NCBI
36	Anderson AC: Tim-3: An emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2:393–398. 2014. View Article : Google Scholar : PubMed/NCBI
37	Liu F, Zeng G, Zhou S, He X, Sun N, Zhu X and Hu A: Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma. Bull Cancer. 105:493–501. 2018. View Article : Google Scholar : PubMed/NCBI
38	Gao J, Qiu X, Li X, Fan H, Zhang F, Lv T and Song Y: Expression profiles and clinical value of plasma exosomal Tim-3 and Galectin-9 in non-small cell lung cancer. Biochem Biophys Res Commun. 498:409–415. 2018. View Article : Google Scholar : PubMed/NCBI
39	Das M, Zhu C and Kuchroo VK: Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 276:97–111. 2017. View Article : Google Scholar : PubMed/NCBI
40	Yu M, Lu B, Liu Y, Me Y, Wang L and Zhang P: Tim-3 is upregulated in human colorectal carcinoma and associated with tumor progression. Mol Med Rep. 15:689–695. 2017. View Article : Google Scholar : PubMed/NCBI